David Kwiatkowski

Summary

Affiliation: Harvard University
Country: USA

Publications

  1. pmc Equivalent benefit of rapamycin and a potent mTOR ATP-competitive inhibitor, MLN0128 (INK128), in a mouse model of tuberous sclerosis
    Yanan Guo
    Division of Translational Medicine, Department of Medicine, Brigham and Women s Hospital, Boston, MA 02115, USA
    Mol Cancer Res 11:467-73. 2013
  2. pmc Molecular dissection of AKT activation in lung cancer cell lines
    Yanan Guo
    Division of Translational Medicine, Department of Medicine, Brigham and Women s Hospital and Harvard Medical School, Boston, MA 02115, USA
    Mol Cancer Res 11:282-93. 2013
  3. pmc Identification of a region required for TSC1 stability by functional analysis of TSC1 missense mutations found in individuals with tuberous sclerosis complex
    Melika Mozaffari
    Department of Clinical Genetics, Erasmus Medical Centre, Rotterdam, The Netherlands
    BMC Med Genet 10:88. 2009
  4. ncbi request reprint Tuberous sclerosis: from tubers to mTOR
    D J Kwiatkowski
    Hematology Division, Department of Medicine, Brigham and Women s Hospital, Harvard Medical School, Boston, MA 02115, USA
    Ann Hum Genet 67:87-96. 2003
  5. ncbi request reprint Tuberous sclerosis: a GAP at the crossroads of multiple signaling pathways
    David J Kwiatkowski
    Department of Medicine, Brigham and Women s Hospital, Harvard Medical School, One Blackfan Circle, 6th Floor, Room 216, Boston, MA 02115, USA
    Hum Mol Genet 14:R251-8. 2005
  6. ncbi request reprint Rhebbing up mTOR: new insights on TSC1 and TSC2, and the pathogenesis of tuberous sclerosis
    David J Kwiatkowski
    Brigham and Women s Hospital, Boston, Massachusetts 02115, USA
    Cancer Biol Ther 2:471-6. 2003
  7. pmc Animal models of lymphangioleiomyomatosis (LAM) and tuberous sclerosis complex (TSC)
    David J Kwiatkowski
    Division of Translational Medicine, Department of Medicine, Brigham and Women s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
    Lymphat Res Biol 8:51-7. 2010
  8. ncbi request reprint A mouse model of TSC1 reveals sex-dependent lethality from liver hemangiomas, and up-regulation of p70S6 kinase activity in Tsc1 null cells
    David J Kwiatkowski
    Genetics Laboratory, Hematology Division, Brigham and Women s Hospital, Harvard Medical School, 221 Longwood Avenue, LM 302, Boston, MA 02115, USA
    Hum Mol Genet 11:525-34. 2002
  9. ncbi request reprint Efficacy of a rapamycin analog (CCI-779) and IFN-gamma in tuberous sclerosis mouse models
    Laifong Lee
    Division of Hematology, Brigham and Women s Hospital, Boston, MA 02115, USA
    Genes Chromosomes Cancer 42:213-27. 2005
  10. ncbi request reprint Association of defensin beta-1 gene polymorphisms with asthma
    Hara Levy
    Children s Hospital, Division of Pulmonary Medicine, Boston, MA, USA
    J Allergy Clin Immunol 115:252-8. 2005

Research Grants

  1. GENOTYPING CENTER FOR INNATE IMMUNITY PGA
    David Kwiatkowski; Fiscal Year: 2004
  2. GELSOLIN: ROLES IN APOPTOSIS AND TUMOR DEVELOPMENT
    David Kwiatkowski; Fiscal Year: 2003
  3. Preclinical Studies of Rapamycin for TSC Brain Disease
    David Kwiatkowski; Fiscal Year: 2006
  4. Tuberous Sclerosis: Mutations and Murine Models
    David Kwiatkowski; Fiscal Year: 2006
  5. Molecular Pathogenesis of the Hamartoma Syndromes
    David Kwiatkowski; Fiscal Year: 2007
  6. Tuberous Sclerosis: Mutations and Murine Models
    David Kwiatkowski; Fiscal Year: 2007
  7. TUBEROUS SCLEROSIS--MUTATIONS AND MURINE MODELS
    David Kwiatkowski; Fiscal Year: 2001
  8. MURINE MODELS OF TSC 1: MECHANISMS AND THERAPIES
    David Kwiatkowski; Fiscal Year: 2001

Detail Information

Publications84

  1. pmc Equivalent benefit of rapamycin and a potent mTOR ATP-competitive inhibitor, MLN0128 (INK128), in a mouse model of tuberous sclerosis
    Yanan Guo
    Division of Translational Medicine, Department of Medicine, Brigham and Women s Hospital, Boston, MA 02115, USA
    Mol Cancer Res 11:467-73. 2013
    ..Differences in side-effect profiles might make MLN0128 more attractive for treatment of patients with TSC-related tumors, but will require additional study in humans...
  2. pmc Molecular dissection of AKT activation in lung cancer cell lines
    Yanan Guo
    Division of Translational Medicine, Department of Medicine, Brigham and Women s Hospital and Harvard Medical School, Boston, MA 02115, USA
    Mol Cancer Res 11:282-93. 2013
    ....
  3. pmc Identification of a region required for TSC1 stability by functional analysis of TSC1 missense mutations found in individuals with tuberous sclerosis complex
    Melika Mozaffari
    Department of Clinical Genetics, Erasmus Medical Centre, Rotterdam, The Netherlands
    BMC Med Genet 10:88. 2009
    ..Recently it has been shown that missense mutations to the TSC1 gene can cause TSC...
  4. ncbi request reprint Tuberous sclerosis: from tubers to mTOR
    D J Kwiatkowski
    Hematology Division, Department of Medicine, Brigham and Women s Hospital, Harvard Medical School, Boston, MA 02115, USA
    Ann Hum Genet 67:87-96. 2003
    ..Epistasis experiments and a variety of biochemical studies that followed have indicated a critical function for these proteins in the highly conserved PI-3-kinase-Akt-mTOR signalling pathway...
  5. ncbi request reprint Tuberous sclerosis: a GAP at the crossroads of multiple signaling pathways
    David J Kwiatkowski
    Department of Medicine, Brigham and Women s Hospital, Harvard Medical School, One Blackfan Circle, 6th Floor, Room 216, Boston, MA 02115, USA
    Hum Mol Genet 14:R251-8. 2005
    ..As a specific inhibitor of mTOR, rapamycin has therapeutic potential for the treatment of TSC hamartomas...
  6. ncbi request reprint Rhebbing up mTOR: new insights on TSC1 and TSC2, and the pathogenesis of tuberous sclerosis
    David J Kwiatkowski
    Brigham and Women s Hospital, Boston, Massachusetts 02115, USA
    Cancer Biol Ther 2:471-6. 2003
    ..These developments provide enhanced understanding of this signaling pathway and fundamental insights into the pathogenesis of tuberous sclerosis, and open the possibility of treatment for hamartomas by several pharmacologic approaches...
  7. pmc Animal models of lymphangioleiomyomatosis (LAM) and tuberous sclerosis complex (TSC)
    David J Kwiatkowski
    Division of Translational Medicine, Department of Medicine, Brigham and Women s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
    Lymphat Res Biol 8:51-7. 2010
    ..Efforts to generate an authentic LAM model are impeded by a lack of understanding of the cell of origin of this process. However, ongoing studies provide hope that such a model will be generated in the coming years...
  8. ncbi request reprint A mouse model of TSC1 reveals sex-dependent lethality from liver hemangiomas, and up-regulation of p70S6 kinase activity in Tsc1 null cells
    David J Kwiatkowski
    Genetics Laboratory, Hematology Division, Brigham and Women s Hospital, Harvard Medical School, 221 Longwood Avenue, LM 302, Boston, MA 02115, USA
    Hum Mol Genet 11:525-34. 2002
    ..Hyperphosphorylation of S6 is also seen in kidney tumors in the heterozygote mice, suggesting that inhibition of this pathway may have benefit in control of TSC hamartomas...
  9. ncbi request reprint Efficacy of a rapamycin analog (CCI-779) and IFN-gamma in tuberous sclerosis mouse models
    Laifong Lee
    Division of Hematology, Brigham and Women s Hospital, Boston, MA 02115, USA
    Genes Chromosomes Cancer 42:213-27. 2005
    ..These results constitute definitive preclinical data that justify proceeding with clinical trials using these agents in selected patients with TSC and related disorders...
  10. ncbi request reprint Association of defensin beta-1 gene polymorphisms with asthma
    Hara Levy
    Children s Hospital, Division of Pulmonary Medicine, Boston, MA, USA
    J Allergy Clin Immunol 115:252-8. 2005
    ..Defensins are antimicrobial peptides that may take part in airway inflammation and hyperresponsiveness...
  11. ncbi request reprint Mutation in TSC2 and activation of mammalian target of rapamycin signalling pathway in renal angiomyolipoma
    Nisreen El-Hashemite
    Brigham and Women Hospital, Department of Medicine, Haematology Division, Boston MA 02115, USA
    Lancet 361:1348-9. 2003
    ..We suggest that treatment with rapamycin and its analogues could benefit such patients...
  12. ncbi request reprint Perturbed IFN-gamma-Jak-signal transducers and activators of transcription signaling in tuberous sclerosis mouse models: synergistic effects of rapamycin-IFN-gamma treatment
    Nisreen El-Hashemite
    Brigham and Women s Hospital, Hematology Division, Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA
    Cancer Res 64:3436-43. 2004
    ..Rapamycin-IFN-gamma has unique potential therapeutic benefit for management of TSC tumors...
  13. ncbi request reprint Tsc2 null murine neuroepithelial cells are a model for human tuber giant cells, and show activation of an mTOR pathway
    Hiroaki Onda
    Department of Medicine, Brigham and Women s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
    Mol Cell Neurosci 21:561-74. 2002
    ..We conclude that giant cells in human tubers likely result from a complete loss of TSC2 expression and activation of an mTOR pathway during cortical development...
  14. pmc Rapamycin-insensitive up-regulation of MMP2 and other genes in tuberous sclerosis complex 2-deficient lymphangioleiomyomatosis-like cells
    Po Shun Lee
    Pulmonary and Critical Care Division, Brigham and Women s Hospital, Boston, Massachusetts, USA
    Am J Respir Cell Mol Biol 42:227-34. 2010
    ....
  15. ncbi request reprint Tuberin regulates p70 S6 kinase activation and ribosomal protein S6 phosphorylation. A role for the TSC2 tumor suppressor gene in pulmonary lymphangioleiomyomatosis (LAM)
    Elena A Goncharova
    Pulmonary, Allergy, and Critical Care Division, Department of Medicine, University of Pennsylvania, 421 Curie Boulevard, 847 BRB II III, Philadelphia, PA 19104, USA
    J Biol Chem 277:30958-67. 2002
    ..These data demonstrate that tuberin negatively regulates the activity of S6 and p70S6K specifically, and suggest a potential mechanism for abnormal cell growth in LAM...
  16. ncbi request reprint Pathogenesis of tuberous sclerosis subependymal giant cell astrocytomas: biallelic inactivation of TSC1 or TSC2 leads to mTOR activation
    Jennifer A Chan
    Division of Neuropathology, Department of Pathology, Brigham and Women s Hospital, Boston, Massachusetts 02115, USA
    J Neuropathol Exp Neurol 63:1236-42. 2004
    ..We conclude that TSC SEGAs likely arise through a two-hit mechanism of biallelic inactivation of TSC1 or TSC2, leading to activation of the mTOR kinase...
  17. pmc Loss of Tsc1/Tsc2 activates mTOR and disrupts PI3K-Akt signaling through downregulation of PDGFR
    Hongbing Zhang
    Department of Medicine, Brigham and Women s Hospital, Harvard Medical School, Boston, Massachusetts, USA
    J Clin Invest 112:1223-33. 2003
    ..This is in contrast to PTEN, which is a negative upstream regulator of this pathway...
  18. pmc A hypomorphic allele of Tsc2 highlights the role of TSC1/TSC2 in signaling to AKT and models mild human TSC2 alleles
    Kristen Pollizzi
    Translational Medicine Division, Department of Medicine, Brigham and Women s Hospital, Boston, MA 02115, USA
    Hum Mol Genet 18:2378-87. 2009
    ..Tsc2-del3 mice also serve as a model for hypomorphic TSC2 missense mutations reported in TSC patients...
  19. pmc Renal and liver tumors in Tsc2(+/-) mice, a model of tuberous sclerosis complex, do not respond to treatment with atorvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor
    Geraldine A Finlay
    Pulmonary and Critical Care Division, Tufts Medical Center, Boston, MA 02111, USA
    Mol Cancer Ther 8:1799-807. 2009
    ....
  20. pmc Response of a neuronal model of tuberous sclerosis to mammalian target of rapamycin (mTOR) inhibitors: effects on mTORC1 and Akt signaling lead to improved survival and function
    Lynsey Meikle
    Division of Translational Medicine, Department of Medicine, Brigham and Women s Hospital, Children s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
    J Neurosci 28:5422-32. 2008
    ..Although caution is appropriate, the results suggest the possibility that rapamycin/RAD001 may have benefit in the treatment of TSC brain disease, including infantile spasms...
  21. pmc Interferon-gamma-Jak-Stat signaling in pulmonary lymphangioleiomyomatosis and renal angiomyolipoma: a potential therapeutic target
    Nisreen El-Hashemite
    Brigham and Women s Hospital, Hematology Division, Department of Medicine, Harvard Medical School, 75 Francis Street, Boston MA 02115, USA
    Am J Respir Cell Mol Biol 33:227-30. 2005
    ..Our results demonstrate that the IFN-gamma-Jak-Stat pathway is perturbed in TSC-related and sporadic LAM and AML, and suggest that IFN-gamma has potential therapeutic benefit for treatment of those lesions...
  22. ncbi request reprint TOLL-like receptor 10 genetic variation is associated with asthma in two independent samples
    Ross Lazarus
    Channing Laboratory, Division of Pulmonary and Critical Care Medicine, Brigham and Women s Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA
    Am J Respir Crit Care Med 170:594-600. 2004
    ..026 for c.+1031G>A). Consistent association in two independent samples and association with an intermediate phenotype provides strong support for TLR10 genetic variation contributing to asthma risk...
  23. ncbi request reprint Family-based association analysis of beta2-adrenergic receptor polymorphisms in the childhood asthma management program
    Edwin K Silverman
    Channing Laboratory, Brigham and Women s Hospital, Boston, Mass 02115, USA
    J Allergy Clin Immunol 112:870-6. 2003
    ..Beta2-adrenergic receptor (B2AR) polymorphisms have been associated with a variety of asthma-related phenotypes, but association results have been inconsistent across different studies...
  24. pmc Equivalent benefit of mTORC1 blockade and combined PI3K-mTOR blockade in a mouse model of tuberous sclerosis
    Kristen Pollizzi
    Translational Medicine Division, Department of Medicine, Brigham and Women s Hospital, Boston, Massachusetts 02115, USA
    Mol Cancer 8:38. 2009
    ..Here we examine the potential benefit of inhibition of both mTOR and AKT signaling in a mouse model of TSC, using a dual pan class I PI3K/mTOR catalytic small molecule inhibitor NVP-BEZ235...
  25. pmc Attempted replication of reported chronic obstructive pulmonary disease candidate gene associations
    Craig P Hersh
    Channing Laboratory, Pulmonary and Critical Care Division, and Hematology Oncology Division, Department of Medicine, Brigham and Women s Hospital, Boston, MA 02115, USA
    Am J Respir Cell Mol Biol 33:71-8. 2005
    ..03). Although some evidence for replication was found for SFTPB and HMOX1, none of the previously published COPD genetic associations was convincingly replicated across both study designs...
  26. ncbi request reprint Magnetic resonance imaging and characterization of spontaneous lesions in a transgenic mouse model of tuberous sclerosis as a model for endothelial cell-based transgene delivery
    Alice B Brown
    Brain Tumor Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
    Hum Gene Ther 16:1367-76. 2005
    ....
  27. ncbi request reprint LKB1 modulates lung cancer differentiation and metastasis
    Hongbin Ji
    Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts 02115, USA
    Nature 448:807-10. 2007
    ..These studies establish LKB1 as a critical barrier to pulmonary tumorigenesis, controlling initiation, differentiation and metastasis...
  28. pmc mTORC1-dependent and -independent regulation of stem cell renewal, differentiation, and mobilization
    Boyi Gan
    Department of Medical Oncology, Belfer Foundation Institute for Innovative Cancer Science, Dana Farber Cancer Institute, Boston, MA 02115, USA
    Proc Natl Acad Sci U S A 105:19384-9. 2008
    ..Thus, TSC1 is a critical regulator of HSC self-renewal, mobilization, and multilineage development and executes these actions via both mTORC1-dependent and -independent pathways...
  29. pmc Tuberous sclerosis complex-1 and -2 gene products function together to inhibit mammalian target of rapamycin (mTOR)-mediated downstream signaling
    Andrew R Tee
    Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA
    Proc Natl Acad Sci U S A 99:13571-6. 2002
    ....
  30. ncbi request reprint SNP identification, haplotype analysis, and parental origin of mutations in TSC2
    Penelope S Roberts
    Hematology Division, Brigham and Women s Hospital, Harvard Medical School, 221 Longwood Ave, Boston, MA 02115, USA
    Hum Genet 111:96-101. 2002
    ..The observations have implications for genetic counseling in TSC...
  31. ncbi request reprint A mouse model of cardiac rhabdomyoma generated by loss of Tsc1 in ventricular myocytes
    Lynsey Meikle
    Department of Medicine, Brigham and Women s Hospital and Harvard Medical School, Boston, MA 02115, USA
    Hum Mol Genet 14:429-35. 2005
    ....
  32. ncbi request reprint Selective inhibition of growth of tuberous sclerosis complex 2 null cells by atorvastatin is associated with impaired Rheb and Rho GTPase function and reduced mTOR/S6 kinase activity
    Geraldine A Finlay
    Pulmonary and Critical Care Division, Department of Medicine, Tupper Research Institute, Tufts New England Medical Center, Boston, MA 02111, USA
    Cancer Res 67:9878-86. 2007
    ..Atorvastatin may have potential therapeutic benefit in TSC syndromes, including LAM...
  33. ncbi request reprint A mouse model of tuberous sclerosis: neuronal loss of Tsc1 causes dysplastic and ectopic neurons, reduced myelination, seizure activity, and limited survival
    Lynsey Meikle
    Division of Translational Medicine, Department of Medicine, Brigham and Women s Hospital, Boston, Massachusetts 02115, USA
    J Neurosci 27:5546-58. 2007
    ..This new TSC brain model replicates several features of human TSC brain lesions and implicates an important function of Tsc1/Tsc2 in neuronal development...
  34. ncbi request reprint Regulation of neuronal morphology and function by the tumor suppressors Tsc1 and Tsc2
    Sohail F Tavazoie
    Department of Neurobiology, Harvard Medical School, 220 Longwood Avenue, Boston, Massachusetts 02115, USA
    Nat Neurosci 8:1727-34. 2005
    ..Thus, the TSC pathway regulates growth and synapse function in neurons, and perturbations of neuronal structure and function are likely to contribute to the pathogenesis of the neurological symptoms of TSC...
  35. pmc Genomewide linkage analysis of quantitative spirometric phenotypes in severe early-onset chronic obstructive pulmonary disease
    Edwin K Silverman
    Channing Laboratory and Division of Pulmonary and Critical Medicine, Department of Medicine, Brigham and Women s Hospital, Harvard Medical School, Boston, MA 02115, USA
    Am J Hum Genet 70:1229-39. 2002
    ..The significant linkage of FEV(1)/FVC to chromosome 2q could reflect one or more genes influencing the development of airflow obstruction or dysanapsis...
  36. ncbi request reprint The transforming growth factor-beta1 (TGFB1) gene is associated with chronic obstructive pulmonary disease (COPD)
    Juan C Celedon
    Channing Laboratory, Division of Pulmonary and Critical Care Medicine, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
    Hum Mol Genet 13:1649-56. 2004
    ..We hypothesize that genetic variants in or near the TGFB1 gene influence the pathogenesis of COPD among cigarette smokers...
  37. ncbi request reprint Single nucleotide polymorphisms in innate immunity genes: abundant variation and potential role in complex human disease
    Ross Lazarus
    Channing Laboratory, Brigham and Women s Hospital and Harvard Medical School, Boston, MA 02115, USA
    Immunol Rev 190:9-25. 2002
    ..These and other factors must be taken into account in the design and analysis of disease association studies...
  38. doi request reprint Clinical activity of mTOR inhibition with sirolimus in malignant perivascular epithelioid cell tumors: targeting the pathogenic activation of mTORC1 in tumors
    Andrew J Wagner
    Center for Sarcoma and Bone Oncology, Dana Farber Cancer Institute, 44 Binney St, Boston, MA 02115, USA
    J Clin Oncol 28:835-40. 2010
    ..The clinical activity of sirolimus in PEComa additionally strengthens the pathobiologic similarities linking PEComas to other neoplasms related to the tuberous sclerosis complex...
  39. ncbi request reprint Mechanisms of gelsolin-dependent and -independent EGF-stimulated cell motility in a human lung epithelial cell line
    Alan S Lader
    Hematology Division, Brigham and Women s Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA
    Exp Cell Res 307:153-63. 2005
    ....
  40. ncbi request reprint Single-nucleotide polymorphisms in the interleukin-10 gene: differences in frequencies, linkage disequilibrium patterns, and haplotypes in three United States ethnic groups
    Ross Lazarus
    Channing Laboratory, Brigham and Women s Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA
    Genomics 80:223-8. 2002
    ..No SNP caused amino acid changes. Differences in pairwise linkage-disequilibrium (LD) patterns and in SNP and haplotype frequency distributions among the three populations may be of potential importance for disease association studies...
  41. pmc Association between a high-expressing interferon-gamma allele and a lower frequency of kidney angiomyolipomas in TSC2 patients
    Sandra L Dabora
    Division of Hematology, Brigham and Women Hospital, Boston, MA 02115, USA
    Am J Hum Genet 71:750-8. 2002
    ..Although these results should be replicated in other populations with TSC, the present study suggests that modifier genes play a role in the variable expression of TSC and also suggests a potential therapy for KAMLs in patients with TSC...
  42. pmc Tuberous sclerosis complex proteins control axon formation
    Yong Jin Choi
    The F M Kirby Neurobiology Center, Department of Neurology, Children s Hospital Boston, Harvard Medical School, Boston, Massachusetts 02115, USA
    Genes Dev 22:2485-95. 2008
    ....
  43. ncbi request reprint Single-nucleotide polymorphisms in the Toll-like receptor 9 gene (TLR9): frequencies, pairwise linkage disequilibrium, and haplotypes in three U.S. ethnic groups and exploratory case-control disease association studies
    Ross Lazarus
    Channing Laboratory, Department of Medicine, Brigham and Women s Hospital and Harvard Medical School, Boston, MA 02115, USA
    Genomics 81:85-91. 2003
    ..This study suggests that there is substantial diversity in human TLR9, possibly associated with asthma in Europeans but not African Americans. No association was detected with three other diseases potentially related to innate immunity...
  44. ncbi request reprint Chromosome 12q harbors multiple genetic loci related to asthma and asthma-related phenotypes
    Benjamin A Raby
    Channing Laboratory, Brigham and Women s Hospital, Harvard Medical School, Boston, MA, USA
    Hum Mol Genet 12:1973-9. 2003
    ..Fine mapping efforts for these loci are warranted...
  45. ncbi request reprint Polymorphisms in toll-like receptor 4 are not associated with asthma or atopy-related phenotypes
    Benjamin A Raby
    Channing Laboratory, Brigham and Women s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
    Am J Respir Crit Care Med 166:1449-56. 2002
    ..Based on these results, we found no evidence that genetic variation in TLR4 contributes to asthma susceptibility...
  46. pmc mTORC1-S6K activation by endotoxin contributes to cytokine up-regulation and early lethality in animals
    Po Shun Lee
    Translational Medicine Division, Brigham and Women s Hospital, Boston, Massachusetts, United States of America
    PLoS ONE 5:e14399. 2010
    ..We investigated the effect of mTORC1 suppression in an animal model of endotoxemia and in a cellular model of endotoxin signaling...
  47. ncbi request reprint Identification of a transcriptional profile associated with in vitro invasion in non-small cell lung cancer cell lines
    Alan S Lader
    Hematology Division, Brigham and Women s Hospital, Boston, Massachusetts 02115, USA
    Cancer Biol Ther 3:624-31. 2004
    ..These and the other genes identified by both analyses represent targets for further study to assess their importance in non-small cell lung cancer invasion and metastasis...
  48. pmc FoxOs enforce a progression checkpoint to constrain mTORC1-activated renal tumorigenesis
    Boyi Gan
    Belfer Institute for Applied Cancer Science, Boston, MA 02115, USA
    Cancer Cell 18:472-84. 2010
    ....
  49. ncbi request reprint ADAM33 polymorphisms and phenotype associations in childhood asthma
    Benjamin A Raby
    Channing Laboratory, Brigham and Women s Hospital, 181 Longwood Avenue, Boston, MA 02115, USA
    J Allergy Clin Immunol 113:1071-8. 2004
    ..However, genetic linkage of asthma phenotypes to chromosome 20p13 (the location of ADAM33) has not been observed in most asthma genome scans, and it is unclear whether these associations with ADAM33 are broadly generalizable...
  50. ncbi request reprint Genome-wide linkage analysis of severe, early-onset chronic obstructive pulmonary disease: airflow obstruction and chronic bronchitis phenotypes
    Edwin K Silverman
    Channing Laboratory, Division of Pulmonary and Critical Medicine, Department of Medicine, Brigham and Women s Hospital, Harvard Medical School, 181 Longwood Avenue, Boston, MA 02115, USA
    Hum Mol Genet 11:623-32. 2002
    ..In smokers only, the maximum two point LOD score for mild airflow obstruction was 3.14. These observations provide suggestive evidence that there is a locus on chromosome 12p which contributes to susceptibility to early-onset COPD...
  51. pmc Ultra deep sequencing detects a low rate of mosaic mutations in tuberous sclerosis complex
    Wei Qin
    Translational Medicine Division, Brigham and Women s Hospital, Harvard Medical School, Boston, MA 02115, USA
    Hum Genet 127:573-82. 2010
    ..These findings indicate the ability of deep sequencing, coupled with secondary confirmatory analyses, to detect low-frequency mosaic mutations...
  52. ncbi request reprint Estrogen enhances whereas tamoxifen retards development of Tsc mouse liver hemangioma: a tumor related to renal angiomyolipoma and pulmonary lymphangioleiomyomatosis
    Nisreen El-Hashemite
    Hematology Division, Department of Medicine, Brigham and Women s Hospital, Boston, MA 02115, USA
    Cancer Res 65:2474-81. 2005
    ....
  53. pmc Feedback inhibition of Akt signaling limits the growth of tumors lacking Tsc2
    Brendan D Manning
    Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, Massachusetts 02115, USA
    Genes Dev 19:1773-8. 2005
    ..However, Pten haploinsufficiency restores Akt signaling in these tumors and dramatically enhances their severity. This study demonstrates that attenuation of the PI3K-Akt pathway in tumors lacking TSC2 contributes to their benign nature...
  54. ncbi request reprint Loss of Tsc1 or Tsc2 induces vascular endothelial growth factor production through mammalian target of rapamycin
    Nisreen El-Hashemite
    Brigham and Women s Hospital, Department of Medicine, Hematology Division, Boston, Massachusetts 02115, USA
    Cancer Res 63:5173-7. 2003
    ..Last, rapamycin or related inhibitors of mTOR may have therapeutic benefit in TSC both by direct tumor cell killing and by inhibiting the development of TSC lesions through impairment of VEGF production...
  55. pmc Genetic loci associated with plasma concentration of low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, apolipoprotein A1, and Apolipoprotein B among 6382 white women in genome-wide analysis with replication
    Daniel I Chasman
    Center for Cardiovascular Disease Prevention, Brigham and Women s Hospital, Harvard Medical School, Boston, MA 02215, USA
    Circ Cardiovasc Genet 1:21-30. 2008
    ....
  56. ncbi request reprint Infantile spasms and intellectual outcomes in children with tuberous sclerosis complex
    Suzanne Goh
    Massachusetts General Hospital, 175 Cambridge Street, Suite 340, Boston, MA 02114 3117, USA
    Neurology 65:235-8. 2005
    ..To assess intellectual outcomes in a clinic-based population of patients with tuberous sclerosis complex (TSC) who also have a history of infantile spasms (IS) and to identify clinical risk factors for mental retardation in these patients...
  57. pmc Are variants in the CAPN10 gene related to risk of type 2 diabetes? A quantitative assessment of population and family-based association studies
    Yiqing Song
    Division of Preventive Medicine, Harvard Medical School and Brigham and Women s Hospital, Boston, MA 02215, USA
    Am J Hum Genet 74:208-22. 2004
    ..Our findings also suggest that both large-scale, well-designed association studies and functional studies are warranted to either reliably confirm or conclusively refute the initial hypothesis regarding the role of CAPN10 in T2D risk...
  58. ncbi request reprint Identification of 54 large deletions/duplications in TSC1 and TSC2 using MLPA, and genotype-phenotype correlations
    Piotr Kozlowski
    Genetics Laboratory, Division of Translational Medicine, Department of Medicine, Brigham and Women s Hospital, Harvard Medical School, Boston, MA 02115, USA
    Hum Genet 121:389-400. 2007
    ..We conclude that large deletions in TSC1 and TSC2 account for about 0.5 and 6% of mutations seen in TSC patients, respectively, and MLPA is a highly sensitive and accurate detection method, including for mosaicism...
  59. pmc Utilization of a whole genome SNP panel for efficient genetic mapping in the mouse
    Jennifer L Moran
    Genetics Division, Brigham and Women s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
    Genome Res 16:436-40. 2006
    ..By using this approach, we identified DNA sequence changes in two ethylnitrosourea-induced mutants...
  60. pmc Regulation of endothelial nitric oxide synthase and postnatal angiogenesis by Rac1
    Naoki Sawada
    Vascular Medicine Research, Department of Medicine, Brigham and Women s Hospital, Cambridge, MA 02139, USA
    Circ Res 103:360-8. 2008
    ..Therapeutic strategies to enhance Rac1 function, therefore, may be important for preventing endothelial dysfunction...
  61. pmc Novel loci, including those related to Crohn disease, psoriasis, and inflammation, identified in a genome-wide association study of fibrinogen in 17 686 women: the Women's Genome Health Study
    Jacqueline S Danik
    Center for Cardiovascular Disease Prevention, Donald W Reynolds Center for Cardiovascular Research, and Translational Medicine Division, Brigham and Women s Hospital, 900 Commonwealth Ave East, Boston, MA 02215, USA
    Circ Cardiovasc Genet 2:134-41. 2009
    ..Despite evidence of crucial biological function and moderate heritability, comprehensive analysis of the influence of genetic variation on fibrinogen is not available...
  62. pmc Tuberous sclerosis complex activity is required to control neuronal stress responses in an mTOR-dependent manner
    Alessia Di Nardo
    The F M Kirby Neurobiology Center, Department of Neurology, Children s Hospital Boston, Harvard Medical School, Boston, Massachusetts 02115, USA
    J Neurosci 29:5926-37. 2009
    ..They also suggest that some of the neuronal dysfunction and neurocognitive deficits seen in TSC patients may be attributable to ER and oxidative stress and therefore potentially responsive to agents moderating these pathways...
  63. pmc Rac1-null mouse embryonic fibroblasts are motile and respond to platelet-derived growth factor
    Luis Vidali
    Department of Medicine, Brigham and Women s Hospital and Harvard Medical School, Boston, MA 02115, USA
    Mol Biol Cell 17:2377-90. 2006
    ..These results refine our understanding of the functions of Rac1, indicate that lamellipodia formation is not required for cell motility, and show that PDGF-induced chemotaxis can occur in the absence of both lamellipodia and Rac1...
  64. ncbi request reprint Rac1 deletion in mouse neutrophils has selective effects on neutrophil functions
    Michael Glogauer
    Brigham and Women s Hospital, Boston, MA 02115, USA
    J Immunol 170:5652-7. 2003
    ..These data demonstrate that although Rac1 and Rac2 are both required for actin-mediated functions, Rac2 is specifically required for activation of the neutrophil NADPH oxidase...
  65. ncbi request reprint Robust method for distinguishing heterozygous from homozygous transgenic alleles by multiplex ligation-dependent probe assay
    Piotr Kozlowski
    Harvard Medical School, Boston, MA, USA
    Biotechniques 42:584, 586, 588. 2007
  66. ncbi request reprint A 34 bp deletion within TSC2 is a rare polymorphism, not a pathogenic mutation
    Penelope S Roberts
    Hematology Division, Department of Medicine, Brigham and Women s Hospital, Harvard Medical School, Boston, MA 02115, USA
    Ann Hum Genet 67:495-503. 2003
    ..We also excluded the possibility of mosaicism in the parents with this variant. We conclude that this deletion is a rare polymorphism that does not cause TSC, but may be a modifier of the TSC phenotype...
  67. ncbi request reprint Atherosclerosis: the path from genomics to therapeutics
    David T Miller
    Division of Hematology, Brigham and Women s Hospital, Boston, Massachusetts 02115, USA
    J Am Coll Cardiol 49:1589-99. 2007
    ..Their continued success will depend on ongoing cooperation within the cardiovascular research community...
  68. ncbi request reprint Estrogen-induced smooth muscle cell growth is regulated by tuberin and associated with altered activation of platelet-derived growth factor receptor-beta and ERK-1/2
    Geraldine A Finlay
    Pulmonary and Critical Care Division, Department of Medicine, Tupper Research Institute, Tufts New England Medical Center, Boston, Massachusetts 02111, USA
    J Biol Chem 279:23114-22. 2004
    ..Furthermore, the opposing effects of tuberin on estrogen-induced activation of PDGFRbeta and ERK-1/-2 suggest a pivotal role for tuberin in directing the signaling events that dictate the growth response to E2...
  69. ncbi request reprint Platelet-derived growth factor-induced p42/44 mitogen-activated protein kinase activation and cellular growth is mediated by reactive oxygen species in the absence of TSC2/tuberin
    Geraldine A Finlay
    Pulmonary and Critical Care Division, Department of Medicine, Tupper Research Institute, New England Medical Center, Boston, Massacusetts 02111, USA
    Cancer Res 65:10881-90. 2005
    ..Together, our data suggest that loss of tuberin, which causes mTOR activation, leads to a novel cellular growth-promoting pathway involving mitochondrial oxidant-dependent p42/44 MAPK activation and mitogenic growth responses to PDGF...
  70. ncbi request reprint Lack of association between genetic variation in 9 innate immunity genes and baseline CRP levels
    Piotr Kozlowski
    Division of Hematology, Brigham and Women s Hospital, Boston, MA 02115, USA
    Ann Hum Genet 70:574-86. 2006
    ....
  71. pmc IL10 gene polymorphisms are associated with asthma phenotypes in children
    Helen Lyon
    Channing Laboratory, Brigham and Women s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
    Genet Epidemiol 26:155-65. 2004
    ..008 and 0.043, respectively). Polymorphisms in IL10 are associated with asthma phenotypes in this cohort. Further studies of variation in the IL10 gene may help elucidate the mechanism of asthma development in children...
  72. pmc Loci related to metabolic-syndrome pathways including LEPR,HNF1A, IL6R, and GCKR associate with plasma C-reactive protein: the Women's Genome Health Study
    Paul M Ridker
    Center for Cardiovascular Disease Prevention, Brigham and Women s Hospital, Harvard Medical School, Boston, MA 02115, USA
    Am J Hum Genet 82:1185-92. 2008
    ....
  73. pmc Molecular pathogenesis of lymphangioleiomyomatosis: lessons learned from orphans
    Stephen C Juvet
    National Jewish Medical and Research Center, 1400 Jackson Street, Denver, CO 80206, USA
    Am J Respir Cell Mol Biol 36:398-408. 2007
    ..This knowledge served as the foundation for novel therapeutic approaches that are currently being used in human clinical trials...
  74. ncbi request reprint Pulmonary cysts consistent with lymphangioleiomyomatosis are common in women with tuberous sclerosis: genetic and radiographic analysis
    Francis McCormack
    Department of Pediatrics, Division of Pulmonary and Critical Care Medicine, University of Cincinnati, Cincinnati, OH 45267 0564, USA
    Chest 121:61S. 2002
  75. ncbi request reprint Neuronal gelsolin prevents apoptosis by enhancing actin depolymerization
    Christoph Harms
    Department of Neurology, Humboldt University of Berlin, Charite, D 10117 Berlin, Germany
    Mol Cell Neurosci 25:69-82. 2004
    ..In conclusion, actin remodeling by endogenous gelsolin or analogues protects neurons from apoptosis mediated by mitochondria and caspase-3...
  76. doi request reprint mTOR-raptor binds and activates SGK1 to regulate p27 phosphorylation
    Feng Hong
    Braman Family Breast Cancer Institute, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL 33136, USA
    Mol Cell 30:701-11. 2008
    ..mTOR may promote G1 progression in part through SGK1 activation and deregulate the cell cycle in cancers through both Akt- and SGK-mediated p27 T157 phosphorylation and cytoplasmic p27 mislocalization...
  77. pmc An efficient and versatile system for acute and chronic modulation of renal tubular function in transgenic mice
    Milena Traykova-Brauch
    Department of Cellular and Molecular Pathology, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
    Nat Med 14:979-84. 2008
    ..These experiments establish Pax8-rtTA mice as a powerful tool for modeling renal diseases in transgenic mice...
  78. pmc Gelsolin mediates collagen phagocytosis through a rac-dependent step
    Pamela D Arora
    Canadian Institutes of Health Research Group in Matrix Dynamics, University of Toronto, Toronto, Ontario, Canada M5S 3E2
    Mol Biol Cell 15:588-99. 2004
    ....
  79. ncbi request reprint Hematopoietic cell regulation by Rac1 and Rac2 guanosine triphosphatases
    Yi Gu
    Division of Experimental Hematology, Cincinnati Children s Hospital Medical Center, Cincinnati, OH 45229, USA
    Science 302:445-9. 2003
    ..Thus, Rac1 and Rac2 regulate unique aspects of hematopoietic development and function...
  80. ncbi request reprint Rapid turnover of actin in dendritic spines and its regulation by activity
    Erin N Star
    Department of Molecular and Cellular Biology, Harvard University, 16 Divinity Ave, Cambridge, Massachusetts 02138, USA
    Nat Neurosci 5:239-46. 2002
    ..Our studies provide new information on the kinetics of actin turnover in spines, its regulation by neural activity and the mechanisms involved in this regulation...
  81. ncbi request reprint Astrocyte-specific TSC1 conditional knockout mice exhibit abnormal neuronal organization and seizures
    Erik J Uhlmann
    Department of Neurology, Washington University School of Medicine, St Louis Children s Hospital, St Louis, MO 63110, USA
    Ann Neurol 52:285-96. 2002
    ..Collectively, our results demonstrate that astrocyte-specific disruption of Tsc1 in mice provides a context-dependent growth advantage for astrocytes that results in abnormalities in neuronal organization and epilepsy...
  82. pmc PDGFRs are critical for PI3K/Akt activation and negatively regulated by mTOR
    Hongbing Zhang
    Department of Physiology, National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People s Republic of China
    J Clin Invest 117:730-8. 2007
    ..In conclusion, PDGFR is a major target of negative feedback regulation in cells with activated mTOR, which limits the growth potential of TSC tumors...
  83. ncbi request reprint Unusually mild tuberous sclerosis phenotype is associated with TSC2 R905Q mutation
    An C Jansen
    Neurogenetics Unit, Montreal Neurological Hospital and Institute, McGill University, Montreal, Quebec, Canada
    Ann Neurol 60:528-39. 2006
    ..To report the clinical manifestations and functional aspects of Tuberous Sclerosis Complex (TSC), resulting from Codon 905 mutations in TSC2 gene...
  84. pmc Reversal of learning deficits in a Tsc2+/- mouse model of tuberous sclerosis
    Dan Ehninger
    Department of Neurobiology, Brain Research Institute, University of California, Los Angeles, 695 Charles E Young Drive South, Los Angeles, California 90095, USA
    Nat Med 14:843-8. 2008
    ....

Research Grants31

  1. GENOTYPING CENTER FOR INNATE IMMUNITY PGA
    David Kwiatkowski; Fiscal Year: 2004
    ..abstract_text> ..
  2. GELSOLIN: ROLES IN APOPTOSIS AND TUMOR DEVELOPMENT
    David Kwiatkowski; Fiscal Year: 2003
    ..The results should provide major insight into the function of gelsolin in these processes and provide potential therapeutic strategies to modulate apoptosis and malignant potential. ..
  3. Preclinical Studies of Rapamycin for TSC Brain Disease
    David Kwiatkowski; Fiscal Year: 2006
    ..These studies will provide critical preclinical data that will support the use of rapamycin or analogues in the treatment of TSC patients with cortical tubers and subependymal giant cell astrocytomas. ..
  4. Tuberous Sclerosis: Mutations and Murine Models
    David Kwiatkowski; Fiscal Year: 2006
    ..Last, the in vivo interaction in the mouse between Tsc2 null alleles and null alleles for p53, p27KIP, p21CIP, Msh2, and gelsolin will be explored. ..
  5. Molecular Pathogenesis of the Hamartoma Syndromes
    David Kwiatkowski; Fiscal Year: 2007
    ....
  6. Tuberous Sclerosis: Mutations and Murine Models
    David Kwiatkowski; Fiscal Year: 2007
    ..This model will permit analysis of genetic and signaling events occurring during renal cyst pathogenesis. ..
  7. TUBEROUS SCLEROSIS--MUTATIONS AND MURINE MODELS
    David Kwiatkowski; Fiscal Year: 2001
    ....
  8. MURINE MODELS OF TSC 1: MECHANISMS AND THERAPIES
    David Kwiatkowski; Fiscal Year: 2001
    ....