Research Topics
Genomes and Genes
| David KwiatkowskiSummaryAffiliation: Harvard University Country: USA Publications
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Detail Information
Publications
Molecular dissection of AKT activation in lung cancer cell linesYanan 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....- Identification of a region required for TSC1 stability by functional analysis of TSC1 missense mutations found in individuals with tuberous sclerosis complexMelika 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... 
Tuberous sclerosis: a GAP at the crossroads of multiple signaling pathwaysDavid 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...- Tuberous sclerosis: from tubers to mTORD 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... - Rhebbing up mTOR: new insights on TSC1 and TSC2, and the pathogenesis of tuberous sclerosisDavid 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... - 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... - A mouse model of TSC1 reveals sex-dependent lethality from liver hemangiomas, and up-regulation of p70S6 kinase activity in Tsc1 null cellsDavid 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... - Efficacy of a rapamycin analog (CCI-779) and IFN-gamma in tuberous sclerosis mouse modelsLaifong 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... - Association of defensin beta-1 gene polymorphisms with asthmaHara 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... - Mutation in TSC2 and activation of mammalian target of rapamycin signalling pathway in renal angiomyolipomaNisreen 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... - Perturbed IFN-gamma-Jak-signal transducers and activators of transcription signaling in tuberous sclerosis mouse models: synergistic effects of rapamycin-IFN-gamma treatmentNisreen 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... - Tsc2 null murine neuroepithelial cells are a model for human tuber giant cells, and show activation of an mTOR pathwayHiroaki 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... - Rapamycin-insensitive up-regulation of MMP2 and other genes in tuberous sclerosis complex 2-deficient lymphangioleiomyomatosis-like cellsPo 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.... - 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 inhibitorGeraldine A Finlay
Pulmonary and Critical Care Division, Tufts Medical Center, Boston, MA 02111, USA
Mol Cancer Ther 8:1799-807. 2009.... - 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... - Pathogenesis of tuberous sclerosis subependymal giant cell astrocytomas: biallelic inactivation of TSC1 or TSC2 leads to mTOR activationJennifer 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... - Loss of Tsc1/Tsc2 activates mTOR and disrupts PI3K-Akt signaling through downregulation of PDGFRHongbing 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... - A hypomorphic allele of Tsc2 highlights the role of TSC1/TSC2 in signaling to AKT and models mild human TSC2 allelesKristen 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... - Interferon-gamma-Jak-Stat signaling in pulmonary lymphangioleiomyomatosis and renal angiomyolipoma: a potential therapeutic targetNisreen 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... - TOLL-like receptor 10 genetic variation is associated with asthma in two independent samplesRoss 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... - 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 functionLynsey 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... - Family-based association analysis of beta2-adrenergic receptor polymorphisms in the childhood asthma management programEdwin 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... - Equivalent benefit of mTORC1 blockade and combined PI3K-mTOR blockade in a mouse model of tuberous sclerosisKristen 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... - Attempted replication of reported chronic obstructive pulmonary disease candidate gene associationsCraig 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... - Magnetic resonance imaging and characterization of spontaneous lesions in a transgenic mouse model of tuberous sclerosis as a model for endothelial cell-based transgene deliveryAlice B Brown
Brain Tumor Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
Hum Gene Ther 16:1367-76. 2005.... - Tuberous sclerosis complex-1 and -2 gene products function together to inhibit mammalian target of rapamycin (mTOR)-mediated downstream signalingAndrew R Tee
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA
Proc Natl Acad Sci U S A 99:13571-6. 2002.... - mTORC1-dependent and -independent regulation of stem cell renewal, differentiation, and mobilizationBoyi 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... - LKB1 modulates lung cancer differentiation and metastasisHongbin 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... - SNP identification, haplotype analysis, and parental origin of mutations in TSC2Penelope 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... - 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 activityGeraldine 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... - A mouse model of tuberous sclerosis: neuronal loss of Tsc1 causes dysplastic and ectopic neurons, reduced myelination, seizure activity, and limited survivalLynsey 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... - A mouse model of cardiac rhabdomyoma generated by loss of Tsc1 in ventricular myocytesLynsey Meikle
Department of Medicine, Brigham and Women s Hospital and Harvard Medical School, Boston, MA 02115, USA
Hum Mol Genet 14:429-35. 2005.... - Association between a high-expressing interferon-gamma allele and a lower frequency of kidney angiomyolipomas in TSC2 patientsSandra 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... - 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 studiesRoss 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... 
Clinical activity of mTOR inhibition with sirolimus in malignant perivascular epithelioid cell tumors: targeting the pathogenic activation of mTORC1 in tumorsAndrew 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...- 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 replicationDaniel 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.... - Genomewide linkage analysis of quantitative spirometric phenotypes in severe early-onset chronic obstructive pulmonary diseaseEdwin 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... - Single nucleotide polymorphisms in innate immunity genes: abundant variation and potential role in complex human diseaseRoss 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... - Polymorphisms in toll-like receptor 4 are not associated with asthma or atopy-related phenotypesBenjamin 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... - Mechanisms of gelsolin-dependent and -independent EGF-stimulated cell motility in a human lung epithelial cell lineAlan 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.... - Single-nucleotide polymorphisms in the interleukin-10 gene: differences in frequencies, linkage disequilibrium patterns, and haplotypes in three United States ethnic groupsRoss 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... - Tuberous sclerosis complex proteins control axon formationYong 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.... - Regulation of neuronal morphology and function by the tumor suppressors Tsc1 and Tsc2Sohail 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... - Feedback inhibition of Akt signaling limits the growth of tumors lacking Tsc2Brendan 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... - ADAM33 polymorphisms and phenotype associations in childhood asthmaBenjamin 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... - Estrogen enhances whereas tamoxifen retards development of Tsc mouse liver hemangioma: a tumor related to renal angiomyolipoma and pulmonary lymphangioleiomyomatosisNisreen El-Hashemite
Hematology Division, Department of Medicine, Brigham and Women s Hospital, Boston, MA 02115, USA
Cancer Res 65:2474-81. 2005.... - Ultra deep sequencing detects a low rate of mosaic mutations in tuberous sclerosis complexWei 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... - FoxOs enforce a progression checkpoint to constrain mTORC1-activated renal tumorigenesisBoyi Gan
Belfer Institute for Applied Cancer Science, Boston, MA 02115, USA
Cancer Cell 18:472-84. 2010.... - Genome-wide linkage analysis of severe, early-onset chronic obstructive pulmonary disease: airflow obstruction and chronic bronchitis phenotypesEdwin 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... - 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... - Loss of Tsc1 or Tsc2 induces vascular endothelial growth factor production through mammalian target of rapamycinNisreen 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... - Identification of a transcriptional profile associated with in vitro invasion in non-small cell lung cancer cell linesAlan 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... - Chromosome 12q harbors multiple genetic loci related to asthma and asthma-related phenotypesBenjamin 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... - mTORC1-S6K activation by endotoxin contributes to cytokine up-regulation and early lethality in animalsPo 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... - Infantile spasms and intellectual outcomes in children with tuberous sclerosis complexSuzanne Goh
Massachusetts General Hospital, 175 Cambridge Street, Suite 340, Boston, MA 02114-3117, USA
Neurology 65:235-8. 2005..The risk of mental retardation increases significantly with prolonged duration of IS, prolonged time from treatment initiation until the cessation of IS, and poor control of subsequent seizures after IS... - Are variants in the CAPN10 gene related to risk of type 2 diabetes? A quantitative assessment of population and family-based association studiesYiqing 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... - Identification of 54 large deletions/duplications in TSC1 and TSC2 using MLPA, and genotype-phenotype correlationsPiotr 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... - Utilization of a whole genome SNP panel for efficient genetic mapping in the mouseJennifer 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... - Lack of association between genetic variation in 9 innate immunity genes and baseline CRP levelsPiotr Kozlowski
Division of Hematology, Brigham and Women s Hospital, Boston, MA 02115, USA
Ann Hum Genet 70:574-86. 2006.... - Estrogen-induced smooth muscle cell growth is regulated by tuberin and associated with altered activation of platelet-derived growth factor receptor-beta and ERK-1/2Geraldine 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... - Rac1 deletion in mouse neutrophils has selective effects on neutrophil functionsMichael 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... - Regulation of endothelial nitric oxide synthase and postnatal angiogenesis by Rac1Naoki 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... - Tuberous sclerosis complex activity is required to control neuronal stress responses in an mTOR-dependent mannerAlessia 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... - 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/tuberinGeraldine 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... - Robust method for distinguishing heterozygous from homozygous transgenic alleles by multiplex ligation-dependent probe assayPiotr Kozlowski
Harvard Medical School, Boston, MA, USA
Biotechniques 42:584, 586, 588. 2007 - Rac1-null mouse embryonic fibroblasts are motile and respond to platelet-derived growth factorLuis 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... - 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 StudyJacqueline 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... - A 34 bp deletion within TSC2 is a rare polymorphism, not a pathogenic mutationPenelope 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... - Atherosclerosis: the path from genomics to therapeuticsDavid 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... - IL10 gene polymorphisms are associated with asthma phenotypes in childrenHelen 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... - Loci related to metabolic-syndrome pathways including LEPR,HNF1A, IL6R, and GCKR associate with plasma C-reactive protein: the Women's Genome Health StudyPaul 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.... - Astrocyte-specific TSC1 conditional knockout mice exhibit abnormal neuronal organization and seizuresErik 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... - Gelsolin mediates collagen phagocytosis through a rac-dependent stepPamela 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.... - Hematopoietic cell regulation by Rac1 and Rac2 guanosine triphosphatasesYi 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... - Rapid turnover of actin in dendritic spines and its regulation by activityErin 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... - Molecular pathogenesis of lymphangioleiomyomatosis: lessons learned from orphansStephen 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... - Neuronal gelsolin prevents apoptosis by enhancing actin depolymerizationChristoph 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... - Unusually mild tuberous sclerosis phenotype is associated with TSC2 R905Q mutationAn C Jansen
Neurogenetics Unit, Montreal Neurological Hospital and Institute, McGill University, Montreal, Quebec, Canada
Ann Neurol 60:528-39. 2006..These findings have implications for the large number of patients with limited clinical features of TSC and for genetic counseling in these families... - PDGFRs are critical for PI3K/Akt activation and negatively regulated by mTORHongbing 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... - Reversal of learning deficits in a Tsc2+/- mouse model of tuberous sclerosisDan 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.... - mTOR-raptor binds and activates SGK1 to regulate p27 phosphorylationFeng 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... - An efficient and versatile system for acute and chronic modulation of renal tubular function in transgenic miceMilena 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... - Pulmonary cysts consistent with lymphangioleiomyomatosis are common in women with tuberous sclerosis: genetic and radiographic analysisFrancis McCormack
Department of Pediatrics, Division of Pulmonary and Critical Care Medicine, University of Cincinnati, Cincinnati, OH 45267-0564, USA
Chest 121:61S. 2002
Research Grants
- GENOTYPING CENTER FOR INNATE IMMUNITY PGADavid Kwiatkowski; Fiscal Year: 2004..abstract_text> ..
- GELSOLIN: ROLES IN APOPTOSIS AND TUMOR DEVELOPMENTDavid 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. ..
- Preclinical Studies of Rapamycin for TSC Brain DiseaseDavid 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. ..
- Tuberous Sclerosis: Mutations and Murine ModelsDavid 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. ..
- Molecular Pathogenesis of the Hamartoma SyndromesDavid Kwiatkowski; Fiscal Year: 2007....
- Tuberous Sclerosis: Mutations and Murine ModelsDavid Kwiatkowski; Fiscal Year: 2007..This model will permit analysis of genetic and signaling events occurring during renal cyst pathogenesis. ..
- TUBEROUS SCLEROSIS--MUTATIONS AND MURINE MODELSDavid Kwiatkowski; Fiscal Year: 2001....
- MURINE MODELS OF TSC 1: MECHANISMS AND THERAPIESDavid Kwiatkowski; Fiscal Year: 2001....