Deciphering the mechanisms associated with high-risk AMD genotypes for ARMS2/HTRA1 andComplement Factor H

破译与 ARMS2/HTRA1 和补体因子 H 的高风险 AMD 基因型相关的机制

基本信息

  • 批准号:
    10581822
  • 负责人:
  • 金额:
    $ 41.89万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-09-30 至 2025-08-31
  • 项目状态:
    未结题

项目摘要

Project Summary This U01 grant application is submitted in response to RFA EY-21-002 “Age-related Macular Degeneration (AMD) Integrative Biology Initiative”, with the goal of determining if patient-derived induced pluripotent stem cell (iPSC)-retinal pigment epithelium (RPE) can be used to discover the underlying pathophysiology of AMD. Studies from our laboratory as well as those of others strongly support the use of iPSC-RPE to understand how specific single-nucleotide polymorphisms (SNP) associated with high risk for advanced AMD influences multiple biological processes in the RPE. Our studies will focus on two SNPs with the highest odds ratio for developing advanced AMD- Age-Related Maculopathy Susceptibility 2/High Temperature Requirement A1 (ARMS2/HTRA1) and Complement Factor H (CFH). We will use the iPSC developed by the NEI and the New York Stem Cell Foundation (NYSCF) and differentiate the parent cells and their reciprocal isogenic lines into RPE using the protocol established in the Bharti laboratory. The parent/isogenic lines provide an excellent model system for deciphering the molecular factors that determine how the presence of SNPs in one or both genes affect the response to stress. We will test the hypothesis that the presence of homozygous risk alleles for either ARMS2/HTRA1 or CFH, independent and in combination, have a negative impact on the RPE stress response. Furthermore, each genetic risk profile will have a unique stress response. Our proposed studies will integrate classical reductionist investigations, coupled with discovery-driven analyses, to test specific hypotheses. Aim 1 will focus on differentiating and characterizing iPSC-RPE cell lines from 10 AMD patients and their isogenic lines. Aim 2 will test the hypothesis that the presence of AMD high-risk SNPs alter the cellular response to stress by performing large-scale quantification of proteins and metabolites, coupled with mt functional assays. Parent cells and their isogenic lines will be compared to determine the impact on metabolism and the stress response in iPSC-RPE (i) with the CFH high-risk SNP and (ii) for high risk ARMS2/HTRA1, alone or in combination with high risk CFH. These studies will address how the presence of specific risk variants affect RPE exposed to a physiologically relevant stress, an important gap in knowledge of AMD pathogenesis. Knowledge about the molecular details has the potential to lead to development of therapies targeting the primary defect in a genetically defined population of AMD patients, which in turn, could lead to a “personalized medicine” approach for treatment of AMD.
项目摘要 本U01资助申请是针对RFA EY-21-002《老年性黄斑变性》提出的 (AMD)综合生物学倡议“,目标是确定患者来源的诱导多能干细胞 (IPSC)-视网膜色素上皮(RPE)可用于发现AMD的潜在病理生理机制。 我们实验室和其他实验室的研究有力地支持了使用IPSC-RPE来理解 与晚期AMD高危相关的特异性单核苷酸多态(SNP)影响多个 RPE中的生物过程。我们的研究将集中在两个赔率最高的SNPs上 晚期AMD老年性黄斑病变易感性2/高温要求A1(ARMS2/HTRA1) 和补体因子H(CFH)。我们将使用NEI和纽约干细胞公司开发的IPSC 基金会(NYSCF)和分化亲本细胞和它们的相互等基因系RPE使用 巴蒂实验室制定的方案。亲本/等基因系提供了一个很好的模型系统 破译决定一个或两个基因中SNPs的存在如何影响 对压力的反应。我们将检验这一假设,即存在纯合子风险等位基因的 ARMS2/HTRA1或CFH单独或联合对RPE应激反应有负面影响。 此外,每个遗传风险特征都会有独特的应激反应。我们提议的研究将整合 经典的简化论研究,加上发现驱动的分析,以检验特定的假设。目标1 将专注于分化和鉴定来自10名AMD患者的IPSC-RPE细胞系及其等基因系。 目标2将验证AMD高危SNPs的存在通过以下方式改变细胞对应激的反应的假设 进行蛋白质和代谢物的大规模量化,并结合mt功能分析。父单元格 并将对它们的等基因系进行比较,以确定它们对新陈代谢和应激反应的影响 IPSC-RPE(I)CFH高危SNP和(Ii)高危ARMS2/HTRA1单独或与HIGH 冒CFH风险。这些研究将解决特定风险变量的存在如何影响暴露于 生理相关应激是AMD发病机制认识上的一个重要空白。关于以下方面的知识 分子细节有可能导致针对原发缺陷的治疗方法的开发 遗传定义的AMD患者群体,这反过来又可能导致“个性化药物”的方法 用于治疗AMD。

项目成果

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Deborah Ann Ferrington其他文献

Deborah Ann Ferrington的其他文献

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{{ truncateString('Deborah Ann Ferrington', 18)}}的其他基金

Deciphering the mechanisms associated with high-risk AMD genotypes for ARMS2/HTRA1 andComplement Factor H
破译与 ARMS2/HTRA1 和补体因子 H 的高风险 AMD 基因型相关的机制
  • 批准号:
    10707245
  • 财政年份:
    2022
  • 资助金额:
    $ 41.89万
  • 项目类别:
Immunoproteasome: A key component of the cellular stress response
免疫蛋白酶体:细胞应激反应的关键组成部分
  • 批准号:
    7510560
  • 财政年份:
    2008
  • 资助金额:
    $ 41.89万
  • 项目类别:
Training Grant: Functional Protemics of Aging
培训补助金:衰老的功能蛋白质学
  • 批准号:
    8850365
  • 财政年份:
    2008
  • 资助金额:
    $ 41.89万
  • 项目类别:
Training Grant: Functional Protemics of Aging
培训补助金:衰老的功能蛋白质学
  • 批准号:
    8792316
  • 财政年份:
    2008
  • 资助金额:
    $ 41.89万
  • 项目类别:
Training Grant: Functional Protemics of Aging
培训补助金:衰老的功能蛋白质学
  • 批准号:
    8475023
  • 财政年份:
    2008
  • 资助金额:
    $ 41.89万
  • 项目类别:
Immunoproteasome: A key component of the cellular stress response
免疫蛋白酶体:细胞应激反应的关键组成部分
  • 批准号:
    7685277
  • 财政年份:
    2008
  • 资助金额:
    $ 41.89万
  • 项目类别:
Proteomics of altered protein in macular degeneration
黄斑变性中蛋白质改变的蛋白质组学
  • 批准号:
    6833434
  • 财政年份:
    2004
  • 资助金额:
    $ 41.89万
  • 项目类别:
Proteomics of altered protein in macular degeneration
黄斑变性中蛋白质改变的蛋白质组学
  • 批准号:
    6992685
  • 财政年份:
    2004
  • 资助金额:
    $ 41.89万
  • 项目类别:
Proteomics of altered protein in macular degeneration
黄斑变性中蛋白质改变的蛋白质组学
  • 批准号:
    6727783
  • 财政年份:
    2004
  • 资助金额:
    $ 41.89万
  • 项目类别:
Proteasome function in the aging retina
蛋白酶体在老化视网膜中的功能
  • 批准号:
    7117222
  • 财政年份:
    2003
  • 资助金额:
    $ 41.89万
  • 项目类别:

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