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Pharmacological studies of rhodopsin metabolism

视紫红质代谢的药理学研究

基本信息

批准号：
10438670
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/10438670
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 Persons 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：弱光视觉色素视紫红质 (Rho) 的基因突变会导致色素性视网膜炎 (RP)，对于这种遗传性视网膜变性，目前还没有有效的药物治疗方法。我们的长期目标是确定导致 RP 中光感受器死亡的分子事件并开发有效的针对这些事件的小分子药物可以保护视网膜结构和视觉功能。 Rho蛋白错误折叠导致 RP 中杆状细胞死亡。我们的中心假设是：稳定 Rho 结构的小分子，或者那些诱导错误折叠的 Rho 降解的药物可以减轻 Rho 相关的 adRP。我们最近发现了两个新颖且有效的先导化合物：1) YC-001，一种 Rho 的非视网膜伴侣，可挽救多重折叠错误折叠的 Rho 突变体导致 RP； 2) 美国食品和药物管理局 (FDA) 批准的药物在体外诱导错误折叠的 Rho 降解，并具有有效的抗炎活性。使用经过充分研究的 Rho P23H 敲入 RP 小鼠模型，我们将确定其功效、作用机制以及这两种化合物的安全性首先在分离的视网膜外植体培养物中进行，然后通过玻璃体内注射封装在控释药物配方中的 YC-001，或通过间歇性玻璃体内注射 FDA 批准的药物的优化间隔。我们将利用最先进的视网膜成像和电生理学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确定调节视紫红质稳态的药物靶向途径。这这项研究的结果将提供两种先导化合物的全面药理学特征 adRP的啮齿动物模型，我们将从中建立一个连接视紫红质表达的清晰的分子网络，随着视网膜变性的进展，折叠、退化和视网膜炎症，我们将评估这些化合物作为 RP 潜在治疗方法的功效。