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.

Peachey 实验室专注于外视网膜，以了解初始阶段的生物学原理 视觉过程并识别与视觉障碍相关的基因突变。 该领域将小鼠遗传学的力量与电生理学、解剖学和生化分析相结合。 转基因、系统性敲除和条件敲除模型允许靶标的表达 操纵并评估了操纵的效果。 最近的 RCS 奖项（2015 年至今）在此突出显示：(A) 为了更好地理解杆和锥视觉 光感受器在强光照射后恢复敏感性的周期 CDA-2 程序 Philip Kiser 利用药物阻断小鼠已知的视觉周期成分（例如 RPE65） 缺乏 DES1 等蛋白质的突变体被认为发挥着关键作用 (B) 澄清。 支持光感受器功能的代谢过程，最近的 VA 优异评审支持以下研究 缺乏转运葡萄糖（通过靶向 GLUT1）或乳酸（通过靶向 basigin）的能力的小鼠 (C) 了解视杆细胞、视锥细胞和视网膜色素上皮 (RPE) 细胞膜的作用。 我们与一组 Rs1 突变体合作，根据视网膜裂素 (RS1) 阐明了疾病表型。 严重的表型，新的 R01 专注于小鼠模型和用途的最早发展阶段 心理物理学测定以确定 RS1 突变是否导致光感受器不完整 (D) 正向遗传学用于开发用于视觉研究的新小鼠模型。 在杰克逊实验室的分包合同的支持下，我们通过眼部屏幕、基因的设计进行合作。 迄今为止，这项合作已开发出超过 20 个突变体。 值得注意的是，这次合作几乎涉及了两个人的基因。 疾病基因，包括最近 RCS 奖项中的 CTNNA1。 Peachey 实验室长期以来一直对定义与年龄相关的遗传风险状况感兴趣。 黄斑变性 (AMD) 始于 2000 年初的一项绩效审查，重点关注候选人。 基因，我们的努力发展成为国际年龄相关黄斑中心的一个网站 变性遗传学联盟 (IAMDGC) 在最近的 RCS 颁奖期间，IAMDGC。 随着 VA 的出现，发表了迄今为止最全面的 AMD 遗传学评估。 百万退伍军人计划 (MVP)，在最近的 RCS 颁奖期间，我们成功提交了一份 在定义准确的 ICD 后，应用程序对 AMD 遗传学进行首次多种族分析。 在没有黄金标准的情况下，基于代码的算法来识别没有 AMD 的 AMD 案例和控制 根据眼部成像结果，我们在欧洲 MVP 中进行了全基因组关联研究 (GWAS) - 美国人 (EA)、非裔美国人 (AA) 和西班牙裔美国人 (HA) 退伍军人 EA GWAS。 与 IAMDGC 数据和其他分析相结合，复制并扩展了 IAMDGC 结果。 在数据库中，我们发现了一些新的 AMD 风险位点，也许更重要的是，我们注意到了标记。 与 AA 和 HA 退伍军人相比，EA 的 AMD 风险状况存在差异 A 新资助的优点。 审查将扩展这种成功的方法，对眼部疾病进行更多的基因研究 根据每种情况的患病率，与退伍军人健康管理局相关。 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， 我们将进行首次分析，比较不同种族群体的遗传风险， 这将是有史以来首次进行的基因分析，以更好地了解诸如眼部疾病之类的疾病。 AMD、青光眼、白内障或糖尿病视网膜病变是减缓/停止治疗的重要一步 疾病进展，并可能降低医疗费用。