Interrogation and Interpretation of Common Fund Data Sets to Identify Novel Ocular Disease Genes

询问和解释共同基金数据集以识别新型眼部疾病基因

基本信息

批准号：
10357382
负责人：
ALA MOSHIRI
金额：
$ 31.48万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-23 至 2024-09-22
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10357382
关键词：
Affect Age Animal Model Anterior Area Autopsy Bioinformatics Biology Blindness Candidate Disease Gene Cell physiology Cellular biology Clinic Code Communities Country Data Data Analyses Data Set Databases Defect Development Diagnosis Disease Drug Targeting Eye Eye Abnormalities Eye diseases Female Foundations Functional disorder Funding Future Gene Expression Genes Genetic Genotype Genotype-Tissue Expression Project Goals Hereditary Disease Histopathology Homologous Gene Human Inherited Institution International Kidney Knock-out Knockout Mice Life Literature Mendelian disorder Molecular Molecular Diagnosis Mus Mutation Ontology Ophthalmic examination and evaluation Ophthalmology Pathology Pathway interactions Patients Phenotype Photoreceptors Prior Therapy Process Protein Analysis Proteins Publishing Research Research Personnel Resources Retina Retinal Cone Retinal Diseases Retinitis Pigmentosa Rod Scientist Signal Pathway Site Software Tools Source Structure Technology Testing The Jackson Laboratory Tissues United States National Institutes of Health base body system ciliopathy clinical phenotype clinically relevant cohort eye formation gene therapy genetic manipulation genome sequencing genome wide association study human disease human tissue knockout gene male member mouse genome mouse model mutant novel novel therapeutic intervention patient population phenotypic data photoreceptor degeneration pre-clinical programs protein complex protein protein interaction sex single-cell RNA sequencing transcriptome sequencing whole genome

项目摘要

Project Summary/Abstract Inherited diseases are a major source of blindness. These diseases are typically single-gene disorders. Some may cause developmental defects in early eye formation, others cause the degeneration of photoreceptor cells, while others may cause anterior segment disease. Historically they have been classified based on the clinical phenotype and then grouped into various disease entities. Retinitis pigmentosa (RP), an example of a rod-cone dystrophy, is the most common form of inherited retinal disease. It has a constellation of classical findings observed on eye examination accompanied by progressive loss of rod and then cone photoreceptors leading to eventual blindness in late stages of the disease. In the past three decades the genetic basis of many forms of inherited retinal diseases, for example, have been discovered leading to the identification of over 270 retinal disease genes. Mutations of over 80 genes are known to be associated with RP alone. However, in spite of the tremendous progress that has been made, the identification of the causative genetic alteration can be identified in only 50-75% of patients with presumed inherited retinal disease, even after whole genome sequencing. Based on this fact, it is presumed that significant numbers of unknown ocular disease genes exist. One approach to identify additional ocular disease genes in the mammalian retina is to take advantage of knockout mouse technology. The Knockout Mouse Phenotyping (KOMP) program is part of the International Mouse Phenotyping Consortium (IMPC), a group of scientists from mouse clinics around the world with the common goal of creating single gene knockout mice for every gene in the mouse genome. To date, over 7,000 single gene knockout mice have been created and phenotyped of the ~24,000 protein coding genes in the mouse genome. The UC Davis Mouse Biology Program is one of just three KOMP/IMPC centers in the US and generates a large number of knockout mice for the KOMP pipeline. Mouse knockouts receive comprehensive phenotyping in every organ system in the first four months of life prior to necropsy and histopathology. Knockout lines are annotated for dozens of specific eye abnormalities which are carefully documented during the phenotyping process. Identification of ocular disease genes in knockout mice provides candidate eye disease genes relevant in people. This proposal seeks to close the gap on the remaining 25-50% of patients with presumed inherited ocular diseases that currently cannot be genetically diagnosed. In this project we will identify all mouse retinal disease genes identified by the KOMP. In addition, we will correlate these novel mouse ocular disease genes for human relevance by cross referencing with the GTEx data base, also supported by the Common Fund. Furthermore, we will deeply analyze the specific cell biology of novel genes, by literature search, Gene Ontology, Panther Pathway, STRING, Syscilia, CiliaCarta, and publicly available ophthalmic GWAS. This proposal will catalyze discoveries and generate novel hypotheses based on clinically relevant pathways previously unimplicated in eye disease.

项目概要/摘要遗传性疾病是失明的主要原因。这些疾病通常是单基因疾病。一些可能会导致早期眼睛形成的发育缺陷，其他则导致感光器退化细胞，而其他细胞则可能导致眼前节疾病。历史上它们的分类依据是临床表型，然后分为各种疾病实体。色素性视网膜炎 (RP)，一个例子视杆细胞营养不良是遗传性视网膜疾病的最常见形式。它有一个古典的星座眼科检查中观察到的结果是视杆细胞和视锥细胞感光细胞逐渐丧失导致疾病晚期最终失明。在过去的三十年中，许多疾病的遗传基础例如，遗传性视网膜疾病的形式已被发现，导致超过 270 种遗传性视网膜疾病的发现视网膜疾病基因。已知 80 多个基因的突变仅与 RP 相关。然而，在尽管已经取得了巨大进展，但致病基因改变的识别仍然可以即使在进行全基因组分析后，也只有 50-75% 的疑似患有遗传性视网膜疾病的患者能够被识别出来测序。基于这一事实，推测存在大量未知的眼部疾病基因。识别哺乳动物视网膜中其他眼部疾病基因的一种方法是利用基因敲除小鼠技术。基因敲除小鼠表型分析 (KOMP) 计划是国际小鼠表型联盟 (IMPC)，由来自世界各地小鼠诊所的科学家组成的小组共同目标是针对小鼠基因组中的每个基因创建单基因敲除小鼠。迄今为止，已有超过 7,000 单基因敲除小鼠已被培育出来，并对大约 24,000 个蛋白质编码基因进行了表型分析。小鼠基因组。加州大学戴维斯分校小鼠生物学项目是美国仅有的三个 KOMP/IMPC 中心之一为 KOMP 管道生成大量敲除小鼠。小鼠基因敲除获得全面在尸检和组织病理学之前对生命前四个月的每个器官系统进行表型分析。淘汰线注释了数十种特定的眼睛异常情况，这些异常情况在过程中被仔细记录表型分析过程。基因敲除小鼠眼部疾病基因的鉴定提供了候选眼睛与人相关的疾病基因。该提案旨在缩小剩余 25-50% 患者的差距患有目前无法通过基因诊断的推测遗传性眼病。在这个项目中我们将鉴定 KOMP 鉴定的所有小鼠视网膜疾病基因。此外，我们还将把这些小说关联起来通过与 GTEx 数据库交叉引用，研究小鼠眼部疾病基因与人类的相关性，由共同基金支持。此外，我们将深入分析新基因的特定细胞生物学，通过文献检索、Gene Ontology、Panther Pathway、STRING、Syscilia、CiliaCarta 和公开可用眼科 GWAS。该提案将促进发现并产生基于临床的新假设以前未涉及眼部疾病的相关途径。