CAPN5-PDGF Signaling in Vitreoretinopathy

玻璃体视网膜病变中的 CAPN5-PDGF 信号转导

基本信息

批准号：
9123760
负责人：
Kellie A Schaefer
金额：
$ 3.18万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-06 至 2021-04-05
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9123760
关键词：
Age Automobile Driving Blindness Calcium Calpain Cell Culture Techniques Cells Cellular Assay Cleaved cell Clinical Dark Adaptation Degenerative Disorder Dependence Diabetic Retinopathy Disease Enzymes Eye diseases Family Study Genes Goals Human In Vitro Inflammation Inflammatory Inherited Link Maps Medicine Molecular Molecular Genetics Molecular Target Morbidity - disease rate Mus Mutation Outcome Study Pathogenesis Pathology Pathway interactions Patients Peptide Hydrolases Phenocopy Phenotype Photoreceptors Platelet-Derived Growth Factor Play Process Protease Domain Protein Fragment Proteins Proteolysis Proto-Oncogene Proteins c-sis Research Retina Retinal Degeneration Role Signal Transduction Site Testing Transgenic Mice Transgenic Organisms Uveitis Visual Work base disease phenotype gain of function mutation gene discovery genetic approach in vivo innovation insight kindred member mouse model mutant neovascular new therapeutic target novel therapeutic intervention overexpression photoreceptor degeneration pre-clinical public health relevance receptor research study therapeutic target therapy design

项目摘要

DESCRIPTION (provided by applicant): The molecular targets for vitreoretinopathy and uveitis (intraocular inflammation) are poorly understood. This proposal builds on our exciting discovery of a calcium-activated protease, CAPN5 (calpain-5), as the cause of Autosomal Dominant Neovascular Inflammatory Vitreoretinopathy (ADNIV), and that CAPN5 processes PDGFB signaling. CAPN5 is the first nonsyndromic uveitis gene, and makes possible a highly innovative molecular-genetic approach for mechanism-based therapies for inflammation induced by photoreceptor degeneration. Photoreceptors express CAPN5, and an hCAPN5-R243L gain of function mutation in mice shows all the phenotypes of human ADNIV disease. The retina photoreceptors might be particularly sensitive to mutations in CAPN5, because high intracellular calcium is necessary and sufficient to regulate dark adaptation in photoreceptors. Our long-term goals are to find better and more specific treatments for inflammatory vitreoretinopathy. Our objective is to use in vitro and in vivo cell culture and mouse models to determine the mechanisms responsible for controlling activity of CAPN5. We will also investigate how uncontrolled CAPN5 activity leads to aberrant signaling of one of its substrates, platelet-derived growth factor B (PDGFB), and how this signaling results in the subsequent ADNIV phenotypes. Our central hypothesis is that an uncontrolled, calcium-activated CAPN5 pathway leads to ADNIV retinal degeneration and uveitis through aberrant PDGFB signaling. By creating a new mouse model we will be able to identify new therapeutic targets. Our specific aims are to (1) Dissect the ADNIV CAPN5 autoproteolysis effect in cells, (2) Determine if ADNIV CAPN5 hyperactively cleaves PDGFB to upregulate signaling, and (3) Test if PDGFB loss rescues the ADNIV phenotype in a preclinical mouse model. Impact. We expect to gain not only a better understanding of calpain activity and the role PDGFB plays in eye disease, but also to identify new therapeutic targets that may be applicable to many eye diseases. Our work should help determine the role of PDGFB signaling in ADNIV and other vitreoretinal degenerative diseases.

描述（由适用提供）：玻璃体炎和葡萄膜炎的分子靶标（眼内炎症）知之甚少。该提案以我们令人兴奋的发现钙激活蛋白酶CAPN5（CAPN5）为基础，是常染色体显性hiovemancular炎症性玻璃体病（ADNIV）的原因，而CAPN5则处理PDGFB信号。 CAPN5是第一个非合成葡萄膜炎基因，它使得基于光感受器变性引起的基于机制的注射疗法是一种高度创新的分子遗传学方法。光感受器Express CAPN5和小鼠功能突变的HCAPN5-R243L增益显示了人类ADNIV疾病的所有表型。视网膜光感受器可能对CAPN5突变特别敏感，因为高细胞内钙是必需的，足以调节光感受器的黑暗适应性。我们的长期目标是为炎症性玻璃体病疗法找到更好，更具体的治疗方法。我们的目标是使用体外和体内细胞培养和小鼠模型来确定负责控制CAPN5活性的机制。我们还将研究不受控制的CAPN5活性如何导致其底物之一，血小板衍生的生长因子B（PDGFB）的异常信号传导，以及该信号如何导致随后的ADNIV表型。我们的中心假设是，通过异常的PDGFB信号传导，未受控制的，钙激活的CAPN5途径导致了ADNIV视网膜变性和葡萄膜炎。通过创建新的鼠标模型，我们将能够识别新的治疗目标。我们的具体目的是（1）剖析细胞中的ADNIV CAPN5自传蛋白解体作用，（2）确定ADNIV CAPN5是否过度裂解PDGFB是否会上调信号传导，并且（3）测试PDGFB损失是否在临床小鼠模型中挽救ADNIV表型。影响。我们期望不仅可以更好地了解钙蛋白酶活性和PDGFB在眼病中的作用，而且还可以确定可能适用于许多眼部疾病的新治疗靶标。我们的工作应有助于确定PDGFB信号传导在ADNIV和其他玻璃体退化性疾病中的作用。