Proteostasis modulation in inherited blinding disorders

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， 治疗此类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。

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.