Scleroderma Renal Crisis as a Genetic Complementopathy

硬皮病肾危象是一种遗传性互补病

• 批准号: 10159866
• 负责人: John Atkinson
• 金额: $ 16.83万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-06 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10159866
• 关键词: Affect; African American; Age; Alternative Complement Pathway; Angiotensin-Converting Enzyme Inhibitors; Antibodies; Autoantibodies; Biochemical; Biological Assay; Blood Vessels; Caucasians; Clinical; Coagulation Process; Complement; Complement Activation; Complement Inactivators; Complication; Connective Tissue; Cutaneous; DNA; Data; Dependence; Deposition; Detection; Development; Dialysis procedure; Diffuse; Disease; Early Intervention; Endothelial Cells; Endothelium; FDA approved; Feedback; Fibrin; Fibrosis; Funding; Genes; Genetic; Genetic Risk; Genetic Variation; Genome; Glucocorticoids; Hemolysis; Hemolytic-Uremic Syndrome; Hypertension; Individual; Infection; International; Kidney; Kidney Diseases; Kidney Failure; Kidney Transplantation; Laboratories; Lead; Link; Logistic Regressions; Methods; Monoclonal Antibodies; Morbidity - disease rate; Morphology; Organ; Outcome; Pathogenesis; Pathology; Pathway interactions; Patients; Phenotype; Population; Process; RNA Polymerase III; Race; Rare Diseases; Regulation; Renal dialysis; Research; Risk; Risk Factors; Role; SNP genotyping; Sampling; Scleroderma; Skin; Surveys; Systemic Scleroderma; Testing; Thrombocytopenia; Tissues; Triad Acrylic Resin; United States National Institutes of Health; Variant; Work; arteriole; cell injury; clinically relevant; cohort; complement C5b; complement pathway; complement system; effective therapy; exome sequencing; fighting; gain of function; genetic predictors; genetic variant; grasp; improved; innovation; kidney biopsy; loss of function; mortality; novel; novel therapeutics; predictive test; prevent; prospective; rare variant; renal damage; risk variant; thrombotic; variant of unknown significance

Abstract Systemic sclerosis (SSc), also called scleroderma, is a rare disease characterized by fibrosis of connective tissues. Some patients with SSc develop a complication called scleroderma renal crisis (SRC), which is characterized by sudden onset of new high blood pressure and evidence of kidney damage. Though patients can be treated with ACE inhibitors, there is still a high morbidity. Many individuals require kidney transplant or dialysis. The pathology of SRC is strikingly similar to a different set of sudden onset kidney diseases called thrombomicroangiopathies, or TMAs. TMAs often have an identified genetic cause, primarily by excessive activation of the complement cascade. Complement activity is an enzymatic cascade that is used to fight infections and dispose of cellular/tissue debris. In individuals with TMAs the complement system activates inappropriately and damages the kidney. Because of the similarity to these two conditions, we propose that SRC may actually be caused in some people by complement activation due to the presence of rare genetic variants. We will identify rare variants associated with altered complement function in both Caucasians (Aim 1) and African-Americans (Aim 2) that have scleroderma and either did or did not develop SRC. By comparing only individuals with scleroderma to each other, we will increase our chances of finding genetic risk variants for SRC only. In Aim 3, we will perform immunohistochemistory on SRC kidney biopsies to identify complement deposition. Ultimately, if our hypothesis proves correct, it will open the door for the development of novel clinical tests to identify individuals with scleroderma at risk of renal crisis, and we would also be able to try new therapeutics that block excessive activation of complement.

摘要 系统性硬化症（SSc），也称为硬皮病，是一种罕见的疾病，其特征是结缔组织纤维化， 组织中一些SSc患者会出现一种称为硬皮病肾危象（SRC）的并发症， 其特征在于新的高血压的突然发作和肾损伤的证据。虽然患者 可以用ACE抑制剂治疗，但仍有较高的发病率。许多人需要肾移植或 透析SRC的病理学与另一组突发性肾脏疾病惊人地相似， 血栓微血管病或TMA。tma通常有一个确定的遗传原因，主要是过度的 补体级联的激活。补体活性是一种酶级联反应， 感染和处理细胞/组织碎片。在患有TMA的个体中， 不适当地和损害肾脏。由于这两个条件的相似性，我们建议， SRC实际上可能是由补体激活引起的，因为存在罕见的遗传因子。 变体。我们将在两个高加索人中鉴定与补体功能改变相关的罕见变异（目的1） 以及患有硬皮病并且发生或未发生SRC的非洲裔美国人（Aim 2）。通过比较 只有患有硬皮病的个体彼此，我们将增加我们发现遗传风险变异的机会， 仅限SRC。在目标3中，我们将对SRC肾活检进行免疫组化，以确定补体 证词最终，如果我们的假设被证明是正确的，它将为小说的发展打开大门 临床试验，以确定个人与硬皮病的风险，肾危机，我们也将能够尝试新的 阻断补体过度活化的治疗剂。