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ApoL1 and its kidney disease associated variants: ion permease activity, molecular structure, and podocyte injury.

ApoL1 及其肾脏疾病相关变异：离子通透酶活性、分子结构和足细胞损伤。

基本信息

批准号：
10371206
负责人：
JOHN C EDWARDS
金额：
$ 37.28万
依托单位：
SAINT LOUIS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10371206
关键词：
APOL1 gene Actins Acute Affect African African American population African Trypanosomiasis African ancestry Anions Biochemical Cations Cell Shape Cell membrane Cells Chronic Kidney Failure Cytoskeletal Modeling Cytoskeleton Data Diphtheria Toxin Disease Disease Progression Endocytosis Endosomes General Population Genes Health Human In Situ Injury Intervention Ion Channel Ions Kidney Diseases Lead Membrane Microfilaments Modeling Molecular Structure Mutation Parasites Pathogenesis Pathogenicity Pathway interactions Permeability Persons Play Pongidae Population Proteins Public Health Recombinants Renal glomerular disease Resistance Resistance to infection Risk Role Serum Serum Proteins Sorting - Cell Movement Testing Toxic effect Trypanosoma United States Vacuole Variant Vesicle autocrine base burden of illness cell motility cost drug discovery endosome membrane gain of function genetic analysis genetic variant glomerular filtration kidney cell novel strategies pH gradient paracrine permease podocyte prevent

项目摘要

Risk of progressive kidney disease is substantially higher in African Americans than in the general population. This increased risk constitutes an enormous burden of disease and a significant public health problem. A recent genetic analysis has shown that most of the racially- associated increased risk is due to genetic variants in the gene encoding ApoL1. These disease-associated variants are common in people of African descent but absent in other populations. ApoL1 was already known to be important in an apparently unrelated disease, African trypanosomiasis. ApoL1 is the factor in human serum than confers resistance to infection by the common African trypanosome. ApoL1 is thought to kill trypanosomes by entering the limiting membrane of the trypanosome endocytic vacuole and functioning as an ion permease. The disease-associated variants of ApoL1 confer resistance to a particularly pathogenic subtype of trypanosome. How these variants exacerbate human kidney diseases is still unknown. Whether “normal” ApoL1 plays a role in kidney disease of non-African populations is also unknown. The central hypothesis of this proposal is that ApoL1 functions in kidney cells in the same way it is toxic to trypanosomes, that is, by inserting into membranes along the endocytic pathway and subsequently acting as an ion channel in situ or after sorting to other compartments such as the plasma membrane; and that variant ApoL1 has cellular toxicity because of alterations in its ion permease activity. We propose to study the ion permease activity, molecular structure, and cellular effects of ApoL1 and its disease-associated variants to look for differences that may explain enhanced disease progression associated with the variants. Successful identification of changes in activity that correlate with cellular toxicity could lead to powerful new approaches to treatment of progressive kidney disease in people who carry the disease-associated variants and perhaps for people who carry wild type ApoL1 as well.

非裔美国人患进行性肾病的风险显著高于非裔美国人。一般人口。这种增加的风险构成了巨大的疾病负担，重大公共卫生问题。最近的一项基因分析表明，大多数种族- 相关的风险增加是由于编码ApoL 1的基因中的遗传变异。这些与疾病相关的变异在非洲人后裔中很常见，但在其他人中却不存在。人口。人们已经知道ApoL 1在一种明显无关的疾病中很重要，非洲人锥虫ApoL 1是人血清中的因子，通过以下途径赋予对感染的抵抗力：常见的非洲锥虫ApoL 1被认为是通过进入锥虫内吞空泡的界膜，起离子渗透酶的作用。 ApoL 1的疾病相关变体赋予对特定致病亚型的抗性锥虫这些变异如何加剧人类肾脏疾病仍然是未知的。 “正常”ApoL 1是否在非非洲人群的肾脏疾病中起作用也是一个问题。未知这一提议的核心假设是，ApoL 1在肾细胞中的作用方式与它在肾细胞中的作用方式相同。对锥虫是有毒的，也就是说，通过沿着内吞途径插入膜中，随后在原位充当离子通道或在分选到其它隔室（例如而ApoL 1变体由于其离子的改变而具有细胞毒性，通透酶活性我们建议研究离子渗透酶的活性，分子结构， ApoL 1及其疾病相关变体的细胞效应，以寻找可能解释与变异相关的疾病进展加快。成功识别与细胞毒性相关的活性变化可能导致强大的新方法，治疗携带疾病相关变异体的人的进行性肾病也许对携带野生型ApoL 1的人也是如此。