Pharmacological studies of rhodopsin metabolism

视紫红质代谢的药理学研究

• 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
• 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' 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

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：昏暗视觉色素，视紫红质（Rho）的基因突变，导致视网膜色素变性（RP）， 并且对于这种遗传性视网膜变性没有有效的药物治疗。我们的长期 目的是确定分子事件，有助于感光细胞死亡的RP和发展有效的 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中的视杆细胞死亡。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降解的那些可减轻Rho相关的adRP。我们最近发现了两个 新的和有效的先导化合物：1）YC-001，Rho的非视网膜伴侣，其拯救多个 导致RP的错误折叠的Rho突变体;和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，并且具有有效的抗炎活性。使用 充分研究的Rho P23 H敲入RP小鼠模型，我们将确定疗效，作用机制， 这两种化合物的安全性，首先在离体视网膜外植体培养，然后在体内通过玻璃体内注射， 注射包封在药物控释制剂中的YC-001，或通过间歇性玻璃体内注射 FDA批准的药物的最佳间隔。我们将利用最先进的视网膜成像技术， 电生理技术评价视网膜结构和视功能。我们将进行生化检查 和转录组分析来鉴定调节视紫红质稳态的药物靶向途径。的 本研究的结果将提供两种先导化合物在 adRP的啮齿动物模型，从中我们将建立一个明确的连接视紫红质表达的分子网络， 折叠，降解和视网膜炎症与视网膜变性的进展，我们将评估 这些化合物作为RP的潜在治疗的功效。