Debomoy Lahiri

Summary

Affiliation: Indiana University
Country: USA

Publications

  1. pmc Transcriptional regulation of beta-secretase by p25/cdk5 leads to enhanced amyloidogenic processing
    Yi Wen
    Taub Institute at Columbia University Medical Center, New York, NY 10032, USA
    Neuron 57:680-90. 2008
  2. pmc Tumor necrosis factor-α synthesis inhibitor 3,6'-dithiothalidomide attenuates markers of inflammation, Alzheimer pathology and behavioral deficits in animal models of neuroinflammation and Alzheimer's disease
    David Tweedie
    Laboratory of Neurosciences, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA
    J Neuroinflammation 9:106. 2012
  3. pmc PuF, an antimetastatic and developmental signaling protein, interacts with the Alzheimer's amyloid-β precursor protein via a tissue-specific proximal regulatory element (PRE)
    Debomoy K Lahiri
    Laboratory of Molecular Neurogenetics, Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, 791 Union Drive, Indianapolis, IN 46202, USA
    BMC Genomics 14:68. 2013
  4. doi request reprint Gene × environment interaction by a longitudinal epigenome-wide association study (LEWAS) overcomes limitations of genome-wide association study (GWAS)
    Debomoy K Lahiri
    Department of Psychiatry, Laboratory of Molecular Neurogenetics, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA
    Epigenomics 4:685-99. 2012
  5. doi request reprint The "LEARn" (latent early-life associated regulation) model: an epigenetic pathway linking metabolic and cognitive disorders
    Debomoy K Lahiri
    Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USA
    J Alzheimers Dis 30:S15-30. 2012
  6. ncbi request reprint Applying epigenetics to Alzheimer's disease via the latent early-life associated regulation (LEARn) model
    Bryan Maloney
    Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA
    Curr Alzheimer Res 9:589-99. 2012
  7. ncbi request reprint Apolipoprotein gene and its interaction with the environmentally driven risk factors: molecular, genetic and epidemiological studies of Alzheimer's disease
    Debomoy K Lahiri
    Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA
    Neurobiol Aging 25:651-60. 2004
  8. ncbi request reprint Where the actions of environment (nutrition), gene and protein meet: beneficial role of fruit and vegetable juices in potentially delaying the onset of Alzheimer's disease
    Debomoy K Lahiri
    Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA
    J Alzheimers Dis 10:359-61; discussion 363-4. 2006
  9. ncbi request reprint Dietary supplementation with melatonin reduces levels of amyloid beta-peptides in the murine cerebral cortex
    Debomoy K Lahiri
    Institute of Psychiatric Research, Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN 46202, USA
    J Pineal Res 36:224-31. 2004
  10. ncbi request reprint Age-related changes in serum melatonin in mice: higher levels of combined melatonin and 6-hydroxymelatonin sulfate in the cerebral cortex than serum, heart, liver and kidney tissues
    Debomoy K Lahiri
    Institute of Psychiatric Research, Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN 46202, USA
    J Pineal Res 36:217-23. 2004

Research Grants

Collaborators

Detail Information

Publications93

  1. pmc Transcriptional regulation of beta-secretase by p25/cdk5 leads to enhanced amyloidogenic processing
    Yi Wen
    Taub Institute at Columbia University Medical Center, New York, NY 10032, USA
    Neuron 57:680-90. 2008
    ..These data demonstrate a pathway by which p25/cdk5 increases the amyloidogenic processing of APP through STAT3-mediated transcriptional control of BACE1 that could have implications for AD pathogenesis...
  2. pmc Tumor necrosis factor-α synthesis inhibitor 3,6'-dithiothalidomide attenuates markers of inflammation, Alzheimer pathology and behavioral deficits in animal models of neuroinflammation and Alzheimer's disease
    David Tweedie
    Laboratory of Neurosciences, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA
    J Neuroinflammation 9:106. 2012
    ..Elevated TNF-α levels are commonly detected in the clinic and animal models of AD...
  3. pmc PuF, an antimetastatic and developmental signaling protein, interacts with the Alzheimer's amyloid-β precursor protein via a tissue-specific proximal regulatory element (PRE)
    Debomoy K Lahiri
    Laboratory of Molecular Neurogenetics, Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, 791 Union Drive, Indianapolis, IN 46202, USA
    BMC Genomics 14:68. 2013
    ..We examined PRE-nuclear protein interaction by gel electrophoretic mobility shift assay (EMSA) and PRE mutant EMSA. This was followed by functional studies of PRE mutant/reporter gene fusion clones...
  4. doi request reprint Gene × environment interaction by a longitudinal epigenome-wide association study (LEWAS) overcomes limitations of genome-wide association study (GWAS)
    Debomoy K Lahiri
    Department of Psychiatry, Laboratory of Molecular Neurogenetics, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA
    Epigenomics 4:685-99. 2012
    ..This Longitudinal epigenome-wide association study, based on the 'dynamic' somatic epitype over the 'static' genotype, merits further investigation...
  5. doi request reprint The "LEARn" (latent early-life associated regulation) model: an epigenetic pathway linking metabolic and cognitive disorders
    Debomoy K Lahiri
    Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USA
    J Alzheimers Dis 30:S15-30. 2012
    ..The possibility of a single metabolic-cognitive disorder opens up the possibility of unified preventative treatments that reduce monetary and social costs of disease. LEARn suggests specific, testable pathways within the large theory...
  6. ncbi request reprint Applying epigenetics to Alzheimer's disease via the latent early-life associated regulation (LEARn) model
    Bryan Maloney
    Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA
    Curr Alzheimer Res 9:589-99. 2012
    ....
  7. ncbi request reprint Apolipoprotein gene and its interaction with the environmentally driven risk factors: molecular, genetic and epidemiological studies of Alzheimer's disease
    Debomoy K Lahiri
    Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA
    Neurobiol Aging 25:651-60. 2004
    ..Thus, ApoE4 contributes to the pathogenesis of AD, but additional environmental risk factors will also be identified independent of ApoE and other genetic polymorphisms...
  8. ncbi request reprint Where the actions of environment (nutrition), gene and protein meet: beneficial role of fruit and vegetable juices in potentially delaying the onset of Alzheimer's disease
    Debomoy K Lahiri
    Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA
    J Alzheimers Dis 10:359-61; discussion 363-4. 2006
  9. ncbi request reprint Dietary supplementation with melatonin reduces levels of amyloid beta-peptides in the murine cerebral cortex
    Debomoy K Lahiri
    Institute of Psychiatric Research, Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN 46202, USA
    J Pineal Res 36:224-31. 2004
    ..Thus, melatonin supplementation may retard neurodegenerative changes associated with brain aging. Depletion of melatonin in the brain of aging mice may in part account for this adverse change...
  10. ncbi request reprint Age-related changes in serum melatonin in mice: higher levels of combined melatonin and 6-hydroxymelatonin sulfate in the cerebral cortex than serum, heart, liver and kidney tissues
    Debomoy K Lahiri
    Institute of Psychiatric Research, Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN 46202, USA
    J Pineal Res 36:217-23. 2004
    ..Thus, any age-related decline of tissue melatonin can be reversed by supplementation with dietary melatonin...
  11. ncbi request reprint How and when environmental agents and dietary factors affect the course of Alzheimer's disease: the "LEARn" model (latent early-life associated regulation) may explain the triggering of AD
    Debomoy K Lahiri
    Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA
    Curr Alzheimer Res 4:219-28. 2007
    ..The LEARn model may explain the etiology of AD and other neuropsychiatric and developmental disorders...
  12. ncbi request reprint A proximal gene promoter region for the beta-amyloid precursor protein provides a link between development, apoptosis, and Alzheimer's disease
    D K Lahiri
    Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA
    Ann N Y Acad Sci 1010:643-7. 2003
    ..Because serum starvation contributes to the induction of apoptosis, these results suggest a role of the 30-bp proximal APP promoter element in enhanced apoptotic neuronal cell death...
  13. ncbi request reprint Does nitric oxide synthase contribute to the pathogenesis of Alzheimer's disease?: effects of beta-amyloid deposition on NOS in transgenic mouse brain with AD pathology
    D K Lahiri
    Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA
    Ann N Y Acad Sci 1010:639-42. 2003
    ..A similar result was obtained for inducible NOS levels. Our results suggest that excess levels of Abeta failed to both trigger NOS activity and change NOS levels...
  14. ncbi request reprint Differential effects of two hexahydropyrroloindole carbamate-based anticholinesterase drugs on the amyloid beta protein pathway involved in Alzheimer's disease
    Debomoy K Lahiri
    Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA
    Neuromolecular Med 9:157-68. 2007
    ..The divergent actions of these two structurally related drugs on the amyloid pathway indicate that the mechanisms underpinning the cholinergic and the amyloid-lowering properties for this class of drugs are independent of each other...
  15. ncbi request reprint Role of the APP promoter in Alzheimer's disease: cell type-specific expression of the beta-amyloid precursor protein
    Debomoy K Lahiri
    Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, 791 Union Drive, Indianapolis, IN 46202, USA
    Ann N Y Acad Sci 1030:310-6. 2004
    ..A 30-bp proximal promoter region was found to be important for cell type-specific APP gene expression...
  16. ncbi request reprint Apolipoprotein E as a target for developing new therapeutics for Alzheimer's disease based on studies from protein, RNA, and regulatory region of the gene
    Debomoy K Lahiri
    Department of Psychiatry and of Medical and Molecular Genetics, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA
    J Mol Neurosci 23:225-33. 2004
    ..The interaction of different transcription factors with the regulatory region of the ApoE gene is important to understand the neuroinflammatory process seen in AD...
  17. ncbi request reprint Amyloid, cholinesterase, melatonin, and metals and their roles in aging and neurodegenerative diseases
    Debomoy K Lahiri
    Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA
    Ann N Y Acad Sci 1056:430-49. 2005
    ..Finally, melatonin is present in edible plants and walnuts, and consuming foodstuffs containing melatonin would be beneficial by enhancing the antioxidative capacity of the organisms...
  18. ncbi request reprint Characterization of two APP gene promoter polymorphisms that appear to influence risk of late-onset Alzheimer's disease
    Debomoy K Lahiri
    Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, 791 N Union Drive, Indianapolis, IN 46202, USA
    Neurobiol Aging 26:1329-41. 2005
    ..Characterization of the activity of a regulatory polymorphism of the APP gene points towards understanding mechanisms that likely underlie the majority of AD cases and may contribute to promoter-based drug design...
  19. ncbi request reprint Taking down the unindicted co-conspirators of amyloid beta-peptide-mediated neuronal death: shared gene regulation of BACE1 and APP genes interacting with CREB, Fe65 and YY1 transcription factors
    Debomoy K Lahiri
    Indiana University School of Medicine, Department of Psychiatry, Institute of Psychiatric Research, Indianapolis, IN 46202, USA
    Curr Alzheimer Res 3:475-83. 2006
    ....
  20. ncbi request reprint The experimental Alzheimer's disease drug posiphen [(+)-phenserine] lowers amyloid-beta peptide levels in cell culture and mice
    Debomoy K Lahiri
    Institute of Psychiatric Research, Department of Psychiatry, Indiana University School of Medicine, 791 Union Drive, Indianapolis, IN 46202, USA
    J Pharmacol Exp Ther 320:386-96. 2007
    ..Posiphen, like phenserine, can lower Abeta via multiple mechanisms and represents an interesting drug candidate for AD treatment...
  21. ncbi request reprint BACE1 gene promoter is differentially regulated: detection of a novel promoter region for its cell type-specific regulation
    Debomoy K Lahiri
    Laboratory of Molecular Neurogenetics, Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA
    J Mol Neurosci 28:193-210. 2006
    ..This fragment might be a useful target to regulate BACE1 expression leading to Abeta production and to understand the neuropathogenesis of AD...
  22. ncbi request reprint Functional domains of the BACE1 and BACE2 promoters and mechanisms of transcriptional suppression of the BACE2 promoter in normal neuronal cells
    Debomoy K Lahiri
    Laboratory of Molecular Neurogenetics, Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN 46202, USA
    J Mol Neurosci 29:65-80. 2006
    ..Two (or more) regulatory pathways might control transcription in BACE2. Thus, BACE2 is partially suppressed in normal neuronal cells and likely to be a highly regulated gene expressed in a particularly tissue-specific fashion...
  23. ncbi request reprint Rationale for the development of cholinesterase inhibitors as anti-Alzheimer agents
    D K Lahiri
    Institute of Psychiatric Research, Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN 46202, USA
    Curr Pharm Des 10:3111-9. 2004
    ..Finally, we examine different neurobiological mechanisms that provide the basis of new targets for AD drug development...
  24. ncbi request reprint Functional characterization of amyloid beta precursor protein regulatory elements: rationale for the identification of genetic polymorphism
    Debomoy K Lahiri
    Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, 791 Union Drive, Indianapolis, IN 46202, USA
    Ann N Y Acad Sci 1030:282-8. 2004
    ..This article describes the rationale and strategy for identifying genetic polymorphisms in the APP regulatory region, including its promoter, to associate any variability with the disease...
  25. ncbi request reprint Characterization of the APP proximal promoter and 5'-untranslated regions: identification of cell type-specific domains and implications in APP gene expression and Alzheimer's disease
    Debomoy K Lahiri
    Department of Psychiatry, Institute of Psychiatric Research, 791 Union Drive, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA
    FASEB J 19:653-5. 2005
    ..Therefore, the -46/54 region appears to be essential for basal expression of the APP gene, the 54/100 and 100/144 regions may have tissue-specific activity, and the "amyloid" CAGA box plays a role in APP gene regulation...
  26. ncbi request reprint Alzheimer's disease--current trends in basic and clinical research. Highlights from the 16th ECNP. September 20-24 2003, Prague, Czech Republic
    Debomoy K Lahiri
    Indiana University School of Medicine, Department of Psychiatry, Institute of Psychiatric Research, Indianapolis, IN 46202 4887, USA
    Expert Opin Investig Drugs 13:79-86. 2004
  27. ncbi request reprint Nicotine reduces the secretion of Alzheimer's beta-amyloid precursor protein containing beta-amyloid peptide in the rat without altering synaptic proteins
    D K Lahiri
    Laboratory of Molecular Neurogenetics, Department of Psychiatry and Neurology, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA
    Ann N Y Acad Sci 965:364-72. 2002
    ....
  28. ncbi request reprint Developmental expression of the beta-amyloid precursor protein and heat-shock protein 70 in the cerebral hemisphere region of the rat brain
    D K Lahiri
    Laboratory of Molecular Neurogenetics, Institute of Psychiatric Research, Department of Psychiatry, Indiana University School of Medicine, Indianapolis, Indiana 46202 4887, USA
    Ann N Y Acad Sci 965:324-33. 2002
    ..These initial results suggest that APP may play an important role in the early development of the rat brain and the alcohol-preferring trait may influence APP processing in the developing brain...
  29. ncbi request reprint Electrophoretic mobility shift assay for the detection of specific DNA-protein complex in nuclear extracts from the cultured cells and frozen autopsy human brain tissue
    D K Lahiri
    Laboratory of Molecular Neurogenetics, Institute of Psychiatric Research, Department of Psychiatry, Indiana University School of Medicine, 791 Union Drive, Indianapolis, IN 46202, USA
    Brain Res Brain Res Protoc 5:257-65. 2000
    ..The RM can be applied to determine the cell type or tissue specificity of transcription factors in an efficient, economical and consistent manner...
  30. ncbi request reprint Analysis of the 5'-flanking region of the beta-amyloid precursor protein gene that contributes to increased promoter activity in differentiated neuronal cells
    D K Lahiri
    Laboratory of Molecular Neurogenetics, Institute of Psychiatric Research, Department of Psychiatry, 791 Union Drive, Room No Pr 313, Indiana University School of Medicine, Indianapolis, IN 46202 4887, USA
    Brain Res Mol Brain Res 77:185-98. 2000
    ..We speculate that any structural alteration(s) due to a specific mutation in these regulatory regions can potentially alter the transcriptional machinery, and that can perhaps affect the level of beta-amyloid protein involved in AD...
  31. ncbi request reprint Effect of a memory-enhancing drug, AIT-082, on the level of synaptophysin
    D K Lahiri
    Department of Psychiatry, Indiana University School of Medicine, Indianapolis 46202, USA
    Ann N Y Acad Sci 903:387-93. 2000
    ....
  32. ncbi request reprint Effect of oxidative stress on DNA damage and beta-amyloid precursor proteins in lymphoblastoid cell lines from a Nigerian population
    D K Lahiri
    Department of Psychiatry, Indiana University School of Medicine, Indianapolis 46202, USA
    Ann N Y Acad Sci 893:331-6. 1999
    ..Our preliminary results suggest that African populations are less vulnerable to chemical-induced oxidative DNA damage...
  33. ncbi request reprint Interactions between melatonin, reactive oxygen species, and nitric oxide
    D K Lahiri
    Department of Psychiatry, Indiana University School of Medicine, Indianapolis 46202 4887, USA
    Ann N Y Acad Sci 893:325-30. 1999
    ..The ROS-scavenging function of melatonin along with its neuroprotective and neurodifferentiating role can be utilized for the prevention of neurodegenerative disorders such as AD...
  34. ncbi request reprint Melatonin affects the metabolism of the beta-amyloid precursor protein in different cell types
    D K Lahiri
    Department of Psychiatry and Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis 46202, USA
    J Pineal Res 26:137-46. 1999
    ..Taken together, these data suggest that melatonin probably affects the secretion of sAPP in the conditioned medium by interfering with its full maturation, and melatonin also affects the presysnaptic terminal marker...
  35. ncbi request reprint The secretion of amyloid beta-peptides is inhibited in the tacrine-treated human neuroblastoma cells
    D K Lahiri
    Institute of Psychiatric Research, Departments of Psychiatry and Neurology, 791 Union Drive, Indiana University School of Medicine, Indianapolis, IN 46202, USA
    Brain Res Mol Brain Res 62:131-40. 1998
    ..This study raises the possibility that tacrine may aid in the treatment of AD due to its effects on betaAPP processing as well as by its effects on the cholinergic pathway...
  36. ncbi request reprint 6th International Conference on Alzheimer's Disease and Parkinson's Disease
    Debomoy K Lahiri
    Indiana University School of Medicine, Department of Psychiatry, Institute of Psychiatric Research, Room PR 313, 791 Union Drive, Indianapolis, IN 46202 4887, USA
    Expert Opin Investig Drugs 12:1433-40. 2003
  37. ncbi request reprint The role of the carboxyl-terminal fragments of amyloid precursor protein in Alzheimer's disease
    D K Lahiri
    Department of Psychiatry, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA
    Ann N Y Acad Sci 973:334-9. 2002
    ..Studying their localization and biogenesis may reveal the biological activities of CTFs of APP. The present study may pave the way for possible antiamyloidogenic therapy in the treatment of AD...
  38. ncbi request reprint Functional characterization of the 5'-regulatory region of the murine apolipoprotein gene
    D K Lahiri
    Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA
    Ann N Y Acad Sci 973:340-4. 2002
    ..Our results suggest that mAPOE can also be expressed in neuronal cells in addition to the astrocytic cells. Characterization of mAPOE promoter is important for the AD drug development discovery and APOE transgenic mice studies...
  39. ncbi request reprint A critical analysis of new molecular targets and strategies for drug developments in Alzheimer's disease
    Debomoy K Lahiri
    Department of Psychiatry and Neurology, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, IN 46202 4887, USA
    Curr Drug Targets 4:97-112. 2003
    ..All these current research efforts should lead to a deeper understanding of the pathobiochemical processes that occur in the AD brain in order to effectively diagnose and prevent their occurrence...
  40. pmc Neuroprotective and neurorescue effects of a novel polymeric nanoparticle formulation of curcumin (NanoCurc™) in the neuronal cell culture and animal model: implications for Alzheimer's disease
    Balmiki Ray
    Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA
    J Alzheimers Dis 23:61-77. 2011
    ..Taken together, these results suggest that NanoCurc™ represents an optimized formulation worthy of assessing the therapeutic value of curcumin in AD...
  41. pmc Beyond the signaling effect role of amyloid-ß42 on the processing of APP, and its clinical implications
    Debomoy K Lahiri
    Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA
    Exp Neurol 225:51-4. 2010
    ..Abeta appears to be a highly multi-functional peptide, and any or all of the pathways it engages in is a likely candidate for antiAD drug development...
  42. doi request reprint Early-life events may trigger biochemical pathways for Alzheimer's disease: the "LEARn" model
    Debomoy K Lahiri
    Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, 791, Union Drive, Indianapolis, IN, 46202, USA
    Biogerontology 9:375-9. 2008
    ..The LEARn model operates through the regulatory region (promoter) of the gene and by affecting the methylation status within the promoter of specific genes...
  43. ncbi request reprint Role of cytokines in the gene expression of amyloid beta-protein precursor: identification of a 5'-UTR-binding nuclear factor and its implications in Alzheimer's disease
    D K Lahiri
    Department of Psychiatry, Institute of Psychiatric Research, 791 Union Drive, Indiana University School of Medicine, Indianapolis, IN 46202, USA
    J Alzheimers Dis 5:81-90. 2003
    ..The characterization of AbetaPP regulatory elements, including the 5'-UTR, will accelerate the development of novel agents against new targets for AD...
  44. pmc The "LEARn" (Latent Early-life Associated Regulation) model integrates environmental risk factors and the developmental basis of Alzheimer's disease, and proposes remedial steps
    Debomoy K Lahiri
    Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, USA
    Exp Gerontol 45:291-6. 2010
    ....
  45. doi request reprint The LEARn model: an epigenetic explanation for idiopathic neurobiological diseases
    D K Lahiri
    Laboratory of Molecular Neurogenetics, Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA
    Mol Psychiatry 14:992-1003. 2009
    ..The LEARn model combines genetic and environmental risk factors in an epigenetic pathway to explain the etiology of the most common, that is, sporadic, forms of neurobiological disorders...
  46. ncbi request reprint Functional characterization of the 5' flanking region of the BACE gene: identification of a 91 bp fragment involved in basal level of BACE promoter expression
    Yuan Wen Ge
    Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, Indiana, USA
    FASEB J 18:1037-9. 2004
    ..Changes in the activity of this region could play an important role in regulating BACE activity in neurons...
  47. ncbi request reprint NF-(kappa)B mediates amyloid beta peptide-stimulated activity of the human apolipoprotein E gene promoter in human astroglial cells
    Yansheng Du
    Department of Neurology, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA
    Brain Res Mol Brain Res 136:177-88. 2005
    ..Our data provide evidence that upregulation of APOE by A(beta) in astroglial cells is mediated by an NF-(kappa)B-element present in the 5'-flanking region of the APOE gene...
  48. pmc Memantine treatment decreases levels of secreted Alzheimer's amyloid precursor protein (APP) and amyloid beta (A beta) peptide in the human neuroblastoma cells
    Balmiki Ray
    Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA
    Neurosci Lett 470:1-5. 2010
    ..Such a novel property of memantine warrants further study to define its therapeutic utility...
  49. ncbi request reprint Mechanism of promoter activity of the beta-amyloid precursor protein gene in different cell lines: identification of a specific 30 bp fragment in the proximal promoter region
    Yuan Wen Ge
    Laboratory of Molecular Neurogenetics, Institute of Psychiatric Research, Department of Psychiatry, Indiana University School of Medicine, Indianapolis, Indiana 46202 4887, USA
    J Neurochem 90:1432-44. 2004
    ..Characterization of the APP regulatory region's interaction with cell type-specific nuclear factor(s) is important to understand tissue-specific expression of APP seen in AD subjects...
  50. pmc A novel effect of rivastigmine on pre-synaptic proteins and neuronal viability in a neurodegeneration model of fetal rat primary cortical cultures and its implication in Alzheimer's disease
    Jason A Bailey
    Laboratory of Molecular Neurogenetics, Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA
    J Neurochem 112:843-53. 2010
    ....
  51. ncbi request reprint Important differences between human and mouse APOE gene promoters: limitation of mouse APOE model in studying Alzheimer's disease
    Bryan Maloney
    Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA
    J Neurochem 103:1237-57. 2007
    ....
  52. ncbi request reprint Presence of a "CAGA box" in the APP gene unique to amyloid plaque-forming species and absent in all APLP-1/2 genes: implications in Alzheimer's disease
    Bryan Maloney
    Departments of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA
    FASEB J 18:1288-90. 2004
    ....
  53. pmc Memantine lowers amyloid-beta peptide levels in neuronal cultures and in APP/PS1 transgenic mice
    George M Alley
    Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USA
    J Neurosci Res 88:143-54. 2010
    ..Memantine's ability to preserve neuronal cells against neurodegeneration, to increase metabolic activity, and to lower Abeta level has therapeutic implications for neurodegenerative disorders...
  54. ncbi request reprint The integrated role of desferrioxamine and phenserine targeted to an iron-responsive element in the APP-mRNA 5'-untranslated region
    Amanda Venti
    Genetics and Aging Research Unit, Department of Psychiatry, Massachusetts General Hospital East, Charlestown, MA 02129, USA
    Ann N Y Acad Sci 1035:34-48. 2004
    ..Phenserine was most efficient to block translation under conditions of intracellular iron chelation with desferrioxamine suggesting that this anticholinesterase operated through an iron (metal)-dependent pathway at the APP 5'-UTR site...
  55. ncbi request reprint An iron-responsive element type II in the 5'-untranslated region of the Alzheimer's amyloid precursor protein transcript
    Jack T Rogers
    Genetics and Aging Research Unit, Department of Psychiatry, Massachusetts General Hospital, Charlestown, Massachusetts 02129 4404, USA
    J Biol Chem 277:45518-28. 2002
    ....
  56. doi request reprint Functional characterization of three single-nucleotide polymorphisms present in the human APOE promoter sequence: Differential effects in neuronal cells and on DNA-protein interactions
    Bryan Maloney
    Department of Psychiatry, Institute of Psychiatric Research, Laboratory of Molecular Neurogenetics, Indiana University School of Medicine, Indianapolis, Indiana, USA
    Am J Med Genet B Neuropsychiatr Genet 153:185-201. 2010
    ..Taken together, these results suggest that APOE expression levels are a risk factor for AD irrespective of APOEepsilon4 allele status...
  57. pmc Iron and the translation of the amyloid precursor protein (APP) and ferritin mRNAs: riboregulation against neural oxidative damage in Alzheimer's disease
    Jack T Rogers
    Department of Psychiatry, Neurochemistry Laboratory, Massachusetts General Hospital, Charlestown, MA 02129, USA
    Biochem Soc Trans 36:1282-7. 2008
    ..The same constellation of RNA-binding proteins [IRP1/IRP2/poly(C) binding protein] control ferritin and APP translation with implications for the biology of metals in AD...
  58. ncbi request reprint Lethal weapon: amyloid beta-peptide, role in the oxidative stress and neurodegeneration of Alzheimer's disease
    Debomoy K Lahiri
    Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, 791 Union Drive, Indianapolis, IN 46202, USA
    Neurobiol Aging 25:581-7. 2004
  59. ncbi request reprint Characterization of the human beta-secretase 2 (BACE2) 5'-flanking region: identification of a 268-bp region as the basal BACE2 promoter
    Bryan Maloney
    Laboratory of Molecular Neurogenetics, Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN 46202, USA
    J Mol Neurosci 29:81-99. 2006
    ..The BACE2 5'-flanking region is likely to be highly regulated and expressed in a tissue type-specific manner...
  60. ncbi request reprint High levels of Alzheimer beta-amyloid precursor protein (APP) in children with severely autistic behavior and aggression
    Deborah K Sokol
    Department of Neurology, Indiana University School of Medicine, 702 Barnhill Drive, Indianapolis, IN 46202, USA
    J Child Neurol 21:444-9. 2006
    ..This favors an increased alpha-secretase pathway in autism (anabolic), opposite to what is seen in Alzheimer disease. Additionally, a complex relationship between age, acetylcholinesterase, and plasma neuronal markers was found...
  61. ncbi request reprint Melatonin, metals, and gene expression: implications in aging and neurodegenerative disorders
    Debomoy K Lahiri
    Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, 46202
    Ann N Y Acad Sci 1035:216-30. 2004
    ....
  62. pmc Molecular and immunocytochemical characterization of primary neuronal cultures from adult rat brain: Differential expression of neuronal and glial protein markers
    Balmiki Ray
    Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, 791 Union Drive, Indianapolis, IN 46202, USA
    J Neurosci Methods 184:294-302. 2009
    ..Such adult neurons serve as a suitable system for the application of neurodegeneration models and for drug target discovery in various brain disorders including Alzheimer's disease...
  63. pmc Determination of high-affinity choline uptake (HACU) and choline acetyltransferase (ChAT) activity in the same population of cultured cells
    Balmiki Ray
    Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA
    Brain Res 1297:160-8. 2009
    ..We believe that these simple methods can be used for neurochemical and drug discovery studies in several models of neurodegenerative disorders including Alzheimer's disease...
  64. pmc An analog of thyrotropin-releasing hormone (TRH) is neuroprotective against glutamate-induced toxicity in fetal rat hippocampal neurons in vitro
    Michael C Veronesi
    Program in Medical Neurobiology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
    Brain Res 1128:79-85. 2007
    ....
  65. ncbi request reprint Neuronal differentiation is accompanied by increased levels of SNAP-25 protein in fetal rat primary cortical neurons: implications in neuronal plasticity and Alzheimer's disease
    Jason A Bailey
    Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, 791 Union Drive, Indianapolis, IN 46202, USA
    Ann N Y Acad Sci 1086:54-65. 2006
    ....
  66. ncbi request reprint Metal and inflammatory targets for Alzheimer's disease
    Jack T Rogers
    Genetics and Aging Research Unit, Department of Psychiatry, Massachusetts General Hospital, Charlestown, MA 02129, USA
    Curr Drug Targets 5:535-51. 2004
    ..These lead drugs are readily testable to measure APP holoprotein expression in a cell based secondary assay, and by use of an APP transgenic mouse model to test potential beneficial effects of lead drug treatments on amyloid burden...
  67. doi request reprint Neuroinflammation in Alzheimer's disease: different molecular targets and potential therapeutic agents including curcumin
    Balmiki Ray
    Laboratory of Molecular Neurogenetics, Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, 791 Union Drive, Indianapolis, IN 46202, USA
    Curr Opin Pharmacol 9:434-44. 2009
    ..Herein, we discuss the neurobiological and neuroinflammatory pathways of AD, evaluate different molecular targets and potential therapeutic agents, including curcumin, for the treatment of AD...
  68. ncbi request reprint A single copy of carbonic anhydrase 2 restores wild-type circadian period to carbonic anhydrase II-deficient mice
    Kari L Kernek
    Program in Medical Neurobiology, Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, 46202, USA
    Behav Genet 36:301-8. 2006
    ..The phenotype of the new lines showed that the long circadian period characteristic of the CA-II-deficient mice arises when functional CA-II is absent, not when DBA/2J alleles are present on proximal chromosome three...
  69. ncbi request reprint The "aged garlic extract:" (AGE) and one of its active ingredients S-allyl-L-cysteine (SAC) as potential preventive and therapeutic agents for Alzheimer's disease (AD)
    B Ray
    Department of Psychiatry, Indiana University School of Medicine, 791Union Drive, Indianapolis IN 46202, USA
    Curr Med Chem 18:3306-13. 2011
    ..Thus, based on the reported positive preliminary results reviewed herein, further research is required to develop the full potential of AGE and/or SAC into an effective preventative strategy for AD...
  70. ncbi request reprint Current drug targets for modulating Alzheimer's amyloid precursor protein: role of specific micro-RNA species
    J M Long
    Department of Psychiatry, Indiana University School of Medicine, 791Union Drive, Indianapolis IN 46202, USA
    Curr Med Chem 18:3314-21. 2011
    ..We conclude by highlighting recent work, including our own, which suggests miRNA are integral components of this regulatory framework and potential targets for future AD therapeutics...
  71. pmc Autism, Alzheimer disease, and fragile X: APP, FMRP, and mGluR5 are molecular links
    D K Sokol
    Department of Neurology, Indiana University School of Medicine, 791 Union Drive, Indianapolis, IN 46202, USA
    Neurology 76:1344-52. 2011
    ..Treatment with mGluR antagonists may help repress APP mRNA translation and reduce secretion of sAPP in FXS and perhaps autism...
  72. pmc Development and validation of the high-quality 'rapid method for swab' to genotype the HTTLPR serotonin transporter (SLC6A4) promoter polymorphism
    Bryan Maloney
    Laboratory of Molecular Neurogenetics, Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA
    Psychiatr Genet 19:72-82. 2009
    ..Samples collected have been shown to produce usable DNA after shipment through conventional mail. The DNA produced by rapid elution of these swabs in chaotropic buffers is, however, of limited quality and low purity...
  73. ncbi request reprint Dietary modulation of age-related changes in cerebral pro-oxidant status
    Stephen C Bondy
    Center for Occupational and Environmental Health, Department of Community and Environmental Medicine, University of California Irvine, Irvine, CA 92697 1820, USA
    Neurochem Int 40:123-30. 2002
    ..While no diet altered motor activity or improved recall of older animals, lipoic acid or tocopherol treatment adversely affected place recall familiarity...
  74. ncbi request reprint Glucagon-like peptide-1 decreases endogenous amyloid-beta peptide (Abeta) levels and protects hippocampal neurons from death induced by Abeta and iron
    TracyAnn Perry
    Section of Drug Design and Development, Laboratory of Neuroscience, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, USA
    J Neurosci Res 72:603-12. 2003
    ..Collectively, these data suggest that GLP-1 can modify APP processing and protect against oxidative injury, two actions that suggest a novel therapeutic target for intervention in Alzheimer's disease...
  75. ncbi request reprint Transforming growth factor-beta 1 potentiates amyloid-beta generation in astrocytes and in transgenic mice
    Sylvain Lesne
    Unité Mixte de Recherche UMR CNRS 6551, IFR47, Universite de Caen, Cyceron, Caen Cedex 14074, France
    J Biol Chem 278:18408-18. 2003
    ..These results demonstrate that TGF-beta1 potentiates Abeta production in human astrocytes and may enhance the formation of plaques burden in the brain of Alzheimer's disease patients...
  76. ncbi request reprint Advances in the cellular and molecular biology of the beta-amyloid protein in Alzheimer's disease
    Kumar Sambamurti
    Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA
    Neuromolecular Med 1:1-31. 2002
    ..The present review summarizes our current understanding of APP metabolism and function and their relationship to other proteins involved in AD...
  77. ncbi request reprint Alzheimer's disease drug discovery targeted to the APP mRNA 5'untranslated region
    Jack T Rogers
    Genetics and Aging Unit, Massachusetts General Hospital Harvard Medical School, Charlestown 02129 4404, USA
    J Mol Neurosci 19:77-82. 2002
    ..These APP 5'UTR directed drugs exemplify a new strategy to identify RNA-directed agents to lower APP translation and A beta peptide output for Alzheimer's disease therapeutics...
  78. ncbi request reprint Butyrylcholinesterase: an important new target in Alzheimer's disease therapy
    Nigel H Greig
    Drug Design and Development Section, Laboratory of Neurosciences, National Institute on Aging, Baltimore, Maryland, USA
    Int Psychogeriatr 14:77-91. 2002
    ..The development of specific BuChE inhibitors and further experience with the dual enzyme inhibitor rivastigmine will improve understanding of the aetiology of AD and should lead to a wider variety of potent treatment options...
  79. ncbi request reprint Nicotine lowers the secretion of the Alzheimer's amyloid beta-protein precursor that contains amyloid beta-peptide in rat
    Tadanobu Utsuki
    Laboratory of Neurosciences, Intramural Research Program, National Institute on Aging, Gerontology Research Center, 5600 Nathan Shock Dr, Baltimore, MD 21224, USA
    J Alzheimers Dis 4:405-15. 2002
    ..These results suggest that within the brain, levels of total sAPP, sAPPgamma and, accordingly, Abeta are subject to cholinergic manipulation, offering therapeutic potential at the level of AbetaPP processing to decrease Abetadeposition...
  80. ncbi request reprint APH1, PEN2, and Nicastrin increase Abeta levels and gamma-secretase activity
    Laura Marlow
    Department of Physiology and Neuroscience, Medical University of South Carolina, 173 Ashley Avenue, Suite 403, Charleston, SC 29425, USA
    Biochem Biophys Res Commun 305:502-9. 2003
    ..In addition, our studies also suggest that the presenilin partners regulate the relative levels of Abeta40 and Abeta42...
  81. ncbi request reprint Gene structure and organization of the human beta-secretase (BACE) promoter
    Kumar Sambamurti
    Medical University of South Carolina, Charleston, South Carolina, USA
    FASEB J 18:1034-6. 2004
    ..Such a study will allow us to further examine the possible role of changes in the promoter of BACE in AD pathogenesis...
  82. pmc Selective butyrylcholinesterase inhibition elevates brain acetylcholine, augments learning and lowers Alzheimer beta-amyloid peptide in rodent
    Nigel H Greig
    Laboratory of Neurosciences and Laboratory of Experimental Gerontology, Intramural Research Program, National Institute on Aging, Baltimore, MD 21224, USA
    Proc Natl Acad Sci U S A 102:17213-8. 2005
    ..Selective, reversible inhibition of brain BChE may represent a treatment for Alzheimer's disease, improving cognition and modulating neuropathological markers of the disease...
  83. pmc Inhibition of human acetyl- and butyrylcholinesterase by novel carbamates of (-)- and (+)-tetrahydrofurobenzofuran and methanobenzodioxepine
    Weiming Luo
    Drug Design and Development Section, Laboratory of Neurosciences, Gerontology Research Center, National Institute on Aging, National Institutes of Health, 5600 Nathan Shock Drive, Baltimore, Maryland 21224, USA
    J Med Chem 49:2174-85. 2006
    ....
  84. ncbi request reprint Identification of novel small molecule inhibitors of amyloid precursor protein synthesis as a route to lower Alzheimer's disease amyloid-beta peptide
    Tada Utsuki
    Department of Biochemistry and Molecular Biology, Feist Weiller Cancer Center, Louisiana State University Health Sciences Center, Shreveport, LA 71115, USA
    J Pharmacol Exp Ther 318:855-62. 2006
    ..Translation of APP and A beta actions to mice was demonstrated with one agent. They thus represent interesting lead molecules for assessment in animal models, to define their tolerance and utility as potential AD therapeutics...
  85. ncbi request reprint Aluminum and copper in drinking water enhance inflammatory or oxidative events specifically in the brain
    Angelica Becaria
    Department of Community and Environmental Medicine, Center for Occupational and Environmental Health Sciences, University of California, Irvine, Irvine, CA 92697 1825, USA
    J Neuroimmunol 176:16-23. 2006
    ..Results suggest that although Al or Cu may independently initiate inflammatory or oxidative events, they may function cooperatively to increase APP levels...
  86. ncbi request reprint The fetal basis of amyloidogenesis: exposure to lead and latent overexpression of amyloid precursor protein and beta-amyloid in the aging brain
    M Riyaz Basha
    Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, Rhode Island 02881, USA
    J Neurosci 25:823-9. 2005
    ..These data suggested that environmental influences occurring during brain development predetermined the expression and regulation of APP later in life, potentially altering the course of amyloidogenesis...
  87. ncbi request reprint Lead (Pb) exposure and its effect on APP proteolysis and Abeta aggregation
    Md Riyaz Basha
    Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, RI 02881, USA
    FASEB J 19:2083-4. 2005
    ..The aforementioned results provide further evidence for the developmental basis of amyloidogenesis and late-life disturbances in AD-associated proteins by environmental agents...
  88. ncbi request reprint Neurine, an acetylcholine autolysis product, elevates secreted amyloid-beta protein precursor and amyloid-beta peptide levels, and lowers neuronal cell viability in culture: a role in Alzheimer's disease?
    David Tweedie
    Section on Drug Design and Delivery, Laboratory of Neurosciences, Intramural Research Program, National Institute on Aging, Baltimore, MD 21224, USA
    J Alzheimers Dis 10:9-16. 2006
    ..Using subtoxic concentrations of neurine, elevations in AbetaPP and Abeta1-40 peptide levels were detected in conditioned media samples...
  89. ncbi request reprint Age-related changes in murine CNS mRNA gene expression are modulated by dietary melatonin
    Edward H Sharman
    Center for Occupational and Environmental Health, Department of Community and Environmental Medicine, University of California, Irvine, CA 92697, USA
    J Pineal Res 36:165-70. 2004
    ..The restoration of a more youthful gene profile to brains of aged animals by melatonin, to a large extent, involves reversal of age-induced elevation of basal inflammatory parameters...
  90. ncbi request reprint Neuropathological and immunochemical studies of brain parenchyma in acetylcholinesterase knockout mice: implications in Alzheimer's disease
    Stephen G Rice
    Barrow Neurological Institute, St Joseph s Hospital and Medical Center, Phoenix, AZ, USA
    J Alzheimers Dis 11:481-9. 2007
    ..Our studies show that neither the absence of AChE nor the presence exclusively of BChE is associated with neuroglial and vascular pathology...
  91. pmc Alzheimer's disease (AD)-like pathology in aged monkeys after infantile exposure to environmental metal lead (Pb): evidence for a developmental origin and environmental link for AD
    Jinfang Wu
    Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, Rhode Island 02881, USA
    J Neurosci 28:3-9. 2008
    ..These data suggest that AD pathogenesis is influenced by early life exposures and argue for both an environmental trigger and a developmental origin of AD...
  92. ncbi request reprint Copper depletion down-regulates expression of the Alzheimer's disease amyloid-beta precursor protein gene
    Shayne A Bellingham
    Department of Genetics, The University of Melbourne, Parkville, Victoria 3010, Australia
    J Biol Chem 279:20378-86. 2004
    ..Copper-regulated APP expression may also provide a potential therapeutic target in Alzheimer's disease...
  93. ncbi request reprint Novel anticholinesterases based on the molecular skeletons of furobenzofuran and methanobenzodioxepine
    Weiming Luo
    Drug Design and Development Section, Laboratory of Neurosciences, National Institute on Aging, National Institutes of Health, 5600 Nathan Shock Drive, Baltimore, Maryland 21224, USA
    J Med Chem 48:986-94. 2005
    ....

Research Grants17

  1. Regulation of APP Pathway Gene Promoters in Alzheimer's
    Debomoy Lahiri; Fiscal Year: 2009
    ..Studying APP and BACE gene regulation is crucial to understand APP production leading to Aa generation. These studies should help developing suitable drug targets for the treatment of Alzheimer's disease. ..
  2. APP GENE PROMOTER IN ALZHEIMER'S DISEASE
    Debomoy Lahiri; Fiscal Year: 2004
    ..Understanding the complex interplay between the promoter domains and the transcription factors may suggest novel methods for therapeutic intervention. ..
  3. Mechanisms of Cholinesterase Inhibitors on Beta-amyloid
    Debomoy Lahiri; Fiscal Year: 2006
    ..This property will be further investigated to maximize their potential effects in decreasing amyloid depositions, and which can be utilized to design better drugs for the treatment of AD. ..
  4. Regulation of APP Pathway Gene Promoters in Alzheimer's
    Debomoy Lahiri; Fiscal Year: 2007
    ..Studying APP and BACE gene regulation is crucial to understand APP production leading to Aa generation. These studies should help developing suitable drug targets for the treatment of Alzheimer's disease. ..
  5. Cholinesterase Inhibitors in Alzheimer's Disease
    Debomoy Lahiri; Fiscal Year: 2009
    ..The outcome of the proposal is to identify mechanisms by which ChEIs block potentially toxic AB levels and to utilize this property in developing novel therapeutic agents. ..
  6. Cholinesterase Inhibitors in Alzheimer's Disease
    Debomoy K Lahiri; Fiscal Year: 2010
    ..The outcome of the proposal is to identify mechanisms by which ChEIs block potentially toxic AB levels and to utilize this property in developing novel therapeutic agents. ..