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Novel Endothelial and Immunologic Mechanisms of Pathophysiology in Sickle Cell Disease

镰状细胞病病理生理学的新内皮和免疫机制

基本信息

批准号：
10226331
负责人：
Patrick Axel Molina
金额：
$ 4.71万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10226331
关键词：
Adaptive Immune System Adoptive Transfer Affect Age Amino Acids Animals Anti-Inflammatory Agents Basic Science CD4 Positive T Lymphocytes CXCR3 gene Cells Cessation of life Chronic Chronic Kidney Failure Clinic Complex Complication Data Development Diagnosis Disease Disease Progression Duct (organ) structure Endothelial Cells Endothelin A Receptor Endothelin B Receptor Endothelin Receptor Endothelin-1 Endothelium Erythrocytes Fellowship Frequencies Functional disorder Future Genes Goals Helper-Inducer T-Lymphocyte Hematological Disease Histologic Immune Immune System Diseases Immunologics In Vitro Individual Infiltration Inflammation Inflammation Mediators Inflammatory Inherited Injury to Kidney Interleukin-17 Kidney Kidney Concentrating Ability Kidney Diseases Knock-out Knockout Mice Knowledge Longevity Lymphokines Mediating Modeling Mus Neuroglia Organ Parents Pathologic Pathology Pathway interactions Patient-Focused Outcomes Patients Peptides Play Population Receptor Activation Reporter Reporting Role Scientist Sickle Cell Sickle Cell Anemia Signal Transduction Source Stress Structure T-Cell Activation T-Lymphocyte Testing Th1 Cells Therapeutic Tissues Training Translational Research Vasoconstrictor Agents Vasodilation Work acute stress aged beta Globin cell type clinically relevant cytokine experimental study hemoglobin AA humanized mouse immune function improved outcome inflammatory marker innovation kidney dysfunction macrophage mouse model mutant novel receptor translational approach vaso-occlusive crisis

项目摘要

Project Summary Sickle cell disease was first identified in the US in 1910 and the first treatment was not proposed until the 1980’s. It is the first identified single gene causative disease and is the most common inherited blood disorder in the US. It presents when individuals inherit two mutant beta globin genes, one from each parent. Kidney disease is found in a large number of patients with sickle cell disease (sickle cell nephropathy) and can progress to death rapidly. Elevated levels of the peptide endothelin 1 and dysregulated immune function have been shown to play a major role in the development of sickle cell nephropathy, However, the cell source for the peptide and immune cell type by which this occurs is poorly misunderstood. The central hypothesis of the proposed studies is that, within the kidney, sickle cell disease promotes endothelial-specific endothelin 1 expression and TH17-mediated damage, leading to renal injury, dysfunction and overall nephropathy. To study the contribution of endothelial-derived endothelin 1, we successfully developed an endothelial-specific endothelin 1 knockout mouse model on the Townes humanized sickle cell mouse background. These animals will be studied rigorously in order to evaluate markers of renal injury and dysfunction, and will undergo studies to determine pathophysiological hallmarks of disease progression. To determine the innovative role of TH17 cells in sickle cell nephropathy, humanized mice will undergo flow cytometric and histopathologic analysis to determine temporal relationship between disease progression and immune cell infiltration. Furthermore, using established adoptive transfer experiments, SCD mice will have in vitro polarized TH17 cells from TH17 reporter mice transferred into them at a young age to evaluate the contribution long-term to sickle cell nephropathy. Finally, we will also evaluate whether endothelial- derived endothelin 1 has a role in the recent observation that SCD mice have elevated intrarenal TH17 cells. These two innovative approaches will seek to provide novel pathways by which to better target sickle cell nephropathy and ultimately improve outcomes for patients with sickle cell disease.

项目总结