BLR&D Research Career Scientist Award

BLR

• 批准号: 10451509
• 负责人: NEAL S. PEACHEY
• 金额: --
• 依托单位: LOUIS STOKES CLEVELAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10451509
• 关键词: Activities of Daily Living; African American; Age related macular degeneration; Algorithms; American; Americas; Anatomy; Area; Automobile Driving; Award; Biochemical; Biochemistry; Biological; Biological Assay; Biology; Blindness; CD147 antigen; Candidate Disease Gene; Cataract; Cell membrane; Cells; Cellular Metabolic Process; Chromosome Mapping; Code; Collaborations; Coupled; DNA Sequence Alteration; Data; Data Analyses; Databases; Development; Diabetic Retinopathy; Disease; Disease Progression; Electrophysiology (science); Ensure; Equilibrium; Ethnic group; European; Exposure to; Eye diseases; Fright; Funding; Genes; Genetic; Genetic Risk; Genetic study; Glaucoma; Glucose Transporter; Gold; Health; Health Care Costs; Healthcare; Hispanic; Hispanic Americans; Human; Human Genetics; International; International Classification of Disease Codes; Investigational Therapies; Knock-out; Laboratories; Laboratory Research; Light; Link; Maintenance; Manuscripts; Measures; Meta-Analysis; Metabolism; Modeling; Monitor; Mus; Mutagenesis; Mutant Strains Mice; Mutation; Nature; Patients; Pharmacology; Phenotype; Photoreceptors; Play; Predisposition; Prevalence; Proteins; Psychophysics; Publishing; RPE65 protein; Reading; Reporting; Research; Research Project Grants; Retina; Retinal Cone; Retinal Diseases; Risk; Role; Running; SLC2A1 gene; Scientist; Site; Structure of retinal pigment epithelium; The Jackson Laboratory; Transgenic Organisms; Translations; Vertebrate Photoreceptors; Veterans; Veterans Health Administration; Vision; Vision Disorders; Vision research; Visual system structure; Work; XLRS1 protein; base; biobank; career; case control; cell type; cohort; conditional knockout; design; disease phenotype; forward genetics; genetic analysis; genetic approach; genome wide association study; glucose transport; human disease; human model; imaging study; improved; interest; meetings; military veteran; mouse genetics; mouse model; multi-ethnic; multidisciplinary; mutant; ocular imaging; procedure cost; programs; retinal rods; reverse genetics; risk variant; success; therapy development; visual cycle; visual process

The Peachey lab is focused on the outer retina, to understand the biology that underlies the initial stages of the visual process and to identify genetic mutations associated with visual disorders. The first research area combines the power of mouse genetics with electrophysiological, anatomical and biochemical assays. Transgenic, systemic knockout and conditional knockout models allow the expression of a target to be manipulated and the effect of that manipulation evaluated. Some projects conducted during the most recent RCS award (2015-date) are highlighted here: (A) To better understand the rod and cone visual cycles by which photoreceptors regain sensitivity following bright light exposure the CDA-2 program of Philip Kiser utilizes pharmacological blockade of known visual cycle components (e.g., RPE65) in mouse mutants lacking proteins such as DES1 that have been proposed as playing key roles. (B) To clarify the metabolic processes that support photoreceptor function, a recent VA Merit Review supported studies of mice lacking the ability to transport glucose (by targeting GLUT1) or lactate (by targeting basigin) across cell membranes of rods, cones and the retinal pigment epithelium (RPE). (C) To understand the role of retinoschisin (RS1) we worked with a panel of Rs1 mutants to clarify the disease phenotype. Based on the severe phenotype, a new R01 focuses on the earliest stages of development in the mouse models and uses psychophysical assays to determine whether RS1 mutations result in incomplete photoreceptor development. (D) Forward genetics is used to develop new mouse models for vision research, in work supported by a subcontract to Jackson Laboratory. We collaborate through design of ocular screens, gene mapping and defining the retinal phenotype. To date, this collaboration has developed >20 mutants involving almost as many genes. Notably this collaboration has led to the identification of two human disease genes, including CTNNA1 during the most recent RCS award. The Peachey lab has a long-standing interest in defining the genetic risk profile for age-related macular degeneration (AMD). This began as a Merit Review in the early 2000’s focused on candidate genes, an effort that developed into our serving as a site within the International Age-Related Macular Degeneration Genetics Consortium (IAMDGC). During the most recent RCS award, the IAMDGC published the most comprehensive assessment of AMD genetics to date. With the advent of the VA Million Veteran Program (MVP), during the most recent RCS award we submitted a successful application to conduct the first multi-ethnic analysis of AMD genetics. After defining an accurate ICD- code based algorithm to identify AMD Cases and Controls without AMD, in the absence of gold-standard ocular imaging results, we conducted genome wide association studies (GWAS) in MVP for European- American (EA), African-American (AA) and Hispanic-American (HA) Veterans. The EA GWAS replicated and extended the IAMDGC results. When coupled with IAMDGC data and analysis of other databases, we identified a number of new AMD risk loci. Perhaps more important, we noted marked differences in the AMD risk profiles of EA as compared to AA and HA Veterans. A newly funded Merit Review will extend this successful approach to conduct additional genetic studies of ocular conditions that are relevant to the Veterans Health Administration based on their prevalence. In each case, we will validate a Case-Control algorithm and then move to a trans-ethnic genetic analysis. For some conditions, we will conduct the first analysis that compares genetic risk across ethnic groups. For other conditions, this will be the first genetic analysis ever conducted. A better understanding of ocular diseases such as AMD, glaucoma, cataract, or diabetic retinopathy is an important step towards treatments to slow/halt disease progression, and possibly reduce healthcare costs.

该实验室的重点是外层视网膜，以了解生物学基础的初始阶段 并确定与视觉障碍相关的基因突变。第一研究 该领域结合了小鼠遗传学与电生理学，解剖学和生物化学测定的力量。 转基因、系统性敲除和条件性敲除模型允许靶的表达是可接受的。 操纵，并评估操纵的效果。一些项目是在大多数 最近的RCS奖（2015年至今）在这里突出显示：（A）为了更好地了解杆和锥视觉 光感受器在强光照射后恢复敏感性的周期， Philip Kiser利用已知视觉周期成分（例如，RPE 65） 缺乏蛋白质如DES 1的突变体被认为起着关键作用。(B)明确 支持光感受器功能的代谢过程，最近的VA Merit Review支持以下研究： 缺乏转运葡萄糖（通过靶向GLUT 1）或乳酸（通过靶向basigin）能力的小鼠 视杆细胞膜、视锥细胞膜和视网膜色素上皮细胞（RPE）。(C)为了理解 我们用一组Rs 1突变体来阐明疾病表型。基于 严重的表型，一个新的R 01集中在发展的最早阶段，在小鼠模型和用途 心理物理学测定以确定RS 1突变是否导致不完整的光感受器 发展(D)正向遗传学用于开发新的小鼠模型用于视觉研究， 由斯托杰克逊实验室支持。我们通过设计视觉屏幕，基因 绘制和定义视网膜表型。到目前为止，这项合作已经开发了20多个突变体， 涉及几乎同样多的基因。值得注意的是，这种合作导致了两个人类的鉴定， 疾病基因，包括在最近的RCS奖CTNNA 1。 Alfrehey实验室长期以来一直致力于确定与年龄相关的遗传风险特征， 黄斑变性（AMD）。这始于2000年初的一次功绩审查，重点是候选人 基因，这一努力发展成为我们作为一个网站内的国际视网膜相关黄斑 变性遗传学联盟（IAMDGC）。在最近的RCS奖项中，IAMDGC 发表了迄今为止最全面的AMD遗传学评估。随着VA的出现， 百万退伍军人计划（MVP），在最近的RCS奖，我们提交了一个成功的 申请进行AMD遗传学的首次多种族分析。在定义了准确的ICD后- 基于代码的算法，用于在没有金标准的情况下识别无AMD的AMD病例和对照 眼成像结果，我们进行了欧洲MVP的全基因组关联研究（GWAS）， 美国（EA），非洲裔美国人（AA）和西班牙裔美国人（HA）退伍军人。EA GWAS 复制和扩展了机构间医疗器械和药物管理理事会的结果。如果再加上机构间排雷和灾害控制小组的数据和对其他 数据库中，我们确定了一些新的AMD风险位点。也许更重要的是，我们注意到， 与AA和HA退伍军人相比，EA的AMD风险特征存在差异。新资助的Merit 综述将扩展这一成功的方法，以进行更多的眼部疾病遗传学研究 与退伍军人健康管理局相关的疾病。在每种情况下，我们将 验证病例对照算法，然后进行跨种族遗传分析。对于某些情况， 我们将进行第一次分析，比较不同种族群体的遗传风险。对于其他情况， 这将是有史以来第一次进行基因分析。更好地了解眼部疾病，如 AMD、青光眼、白内障或糖尿病视网膜病变是治疗减缓/停止 疾病进展，并可能降低医疗费用。