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The Role of TULP1 in Photoreceptor Cells

TULP1 在感光细胞中的作用

基本信息

批准号：
7386580
负责人：
STEPHANIE A HAGSTROM
金额：
$ 29.4万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-04-01 至 2010-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7386580
关键词：
Address Affect Affinity Binding Biochemical Pathway Biological Models Biology C-terminal Carrier Proteins Cell membrane Data Defect Development Disease Dynamin Dynamin I Engineering Family Family member Foundations Future Genes Genetic Predisposition to Disease Human Immunoelectron Microscopy Inherited Intracellular Transport Knock-out Knowledge Light Link Messenger RNA Modality Molecular Mus Mutagenesis Mutate Mutation Neurons Pathologic Pathway interactions Phenotype Photoreceptors Physiological Positioning Attribute Process Protein translocation Proteins Publishing Retina Retinal Retinal Degeneration Retinal Diseases Retinitis Pigmentosa Rhodopsin Role Signaling Protein Synapses Testing Therapeutic Vesicle Wild Type Mouse Work base design early onset extracellular immunocytochemistry intracellular protein transport mutant photoreceptor degeneration protein expression protein protein interaction protein transport research study trafficking trans-Golgi Network

项目摘要

TULP1 is a gene we identified to cause autosomal recessive retinitis pigmentosa, a hereditary retinal degeneration blinding nearly 1 million people worldwide. The genetic etiology of RP is known for about 50% of cases; however, the biochemical pathways involved in causing the disease much less. The overall objectives of the proposed studies are to explore the physiologic function of TULP1 in the retina and to define the pathologic mechanism leading to photoreceptor degeneration associated with TULP1 mutations. The TULP family consists of four proteins of unknown function, two of which are linked to photoreceptor degeneration. The two specific aims of this application are designed to test the central hypothesis that TULP1 is a component of the molecular machinery involved in the directional translocation of proteins in photoreceptor cells. The first specific aim is to determine the role of TULP1 in photoreceptor transport pathways. This will be accomplished by using immunocytochemistry to determine whether outer segment proteins, intracellular transport proteins and synaptic proteins are mistargeted in tulpt-/- retinas. Immunoelectron microscopy will be performed to determine if the proteins that are incorrectly transported are cargo on the extracellular vesicles in tulpl-/- retinas. The second specific aim is to determine the function of the TULP1/Dynamin-1 interaction identified in photoreceptor cells. This will be done by identifying the functional domains that interact between TULP1 and Dynamin-1 and determining whether TULP1 mutations that cause RP alter the binding between the two proteins. Experiments are also proposed to generate and phenotype mice lacking Dynamin-1 in photoreceptor cells using Cre-loxP mutagenesis. Transport pathways will be evaluated in these mice as described in aim 1. Since little is known about TULP proteins, discovering information regarding the function of TULP proteins should provide knowledge about the pathways involved in photoreceptor degeneration. It is possible that this work could form the foundation for future studies aimed at evaluating therapeutic modalities that might slow, stop, or reverse the course of retinal degeneration.

TULP1是一个基因，我们确定导致常染色体隐性视网膜色素变性，遗传性视网膜