Scleroderma Renal Crisis as a Genetic Complementopathy

硬皮病肾危象是一种遗传性互补病

基本信息

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
项目类别：
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

项目摘要

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.

抽象的系统性硬化症（SSC），也称为硬皮病，是一种罕见疾病，其特征是结缔组织纤维化组织。一些SSC患者出现一种称为硬皮病肾脏危机（SRC）的并发症，这是其特征是突然发作新的高血压和肾脏损伤的证据。虽然病人可以用ACE抑制剂治疗，仍然存在高发病率。许多人需要肾脏移植或透析。 SRC的病理与不同的突然发作肾脏疾病非常相似血小板性血管疾病或TMA。 TMA通常具有确定的遗传原因，主要是通过过量补体级联激活。补体活动是用于战斗的酶促级联感染和处置细胞/组织碎屑。在具有TMA的个体中，补体系统激活不适当地损坏肾脏。由于与这两个条件的相似性，我们建议由于存在稀有遗传变体。我们将确定两种高加索人中与补体功能改变相关的稀有变体（AIM 1）和具有硬皮病的非裔美国人（AIM 2），或者没有发展或不发展SRC。通过比较只有彼此硬皮病的人，我们将增加寻找遗传风险变异的机会仅SRC。在AIM 3中，我们将对SRC肾脏活检进行免疫组织化学，以识别补充沉积。最终，如果我们的假设被证明是正确的，它将为发展的发展打开大门临床测试以识别患有肾脏危机风险的硬皮病患者，我们也可以尝试新的阻止过度激活补体的治疗剂。