Conformational Diseases of the Secretory Pathway

描述(由申请人提供)： 在真核细胞中，前往细胞表面或外部环境的蛋白质首先被转运到内质网(ER)，在那里发生初始蛋白质折叠和修饰，这对于蛋白质在转运到细胞表面之前获得其适当的功能构象是必不可少的。初级氨基酸序列的突变会导致蛋白质的错误折叠，从而导致疾病的发生。最近，我们对指导蛋白质折叠、修饰、运输、聚集和降解以确保最终产品保真度的细胞机制的基本理解取得了重大突破。特别是，新的见解表明，二硫键形成和碳水化合物修饰的调节直接指导了蛋白质的最终目的地。许多蛋白质伴侣已被鉴定为与折叠中间体瞬时相互作用，它们在促进蛋白质折叠中的作用正在迅速被阐明。现在很明显，细胞对蛋白质错误折叠的反应有助于许多疾病状态的病理，这些途径正在迅速被阐明。这次会议将集中在一种新的遗传、生化和细胞生物学方法上，以揭开体内早期分泌途径中蛋白质折叠、加工和运输的复杂性。识别分泌中的限速步骤将提高从真核细胞高水平生产复杂蛋白质的能力。研讨会将致力于阐明蛋白质伴侣在蛋白质折叠中的作用。了解野生型和突变蛋白折叠的基本过程，为这些过程开发治疗有用的抑制剂或增强剂，以针对从癌症、感染和免疫疾病以及遗传疾病等一系列疾病。本次会议将聚焦于研究这一快速发展的领域的新技术和新方法，以剖析ER功能的复杂性和多样性。

DESCRIPTION (provided by applicant): In eukaryotic cells, proteins destined for the cell surface or for the external milieu are first translocated into the endoplasmic reticulum (ER) where initial protein folding and modifications occur that are essential for the protein to attain its appropriate functional conformation prior to transit to the cell surface. Mutation in the primary amino acid sequence cause protein misfolding and contribute to disease pathogenesis. Recently there have been significant breakthroughs in our fundamental understanding of the cellular machinery that direct protein folding, modification, transport, aggregation, and degradation to ensure fidelity of the final product. In particular new insights show that regulation of disulfide bond formation and carbohydrate modification direct the ultimate destination for the protein. A number of protein chaperones have been identified that interact transiently with folding intermediates and their roles in facilitating protein folding are rapidly being elucidated. It is now evident that cellular responses to protein misfolding contribute to the pathology of numerous disease states and these pathways are rapidly being elucidated. This conference will focus on a novel genetic, biochemical, and cell biological approaches to unravel the complexities of protein folding, processing, and transport within the early secretory pathway in vivo. Identifying the rate limiting steps in secretion will improve the ability to produce complex proteins at high levels from eukaryotic cells. A workshop will be devoted to elucidate the role of protein chaperones in protein folding. Understanding the fundamental processes of how wild-type and mutant proteins fold can be exploited to develop therapeutically useful inhibitors or potentiators for these processes to target pathologies ranging from cancer, infection and immunological disorders, and genetic disease. This conference will focus on new technologies and methodologies to study this rapidly moving field in order to dissect the complexity and diversity of ER function.