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

• 批准号: 10059141
• 负责人: Patrick Axel Molina
• 金额: $ 3.88万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 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/10059141
• 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

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.

项目摘要 直到1980年代才提出镰状细胞疾病在teast治疗中首次进行。 这是美国第一个鉴定出的单个基因致病性疾病，也是美国最常见的遗传性血液疾病。 它表现出个人，即个人继承了两个突变的β球蛋白基因，每种肾脏疾病。 在大量患有镰状细胞疾病（镰状细胞肾病）的患者中，可以迅速死亡。 肽内皮素1的水平升高和免疫功能失调的功能是发挥作用 然而，在镰状细胞肾病的发育中的作用，是肽和免疫细胞类型的细胞来源 通过这种误解的操作系统的核心假设是在你内部 肾脏，镰状细胞疾病促进内皮特异性内皮素1表达和Th17介导的损伤， 导致肾脏损伤，功能障碍和整体肾病。 内皮素1，我们成功地开发了一个特异性的内皮素1基因敲除鼠标模型 城镇人性化的小鼠小鼠背景将被严格研究 肾脏损伤和功能障碍的标志物，并将接受研究以确定病理生理标志 疾病进展。 将进行流式细胞仪和组织病理学分析，以确定疾病之间的暂时性 进展和免疫细胞浸润。 小鼠将在年龄转移到ATO中的17个记者小鼠的体外极化Th17细胞。 长期评估镰状细胞肾病的贡献。 衍生的内皮素1在最近的观察结果中，即SCD小鼠具有甲状腺丙烯型Th17细胞。 这两种创新的方法将寻求提供新的途径，以更好地靶向镰状细胞 肾病，并最终改善镰状细胞病患者的预后。