Deciphering novel protein quality control pathways in the nuclear periphery

描述（由申请人提供） 翻译后摘要：核血管病包括各种疾病，从肌肉骨骼疾病神经元缺陷。其中最严重的表现是早衰综合征和埃默里-德赖富斯营养不良（EMD）。患有早衰综合征的儿童遭受严重加剧的衰老症状，并在青少年中期死于这种疾病。EMD表现为肌肉萎缩、运动性进行性丧失、心力衰竭，并可导致猝死。 包膜病是由突变引起的，这些突变影响了存在于核膜或底层的蛋白质，这是一种有助于核稳定性的丝状网络。虽然许多这些疾病的遗传基础已经建立，但导致病理学的潜在机制仍然知之甚少。发现显性等位基因作为许多核分裂症的遗传基础，以及这些等位基因中的几个在动物模型中遗传消融后不显示表型的事实，使我们提出这些等位基因至少部分通过蛋白毒性起作用。这些疾病的共同点是受影响的蛋白质定位于核膜和核纤层。在这些位点负责蛋白质修复和周转的细胞机制在很大程度上是未知的。重要的是，目前还没有已知的机制来解释细胞核中蛋白质聚集体的周转，这在我们对细胞蛋白质质量控制的理解中定义了一个主要的空白。目前，没有合适的读数可用于评估蛋白毒性是否实际上是核毒性病因学的一个促成因素。我们建议开发一种新的方法，使我们能够从蛋白质质量控制的角度来仔细检查细胞病变，并确定细胞机制，保障蛋白质质量控制在核膜和纤层。此外，我们将利用保守的疱疹病毒装配机械作为独特的手柄，以确定涉及调节核膜的动态，特别是蛋白质聚集体跨核膜的运输的细胞因子。总的来说，我们的努力将使我们能够确定在核外围保护蛋白质稳态的有效途径。我们的研究成果与核移植和病毒感染的治疗直接相关。 公共卫生相关性：细胞蛋白质质量控制系统的已知组分的药理学调节剂已经用于治疗囊性纤维化和癌症等多种疾病，或者处于临床试验的后期阶段。通过描述核外围的质量控制机制，我们将增加药物靶点的库，并促进随后开发可用于治疗核血管病的新治疗策略。此外，所提出的活性将导致病毒组装所需的细胞因子的鉴定，从而定义用于治疗性干预的新靶点，可用于治疗病毒感染。

DESCRIPTION (Provided by the applicant) Abstract: Nuclear envelopathies encompass a variety of diseases, ranging from musculoskeletal disorders to neuronal defects. Amongst the most severe manifestations are progeria syndromes and Emery-Dreifuss dystrophies (EMD). Children affected with progeria syndromes suffer from grossly exacerbated aging symptoms and succumb to the disease in their mid-teens. EMD presents with muscle wasting, progressive loss of motility, heart failure and can lead to sudden death. Envelopathies are caused by mutations that affect proteins that reside in the nuclear envelope or the underlying lamina, a filamentous network that contributes to nuclear stability. Although the genetic basis for many of these diseases is established, the underlying mechanisms that lead to pathology remain poorly understood. The discovery of dominant alleles as genetic basis for many nuclear envelopathies, and the fact that several of those alleles do not display a phenotype upon genetic ablation in animal models, lead us to propose that these alleles act at least in part through proteotoxicity. Common to these diseases is the localization of the affected proteins to the nuclear envelope and lamina. The cellular mechanisms responsible for protein repair and turnover at these sites are largely unknown. Importantly, there is no known mechanism that accounts for turnover of protein aggregates in the nucleus, defining a major gap in our understanding of cellular protein quality control. At present, there are no suitable readouts available to assess whether proteotoxicity is in fact a contributing factor in the etiology of nuclear envelopathies. We propose to develop novel methodology that will allow us to scrutinize envelopathies from the perspective of protein quality control, and to identify the cellular mechanisms that safeguard protein quality control in the nuclear envelope and lamina. Moreover, we will exploit the conserved herpesvirus assembly machinery as unique handle to identify cellular factors implicated in regulating the dynamics of the nuclear envelope, and, specifically, transport of protein aggregates across the nuclear envelope. Collectively, our efforts will enable us to identify the pathways that are operative to safeguard protein homeostasis in the nuclear periphery. The results from our research endeavors have direct relevance for treatment of nuclear envelopathies and viral infections. Public Health Relevance: Pharmacological modulators of known components of the cellular protein quality control system are already in use for treatment of diseases as diverse as cystic fibrosis and cancer, or are in late stages of clinical trials. By delineating the quality control mechanisms in the nuclear periphery, we will add to the repertoire of drug targets, and facilitate the subsequent development of novel therapeutic strategies that can be used to treat nuclear envelopathies. In addition, the proposed activity will lead to the identification of cellular factors required for virus assembly, and thus define novel targets for therapeutic intervention, useful for the treatment of viral infections.