The Role of Interleukin-15 Receptor-alpha Variants in the Pathogenesis of FSGS

摘要 局灶节段性肾小球硬化症（FSGS）是一种临床病理诊断， 难治性肾病综合征（NS），肾小球毛细血管簇的局灶性瘢痕形成和快速进展至终末期 阶段性肾病（ESKD）。在过去的三年里，FSGS的发病率增加了10倍以上。 几十年来，这种疾病在非洲裔美国人（AA）人群中非常普遍。的确， 尽管仅占一般人群的13%，但仍有40%的ESKD病例是由FSGS引起的。 FSGS是目前引起ESKD最常见的原发性肾小球疾病。的特性特征 疾病是肾小球足细胞数量减少。因此，足细胞被认为是起着关键作用， FSGS的发病机制。 对FSGS家族形式的研究为疾病过程提供了关键的见解。这些研究 已经鉴定了30多个基因的突变，这些基因在肾小球足细胞中富集。这些基因的突变 尽管AA人群进展为ESKD的风险较高，但在AA中罕见。本实验室 收集了30多个具有常染色体显性FSGS的AA激酶。利用这一独特的资源，我发现了一个 白细胞介素-15受体-α（IL-15 R α K47 R）中罕见的杂合错义变体是唯一一种 在常染色体显性FSGS的AA家系中与疾病分离。该变量发生在 受体的高亲和力“sushi”配体结合结构域，并被预测为通过SIFT和 polyphen分析为了支持突变的破坏作用，我们发现IL-15 R α K47 R点 突变损害IL-15诱导的促存活信号传导。根据这些初步数据，我假设 IL-15 R α K47 R是一种亚型、功能丧失的变体，可促进受损的促生存信号传导，导致 足细胞凋亡为了研究这一假设，提出了3个具体目标： 1.确定IL-15 R α K47 R变体对足细胞促存活信号传导的影响 2.表征IL-15 R α缺陷小鼠的肾脏表型，以及 3.确定我们的FSGS AA患者队列中IL-15 R α罕见变异的患病率。 拟议的实验将产生深入了解FSGS的分子发病机制，并可能揭示 新的治疗靶点。 在这个奖项的任期内，我希望在人类肾小球疾病小鼠模型方面发展新的技能 并生成提交独立调查员奖所需的数据， FSGS的分子发病机制。我的导师罗伯特·斯伯尼博士是这一领域的领导者 细胞生物学和整体动物模型，并有丰富的经验，作为一个研究导师。而且我 导师团队，我在生物化学和肾脏病学方面的经验，以及杜克独特的培训环境 大学使我能够实现本提案中概述的科学目标。

ABSTRACT Focal segmental glomerulosclerosis (FSGS) is a clinical-pathologic diagnosis characterized by steroid resistant nephrotic syndrome (NS), focal scarring of the glomerular capillary tuft and rapid progression to end stage kidney disease (ESKD). The incidence of FSGS has increased more than 10-fold over the past three decades and the disease is highly prevalent in the African Americans (AA) population. Indeed, AAs account for 40% of all cases of ESKD due to FSGS despite comprising only 13% of the general population. FSGS is now the most common primary glomerular disorder causing ESKD. A characteristic feature of the disease is a reduced number of glomerular podocytes. As a result, podocytes are thought to play a pivotal role in the pathogenesis of FSGS. The study of familial forms of FSGS has provided key insights into the disease process. These studies have identified mutations in over 30 genes that are enriched in glomerular podocytes. Mutations in these genes are rare in AAs despite the high risk for progression to ESKD in the AA population. Our laboratory has collected over 30 AA kindreds with autosomal dominant FSGS. Using this unique resource, I have identified a rare heterozygous missense variant in the interleukin-15 receptor-α (IL-15RαK47R) as the only variant that segregates with the disease in an AA kindred with autosomal dominant FSGS. The variant occurs within the high-affinity “sushi” ligand binding domain of the receptor and is predicted to be damaging by SIFT and polyphen analyses. In support of a damaging effect of the mutation, we found that the IL-15RαK47R point mutation impairs IL-15-induced prosuvival signaling. Based on these preliminary data, I hypothesize that the IL-15RαK47R is a hypomorphic, loss-of-function variant that promotes impaired prosurvival signaling, resulting in podocyte apoptosis. To investigate this hypothesis, 3 specific aims are proposed: 1. Determine the effect of the IL-15Rα K47R variant on podocyte pro-survival signaling 2. Characterize the renal phenotype of the IL-15Rα-deficient mouse, and 3. Determine the prevalence of rare variants in IL-15Rα in our cohort of AA patients with FSGS. The proposed experiments will generate insights into the molecular pathogenesis of FSGS and may uncover novel therapeutic targets. Over the term of this award, I hope to develop new skills in human glomerular disease modeling in mice and to generate the data necessary for submission of an independent investigator award focused on defining the molecular pathogenesis of FSGS. My mentor for this proposal, Dr. Robert Spurney, is a leader in the field of cell biology and whole animal modeling and has extensive experience as a research mentor. Moreover, my mentor team, my experience in biochemistry and Nephrology, and the unique training environment of Duke University uniquely positions me to achieve the scientific objectives outlined in this proposal.