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明显高于白人这种增加的风险构成了巨大的疾病负担。最近的一项基因分析表明，大多数种族- 相关风险增加是由于 ApoL1 编码基因的遗传变异所致。疾病相关变异在非洲人后裔中很常见，但在其他人中不存在人口。人们已经知道 ApoL1 在一种看似无关的疾病（非洲疾病）中发挥着重要作用。 ApoL1 是人血清中赋予锥虫感染抵抗力的因子。常见的非洲锥虫 ApoL1 被认为可以通过进入体内杀死锥虫。锥虫内吞真空的限制膜并充当离子渗透酶。与疾病相关的 ApoL1 变异赋予对特定致病亚型的抵抗力这些变异如何恶化人类肾脏疾病仍不清楚。 “正常”ApoL1 是否在非非洲人群的肾脏疾病中发挥作用也有待研究。未知。该提案的中心假设是 ApoL1 在肾细胞中的功能与它在肾细胞中的功能相同。对锥虫有毒，即通过沿着内吞途径插入细胞膜并随后在原位或在分选到其他室（例如质膜；并且变体 ApoL1 由于其离子的改变而具有细胞毒性我们建议研究离子渗透酶活性、分子结构和 ApoL1 及其疾病相关变体的细胞效应，以寻找可能的差异解释与变异相关的增强的疾病进展。与细胞毒性相关的活性变化可能会导致强大的新方法治疗携带疾病相关变异的人的进行性肾病也许对于携带野生型 ApoL1 的人来说也是如此。