Pathophysiology of FSGS

FSGS 的病理生理学

基本信息

批准号：
10523107
负责人：
STUART E DRYER
金额：
$ 34.1万
依托单位：
UNIVERSITY OF HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-12-15 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10523107
关键词：
APOL1 gene Adipocytes Affect Albuminuria Alzheimer&apos s disease patient Angiotensin II Animal Model Autoimmune Automobile Driving Biological Availability CRISPR/Cas technology Calcium-Activated Potassium Channel Cell surface Cells Chronic Chronic Kidney Failure Circulation Clinical Complex Coupled Data Disease Progression Disease model Exhibits Exposure to Focal and Segmental Glomerulosclerosis Functional disorder Funding Glomerulonephritis Human Image Inflammatory Integrin alphaVbeta3 Ion Channel Kidney Diseases Kidney Failure Knock-out Knowledge Literature Mediating Modeling Molecular Monovalent Cations Mus NPHS2 protein Nephrosis Normal Cell Oral Oxidative Stress Pathogenicity Pathologic Pathway interactions Patients Permeability Pharmaceutical Preparations Phase II/III Clinical Trial Plasma Prognostic Marker Property Proteins Puromycin Aminonucleoside Rattus Reactive Oxygen Species Receptor Signaling Recurrence Refractory Renal function Renal glomerular disease Research Role SRC gene Sampling Serum Signal Pathway Signal Transduction System TNF gene Testing Time Urokinase Plasminogen Activator Receptor Variant Virulence Factors antagonist autosome biophysical properties cell type density driving force drug discovery gain of function mutation glomerulosclerosis kidney fibrosis mouse model nephrin novel overexpression patient subsets podocyte preservation programs receptor receptor for advanced glycation endproducts response slit diaphragm small molecule therapeutic target virtual

项目摘要

PROJECT SUMMARY Canonical transient receptor potential-6 (TRPC6) channels drive certain familial forms of focal and segmental glomerulosclerosis (FSGS) and there is evidence that they contribute to much more common acquired forms of FSGS and to renal fibrosis. TRPC6 dysregulation in podocytes occurs in animal models of FSGS, and in podocytes exposed to serum or plasma from patients with recurrent FSGS, or in cells treated with the soluble urokinase receptor (suPAR). While it is known that TRPC6 activation is required for Ca2+ influx driven by e.g. angiotensin II, the Ca2+-permeability of TRPC6 is quite limited, and there are many conditions in which TRPC6 functions primarily as a monovalent cation channel. This fundamental property of TRPC6 suggests that while it is necessary, it may not be sufficient to drive Ca2+ overload in podocytes or other cells. Specific Aim 1 of this proposal tests the hypothesis that TRPC6 is part of a multichannel complex that includes KCa1.1 channels, and that coordinated KCa1.1 activation is necessary for TRPC6 to drive significant Ca2+ influx into podocytes. KCa1.1 is a Ca2+-activated K+ channel that interacts with TRPC6 and other slit diaphragm proteins including nephrin, Neph1, and podocin. Preliminary data show that KCa1.1 activation in podocytes is coupled to TRPC6, and that KCa1.1 is dysregulated in an animal model of FSGS and in response to recurrent FSGS plasma samples or suPAR. Specific Aim 1 will characterize changes in KCa1.1 gating and current density in glomerular disease models previously shown to alter TRPC6. Quantitative Ca2+ imaging will address if KCa1.1 or its auxiliary β- and γ-subunits facilitate TRPC6-dependent Ca2+ influx into podocytes, which drives normal cell signaling as well as pathological Ca2+ overload. There is now extensive evidence that suPAR contributes to progression of multiple kidney diseases, including some cases of primary FSGS, but the mechanisms of its signaling pathways are not well understood. Preliminary data show that the receptor for advanced glycation endproducts (RAGE) functions as an essential co-receptor for suPAR on the pathway leading to Rac1, oxidative stress, c-Src, and dysregulation of podocyte TRPC6. Specific Aim 2 will examine the role of RAGE in driving albuminuria and glomerulosclerosis in a mouse model (suPAR2-Tg) that overexpresses a suPAR variant in adipocytes and secretes it into the circulation. These mice exhibit albuminuria that later progresses to glomerulosclerosis in a manner similar to human FSGS. In Specific Aim 2 we will cross suPAR2-Tg mice with mice homozygous for an inducible knockout of RAGE. We will induce RAGE knockout both prior to and after the onset of albuminuria. We will also determine if two different small molecule RAGE antagonists reduce albuminuria and glomerulosclerosis in suPAR2-Tg mice. One of these antagonists, azeliragon, is orally bioavailable in mice and humans, and is currently undergoing a Phase 2/3 clinical trial in a subset of patients with Alzheimer's disease. Therefore, a positive result in Specific Aim 2 could have considerable translational significance for primary and recurrent FSGS, which in many patients is refractory to current treatments.

项目摘要规范瞬态接收器电位-6（TRPC6）通道驱动某些家庭形式的焦点和分段肾小球硬化症（FSGS），有证据表明它们有助于更常见的获得形式 FSG和肾纤维化。足细胞中的TRPC6失调发生在FSG的动物模型中，在暴露于复发性FSG患者或用可溶性治疗的细胞中的血清或血浆的足细胞尿激酶受体（SUPAR）。众所周知，Ca2+的影响是由例如血管紧张素II，TRPC6的Ca2+渗透性非常有限，并且在许多条件下TRPC6 功能主要作为单价阳离子通道。 TRPC6的这种基本属性表明，这是必要的，在足细胞或其他单元格中驱动Ca2+过载可能不足以驱动Ca2+过载。具体目标1 该提案检验了TRPC6是包括KCA1.1的多通道复合物的一部分的假设。频道，并且TRPC6将显着的Ca2+影响驱动到足细胞。 KCA1.1是Ca2+活化的K+通道，与TRPC6和其他缝隙diaphragm蛋白相互作用包括肾素，NEPH1和Podocin。初步数据表明，kca1.1在足细胞中的激活是耦合的到TRPC6，并且在FSG的动物模型中，KCA1.1在反复发作的FSG中失调血浆样品或supar。特定的目标1将表征KCA1.1门控和电流密度的变化肾小球疾病模型先前证明会改变TRPC6。定量Ca2+成像是否可以解决KCA1.1 或其辅助β-和γ-亚基促进trpc6依赖性Ca2+影响到足细胞，这使得驱动正常细胞信号传导以及病理CA2+过载。现在有大量证据表明Supar贡献多种肾脏疾病的进展，包括某些原发性FSG的情况，但是它的信号通路尚不清楚。初步数据显示高级糖基的接收器最终产物（RAGE）在通往Rac1的途径上充当SUPAR的必不可少的共受体。 Podocyte TRPC6的氧化应激，C-SRC和失调。具体目标2将检查愤怒的作用在驱动蛋白尿和肾小球硬化中的小鼠模型（SUPAR2-TG）中，它过表达了supar 脂肪细胞的变体并将其分泌到循环中。这些小鼠暴露了蛋白尿，后来进展以类似于人类FSG的方式进行肾小球硬化。在特定目标2中，我们将跨越supar2-TG小鼠小鼠纯合子诱发了愤怒的敲除。我们将在之前引起愤怒的淘汰蛋白尿发作后。我们还将确定两个不同的小分子愤怒拮抗剂是否减少 Supar2-TG小鼠中的蛋白尿和肾小球硬化。这些拮抗剂之一，阿塞拉贡（Azeliragon），是口头的在小鼠和人类中可生物利用，目前正在一部分患者中进行2/3期临床试验患阿尔茨海默氏病。因此，特定目标2的积极结果可以考虑转化对原发性和复发性FSG的显着性，在许多患者中，这对当前治疗是难治性的。