Proteostasis modulation in inherited blinding disorders

标题：遗传性失明障碍中的蛋白平衡调节。 摘要：RPE或光感受器特异基因的错义突变常导致遗传性 致盲障碍。这些突变的基因经常产生高密度的蛋白质产物 不稳定，易于蛋白酶体降解。我们最近发明了一种新药 策略，并确定了一种能够稳定这些突变蛋白产物的小分子。在……里面 在这个项目中，我们将检验蛋白质平衡调节是一种可行的和 治疗此类蛋白所致遗传性致盲障碍的一般治疗策略 不稳定的错义突变。目前，还没有治愈或治疗大多数 这些令人眼花缭乱的疾病。为了满足这些未得到满足的医疗需求，我们将研究 我们新发现的小分子小分子蛋白抑制蛋白的特异性(Aim1)和机制(AIM2) 分子。此外，我们将用蛋白质平衡调节疗法的概念来证明 严重视力损害和失明的小鼠模型(Aim3)。这项研究将揭示小说 稳定功能丧失与遗传相关的蛋白质的分子途径 精神错乱。这样的通路将成为各种治疗分子的诱人靶点。

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.