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：
9896822
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/9896822
关键词：
APOL1 gene Actins Acute Affect African African American African Trypanosomiasis 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 Play Pongidae Population Proteins Public Health Recombinants Renal glomerular disease Resistance Resistance to infection Risk Role Serum Serum Proteins Sorting - Cell Movement Structure 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.

非裔美国人的进行性肾脏疾病的风险大大高于一般人口。这种增加的风险构成了疾病的巨大燃烧和重大的公共卫生问题。最近的遗传分析表明，大多数种族相关的增加风险是由于编码APOL1的基因中的遗传变异。这些与疾病相关的变体在非洲血统中很常见，但在其他方面不存在人群。 apol1在明显无关的疾病中已经很重要锥虫病。 apol1是人血清的因素，而不是同意对感染的抗性普通的非洲锥体。 apol1被认为可以通过进入将锥虫内吞真空吸尘器的限制膜，并用作离子拷贝。 APOL1会议抗性的疾病相关变体对特别致病性亚型的抗性锥虫。这些变体如何加剧人类肾脏疾病仍然未知。 “正常” APOL1是否在非非洲人群的肾脏疾病中起作用未知。该提议的中心假设是APOL1以相同的方式在肾细胞中起作用对锥虫有毒，也就是说，沿着内吞途径插入膜和随后用作原位的离子通道或在对其他隔间进行排序之后，例如质膜；并且该变体Apol1由于离子的改变而具有细胞毒性渗透活动。我们建议研究离子渗透酶活性，分子结构和 Apol1及其疾病相关的变体的细胞效应，以寻找可能的差异解释与变体相关的增强疾病进展。成功识别与细胞毒性相关的活动的变化可能会导致强大的新方法携带疾病相关变体的人的进行性肾脏疾病的治疗对于那些携带野生型apol1的人也可能。