Deciphering novel protein quality control pathways in the nuclear periphery

破译核外围新的蛋白质质量控​​制途径

• 批准号: 8146585
• 负责人: Christian Dirk Schlieker
• 金额: $ 249.35万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-30 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8146585
• 关键词: Ablation; Accounting; Affect; Aging; Alleles; Animal Model; Carrier Proteins; Cell Nucleus; Child; Clinical Trials; Cystic Fibrosis; Defect; Development; Disease; Drug Delivery Systems; Emery-Dreifuss Muscular Dystrophy; Etiology; Genetic; Heart failure; Herpesviridae; Homeostasis; Lead; Malignant Neoplasms; Methodology; Muscle; Musculoskeletal Diseases; Mutation; Neurons; Nuclear; Nuclear Envelope; Nuclear Lamina; Pathology; Pathway interactions; Phenotype; Progeria; Proteins; Quality Control; Research; Site; Staging; Sudden Death; Symptoms; Syndrome; System; Teenagers; Therapeutic Intervention; Virus Assembly; Virus Diseases; abstracting; base; cell motility; novel; novel therapeutics; protein aggregate; public health relevance; repaired; wasting

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.

描述（由申请人提供） 摘要：核包膜病涵盖多种疾病，从肌肉骨骼疾病到神经元缺陷。最严重的表现是早衰综合症和 Emery-Dreifuss 营养不良 (EMD)。患有早衰综合症的儿童会遭受严重加剧的衰老症状，并在十几岁的时候死于这种疾病。 EMD 表现为肌肉萎缩、进行性运动丧失、心力衰竭，并可能导致猝死。 包膜病是由影响核膜或底层核膜中蛋白质的突变引起的，核膜是一种有助于核稳定性的丝状网络。尽管许多这些疾病的遗传基础已经确定，但导致病理学的潜在机制仍然知之甚少。显性等位基因作为许多核包膜病的遗传基础的发现，以及其中一些等位基因在动物模型中基因消融后不表现出表型的事实，使我们提出这些等位基因至少部分通过蛋白质毒性起作用。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。负责这些位点的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，没有已知的机制可以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​​制的理解上存在重大差距。目前，还没有合适的读数来评估蛋白毒性实际上是否是核包膜病病因学的一个促成因素。我们建议开发新的方法，使我们能够从蛋白质质量控​​制的角度仔细检查包膜病，并确定保障核膜和核纤层中蛋白质质量控​​制的细胞机制。此外，我们将利用保守的疱疹病毒组装机制作为独特的手柄来识别与调节核膜动力学有关的细胞因子，特别是跨核膜的蛋白质聚集体运输。总的来说，我们的努力将使我们能够确定可有效维护核外围蛋白质稳态的途径。我们的研究成果与核包膜病和病毒感染的治疗有直接关系。 公共健康相关性：细胞蛋白质质量控​​制系统已知成分的药理学调节剂已用于治疗囊性纤维化和癌症等多种疾病，或处于临床试验的后期阶段。通过描绘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包膜病的新型治疗策略。此外，所提出的活动将导致病毒组装所需的细胞因子的鉴定，从而确定治疗干预的新靶标，可用于治疗病毒感染。