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Proteostasis modulation in inherited blinding disorders

遗传性致盲疾病中的蛋白质稳态调节

基本信息

批准号：
10215855
负责人：
Yoshikazu Imanishi
金额：
$ 36.71万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-01 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10215855
关键词：
11 cis Retinal Affect Ashkenazim Binding Biology Blindness Blood Blood-Retinal Barrier Cell membrane Cellular biology Chemicals Clarin-1 Cochlea Cone Cultured Cells Disease Gene Mutation Genes Genetic Goals HSF1 Hearing Heat shock proteins Heat-Shock Response Hereditary Disease Human In Vitro Industrialization Inherited Lead Location Mediating Medical Membrane Proteins Missense Mutation Modeling Molecular Molecular Chaperones Mus Mutate Mutation Nature Neurons North America Opsin Pathway interactions Pharmaceutical Chemistry Photoreceptors Production Proteasome Inhibitor Proteins Proteomics RPE65 protein Regulation Research Retinal Degeneration Rhodopsin Scientist Specificity Structure Systemic Therapy Technology Testing Therapeutic Therapeutic Agents Up-Regulation Usher Syndrome Type 3 Vision Vision research Visual impairment base chromophore drug candidate drug discovery glycosylation hearing impairment improved in vivo insight loss of function mouse model multicatalytic endopeptidase complex mutant neurotoxicity novel novel therapeutics photoreceptor degeneration prevent protein degradation protein folding proteostasis response retinol isomerase screening small molecule success therapeutic evaluation tool

项目摘要

Title: Proteostasis modulation in inherited blinding disorders. Abstract: Missense mutations of RPE or photoreceptor specific genes often cause inherited blinding disorders. These mutated genes frequently yield protein products that are highly unstable and prone to proteasomal degradation. We recently invented a novel drug discovery strategy and identified a small molecule which can stabilize these mutated protein products. In this project, we will test the therapeutic hypothesis that proteostasis modulation is a viable and general therapeutic strategy for treating inherited blinding disorders caused by such protein destabilizing missense mutations. Currently, no cures or treatments exist for the majority of these blinding disorders. Toward the goal of fulfilling such unmet medical needs, we will study the specificity (Aim1) and mechanism (Aim2) of the proteostasis modulation by our novel small molecule. Moreover, we will prove the concept of the proteostasis modulation therapy using mouse models of severe visual impairment and blindness (Aim3). This study will reveal novel molecular pathways for stabilizing proteins whose loss of functions are associated with inherited disorders. Such pathways will become attractive targets for various therapeutic molecules.

标题：遗传性致盲性疾病中的蛋白稳态调节。翻译后摘要：RPE或感光细胞特异性基因的错义突变往往导致遗传性致盲性疾病这些突变的基因经常产生蛋白质产物，不稳定且易于蛋白酶体降解。我们最近发明了一种新药策略，并确定了一个小分子，可以稳定这些突变的蛋白质产物。在在这个项目中，我们将测试治疗假设，即蛋白质稳态调节是一种可行的，治疗由这种蛋白质引起的遗传性致盲疾病的一般治疗策略破坏稳定的错义突变目前，对于大多数人来说，没有治愈或治疗方法。这些致盲性疾病为了满足这些未满足的医疗需求，我们将研究我们的新的小的蛋白抑制调节的特异性（Aim 1）和机制（Aim 2）分子。此外，我们将证明蛋白质稳态调节疗法的概念，严重视觉损伤和失明的小鼠模型（Aim3）。这项研究将揭示新的稳定蛋白质的分子途径，这些蛋白质的功能丧失与遗传性紊乱这些途径将成为各种治疗分子的有吸引力的靶标。