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Novel neuroprotective activities of flavonoids against retinal degenerative diseases

黄酮类化合物对视网膜退行性疾病的新型神经保护活性

基本信息

批准号：
10428740
负责人：
Beata Jastrzebska
金额：
$ 46.69万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-30 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10428740
关键词：
11 cis Retinal Adjuvant Animals Apoproteins Apoptosis Architecture BCL2 gene Binding Binding Sites Biochemical Blindness Cell Culture Techniques Cell Death Cell physiology Cells Cellular Stress Cellular Stress Response Cessation of life Clinical Research Complex Crystallography Data Development Dietary Flavonoid Disease Enhancers Equilibrium Eye diseases Flavonoids G-Protein-Coupled Receptors Gene Expression Genes Genetic Health Hybrids Impairment In Vitro Inherited Knock-in Knock-out Knowledge Learning Libraries Light Link Mass Spectrum Analysis Mediating Membrane Modeling Molecular Molecular Chaperones Molecular Target Morphology Mus Mutation Natural regeneration Opsin Pathogenicity Pathologic Pathology Patients Pharmacology Phenotype Photoreceptors Phototransduction Quercetin Reporting Research Personnel Retina Retinal Degeneration Retinal Diseases Retinitis Pigmentosa Rhodopsin Role Signal Transduction Stress Techniques Testing Therapeutic Therapeutic Effect Transcriptional Regulation Variant Vertebral column Vision Visual system structure analog base biophysical analysis chromophore combat design disease phenotype effective therapy effectiveness evaluation fitness high throughput screening improved in vivo inhibitor injured mouse model mutant mutation screening neuroprotection novel novel therapeutics photoreceptor degeneration prevent response small molecule small molecule inhibitor therapeutically effective trafficking treatment effect

项目摘要

ABSTRACT Functional rhodopsin (Rho) composed of apoprotein opsin and covalently bound 11-cis-retinal chromophore is required for normal phototransduction and vision. Inherited mutations compromise proper folding, binding of 11-cis-retinal, and stability of Rho, leading to retinitis pigmentosa (RP), a progressive degenerative eye disease that causes blindness. Currently, there are no treatment options available to combat RP. Retinal- based pharmacological chaperones and non-retinal small molecules, including flavonoids, can stabilize certain Rho mutants in vitro. However, effective and safe therapy for RP has yet to be established. Dietary flavonoids have been reported to show beneficial effects in ocular impairments. Our preliminary studies showed that common flavonoid quercetin could stabilize pathogenic Rho, improve its folding, membrane integration, and retinal binding. We also found that quercetin inhibits stress-induced cellular responses related to pathogenic mutants triggering Bax-mediated apoptosis with beneficial consequences to retinal health. Here we propose to study, the therapeutic potential of quercetin and its combinations with retinal analogs, and novel small molecule Bax inhibitor to rescue RP pathology. First, we will evaluate quercetin positive effects on RP mutants independently of the genetic background in vitro. Then, we will assess their ability to revert the RP phenotype in vivo in mouse models of RP. To understand the underlying molecular mechanism of Rho mutant’s stabilization offered by quercetin we will perform structural studies to delineate the architecture of quercetin-Rho complexes by applying crystallographic and hybrid mass-spectrometry techniques. In addition, we will search for more effective compounds stabilizing Rho mutants by high-throughput screening of flavonoid-related compound libraries, which then will be validated with systematic biochemical and biophysical analyses (Aim 1). Second, we will examine the role of quercetin as an adjuvant for the specific retinal analogs stably accommodating the retinal-binding pocket. Some of these retinals improve the folding of the P23H pathogenic Rho mutant. We will examine the potential corrective effect of new locked retinal and backbone- modified retinal analogs for P23H Rho and determine if the binding of these retinals could be enhanced by quercetin to gain a greater therapeutic effect in RP (Aim 2). Third, we will study the cellular processes in RP. To gain a better understanding of RP pathology we will look for molecular targets activated by cellular stress signals in RP and assess if quercetin can modulate these cellular processes to revert the disease phenotype (Aim 3). At first, we will examine the effect of quercetin on Bax-mediated apoptosis to learn if its effect is related to direct or indirect inhibition of Bax, or both. In these studies, we will also use a novel bioavailable small molecule Bax inhibitor. We will determine the effectiveness of this new Bax inhibitor and its combination with quercetin against Rho-related RP. Altogether, the knowledge gained from this study will pave the way to design an effective therapeutic remedy to prevent or slow down RP pathology.

摘要