Pharmacological studies of rhodopsin metabolism

视紫红质代谢的药理学研究

基本信息

批准号：
10224916
负责人：
Yuanyuan Chen
金额：
$ 34.16万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10224916
关键词：
Acquired Blindness Acute Affect Age Anabolism Animal Model Anti-Inflammatory Agents Biochemical Biochemistry Blindness Cell Count Cell Culture Techniques Cell Death Cell Survival Cells Cellular Stress Cessation of life Chemicals Chronic Clinical Clinical Trials DNA Sequence Alteration Data Development Disease Dose Drug Kinetics Drug Targeting Electrophysiology (science)Encapsulated Event Eye Future G-Protein-Coupled Receptors Genes Genetic study Goals Homeostasis Image Immune response In Vitro Inflammation Inflammatory Inherited Knock-in Mouse Lead Learning Light Lysosomes Mediating Metabolism Methotrexate Microspheres Modeling Molecular Molecular Chaperones Morphology Mus Mutation Night Blindness Pathway interactions Pharmaceutical Preparations Pharmacological Treatment Pharmacology Pharmacology Study Pharmacotherapy Photoreceptors Protocols documentation Quality of life Regimen Retina Retinal Degeneration Retinal Diseases Retinal Pigments Retinitis Pigmentosa Rheumatoid Arthritis Rhodopsin Rod Rod Outer Segments Rodent Model Role Safety Stress Structure System Techniques Testing Therapeutic United States Food and Drug Administration Vision autosomal dominant Alzheimer&apos s disease base biomaterial compatibility chemical genetics design drug candidate effective therapy efficacy evaluation glycosylation high resolution imaging high throughput screening imaging modality improved in vivo inherited retinal degeneration insight intravitreal injection lens mouse model mutant novel preservation prevent protein degradation protein misfolding proteostasis receptor retinal imaging retinal rods small molecule success therapeutic target tool trafficking transcriptome transcriptome sequencing transcriptomics treatment strategy

项目摘要

Summary: Genetic mutations of the dim-light visual pigment, rhodopsin (Rho), cause retinitis pigmentosa (RP), and no effective pharmacological treatment is available for this inherited retinal degeneration. Our long-term goal is to determine the molecular events that contribute to photoreceptor death in RP and develop effective small molecule drugs targeting these events that preserve the retinal structure and visual function. Rho protein misfolding causes rod cell death in RP. Our central hypothesis is: small molecules that stabilize Rho structure, or those induce degradation of misfolded Rho can mitigate Rho-associated adRP. We recently discovered two novel and potent lead compounds: 1) YC-001, a non-retinal chaperone of Rho that rescues folding of multiple misfolded Rho mutants that cause RP; and 2) a U.S. Food and Drug Administration (FDA)-approved drug that induces misfolded Rho degradation in vitro, and that possesses potent anti-inflammatory activity. Using the well-studied Rho P23H knock-in mouse model of RP, we will determine the efficacy, mechanism of action, and safety of these two compounds firstly in the isolated retinae explant culture, and then in vivo by an intravitreal injection of YC-001 encapsulated in a controlled drug release formula, or via intermittent intravitreal injections of the FDA-approved drug with optimized intervals. We will utilize state-of-the-art retinal imaging and electrophysiology techniques to evaluate the retinal structure and visual function. We will conduct biochemical and transcriptome analyses to identify the drug targeting pathways that regulate rhodopsin homeostasis. The results from this study will provide comprehensive pharmacological profiles of the two lead compounds in a rodent model of adRP, from which we will build a clear molecular network connecting rhodopsin expression, folding, degradation and retinal inflammation with the progression of retinal degeneration and we will assess the efficacy of these compounds as potential treatments for RP.

摘要：昏暗的视觉色素，视紫红质（Rho）的遗传突变，引起色素性视网膜炎（RP），，，并且该遗传性视网膜变性没有有效的药理治疗。我们的长期目标是确定导致RP感光受体死亡并发展有效的分子事件针对保留视网膜结构和视觉功能的这些事件的小分子药物。 Rho蛋白错误折叠会导致RP中的杆细胞死亡。我们的中心假设是：稳定Rho结构的小分子，或诱导错误折叠的RHO降解的人可以减轻与Rho相关的ADRP。我们最近发现了两个新颖和有效的铅化合物：1）YC-001，Rho的非视视网膜伴侣，可挽救多重折叠引起RP的Rho突变体错误折叠； 2）美国食品药品监督管理局（FDA）批准的药物在体外诱导Rho降解错误，并具有有效的抗炎活性。使用经过精心研究的Rho P23H敲入RP的小鼠模型，我们将确定功效，作用机理和这两种化合物的安全性首先是在孤立的视网膜外植体培养中，然后在体内通过玻璃体内的注入封装在受控药物释放公式的YC-001，或通过间歇性注射具有优化间隔的FDA批准的药物。我们将利用最先进的视网膜成像和电生理技术评估视网膜结构和视觉功能。我们将进行生化和转录组分析以识别调节视紫红质稳态的药物靶向途径。这这项研究的结果将在A中提供两种铅化合物的全面药理特征 ADRP的啮齿动物模型，我们将构建一个连接视紫红质表达的清晰分子网络，随着视网膜变性的进展，折叠，降解和视网膜炎症，我们将评估这些化合物作为RP的潜在疗法的功效。