This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Primary immunodeficiency diseases are unique human models to study the molecular events that ultimately lead to an efficient immune response. With the support of this grant, our group has participated in the identification of genes involved in X-linked immunodeficiency diseases and in the functional analysis of the products of these genes. The understanding of the molecular basis for immune disorders has contributed greatly to the concept of receptor-ligand interaction, and the principles of lymphocyte activation, differentiation, signal transduction and immunoglobulin isotype switching.
Three specific aims will be addressed. (1) Elucidation of the gene responsible for the Wiskott-Aldrich syndrome (WAS) and its product, the WAS protein. We have been part of a team that recently isolated the gene mutated in patients with WAS, a disorder in which most hematopoietic cell lineages are affected. Our collection of B and T cell lines derived from members of over 50 affected families will permit a representative mutation analysis of WAS and will answer the question of whether a correlation exists between clinical phenotype and type of mutation. Based on the amino acid composition derived from the known cDNA sequence, we have outlined strategies to analyze the nature of the WAS protein. We will focus on WAS gene expression and its control, its distribution within the cell, the physical and functional properties of the WAS protein, will identify other proteins that interact with WASP. (2) Explore the role of defective transcriptional activation of T cells in patients with common variable immunodeficiency (CVI). We have identified a subgroup of CVI patients who have in common a broad defect of T cell activation, suggesting that the transcription of multiple lymphokines and membrane bound activation molecules may be abnormal. Using gelshift assays, we will determine if the defect is due to abnormal binding of NF-AT or other nuclear factors related to the IL-2 gene. If decreased binding is demonstrated, we will search for defective production of proteins of the NF-AT complex and analyze its distribution in the cytoplasm and in the nuclear fraction, and its phosphorylation state. (3) Explore the feasibility of gene therapy for patients with X-linked immunodeficiencies. We have initiated collaboration with several investigators involved in the design of viral vectors that efficiently transfer the candidate genes into target cells, e.g., T and B cell lines or stem cells derived from patients.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
General Clinical Research Centers Program (M01)
Project #
5M01RR000037-46
Application #
7379391
Study Section
National Center for Research Resources Initial Review Group (RIRG)
Project Start
2006-04-01
Project End
2007-03-31
Budget Start
2006-04-01
Budget End
2007-03-31
Support Year
46
Fiscal Year
2006
Total Cost
$5,788
Indirect Cost
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Courcoulas, Anita P; King, Wendy C; Belle, Steven H et al. (2018) Seven-Year Weight Trajectories and Health Outcomes in the Longitudinal Assessment of Bariatric Surgery (LABS) Study. JAMA Surg 153:427-434
Field, Alison E; Inge, Thomas H; Belle, Steven H et al. (2018) Association of Obesity Subtypes in the Longitudinal Assessment of Bariatric Surgery Study and 3-Year Postoperative Weight Change. Obesity (Silver Spring) 26:1931-1937
O'Rourke, Robert W; Johnson, Geoffrey S; Purnell, Jonathan Q et al. (2018) Serum biomarkers of inflammation and adiposity in the LABS cohort: associations with metabolic disease and surgical outcomes. Int J Obes (Lond) :
Cherrier, M M; Cross, D J; Higano, C S et al. (2018) Changes in cerebral metabolic activity in men undergoing androgen deprivation therapy for non-metastatic prostate cancer. Prostate Cancer Prostatic Dis 21:394-402
Duggan, Catherine; Baumgartner, Richard N; Baumgartner, Kathy B et al. (2018) Genetic variation in TNF?, PPAR?, and IRS-1 genes, and their association with breast-cancer survival in the HEAL cohort. Breast Cancer Res Treat 168:567-576
Han, Seung Jin; Boyko, Edward J; Kim, Soo Kyung et al. (2018) Association of Thigh Muscle Mass with Insulin Resistance and Incident Type 2 Diabetes Mellitus in Japanese Americans. Diabetes Metab J 42:488-495
Wander, Pandora L; Hayashi, Tomoshige; Sato, Kyoko Kogawa et al. (2018) Design and validation of a novel estimator of visceral adipose tissue area and comparison to existing adiposity surrogates. J Diabetes Complications 32:1062-1067
Purnell, Jonathan Q; Johnson, Geoffrey S; Wahed, Abdus S et al. (2018) Prospective evaluation of insulin and incretin dynamics in obese adults with and without diabetes for 2 years after Roux-en-Y gastric bypass. Diabetologia 61:1142-1154
King, Wendy C; Hinerman, Amanda S; Belle, Steven H et al. (2018) Comparison of the Performance of Common Measures of Weight Regain After Bariatric Surgery for Association With Clinical Outcomes. JAMA 320:1560-1569
Han, Seung Jin; Fujimoto, Wilfred Y; Kahn, Steven E et al. (2018) Change in visceral adiposity is an independent predictor of future arterial pulse pressure. J Hypertens 36:299-305

Showing the most recent 10 out of 563 publications