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Cep290 function in photoreceptor structure and disease.

Cep290 在光感受器结构和疾病中发挥作用。

基本信息

批准号：
10349489
负责人：
Abigail R Moye
金额：
$ 6.2万
依托单位：
BAYLOR COLLEGE OF MEDICINE
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：
2021-03-01 至 2022-12-26
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10349489
关键词：
Affect Animal Model Antibodies Area Blindness Cells Cilia Clinical Trials Complex Cultured Cells Data Defect Development Diffusion Disease Embryo Eukaryotic Cell Exhibits Eye Fibroblasts Foundations Goals Growth Health Human Image Immunofluorescence Immunologic Interphase Cell Lead Leber&apos s amaurosis Length Light Link Location Maintenance Maps Membrane Microscopy Microtubules Morphogenesis Mus Mutant Strains Mice Mutate Mutation Neurons Nuclear Pore Complex Proteins Optics Organ Organelles Patients Photoreceptors Play Process Proteins Proteomics Research Resolution Retina Retinal Degeneration Role Sensory Signal Transduction Stains Structural defect Structure Syndrome Techniques Tertiary Protein Structure Testing Time Transmission Electron Microscopy Work base cell type ciliopathy clinically significant experimental study extracellular vesicles insight knowledge base mutant nanometer resolution nanoscale novel novel therapeutic intervention photoreceptor degeneration protein complex reconstruction retinal rods trafficking

项目摘要

ABSTRACT Photoreceptor neurons are specialized cells that possess elaborated outer segments (OS) containing disc like structures and are anchored by connecting cilia (CC). The delineation of the OS proteins involved in the conversion of light to electrical signal has been extensive, nevertheless OS elaboration, maintenance, and the structural complexes sustaining these processes have yet to be elucidated. Therefore, my short-term goal is to define the role of CC-resident protein complexes and Y-link structures within the CC, specifically in regards to the growth and organization of the outer segment. This goal is of clinical significance as defects in OS organization and in proteins associated with the Y- link structures lead to blindness. My ultimate goal is to characterize the CC structure and interactions of proteins within it, and to understand the mechanistic connections between changes in cilia structure and functional defects in retinal ciliopathies. The central hypothesis of this application is that defects in CEP290 interfere with the structure and function of the Y-links in the CC, thereby disrupting ciliary function and resulting in aberrant OS morphogenesis. My hypothesis has been formed based on preliminary data from patients with mutations in Cep290, as well as from the analysis of Cep290 mutant mouse lines. The specific aims of this proposal are to 1) Localize CEP290 in primary cilia of cultured cells and the CC of rod cells with sufficient resolution to determine its structural relationship to the Y-links and the ciliary membrane, and 2) Test the hypothesis that CEP290 functions as a component of a ciliary trafficking filter. Using multiple animal models with mutations in Cep290 or lacking Cep290, my goal is to identify the exact location of CEP290 within photoreceptor CC and to determine CEP290’s role in the filtering of proteins into the cilium. This research will impact the health field by contributing to the mechanistic knowledge base for Leber Congenital Amaurosis and other cilia-related retinal degeneration diseases, and it will provide an opportunity to create novel treatments for these diseases.

摘要