Conformational Diseases of the Secretory Pathway

描述（由申请人提供）： 在真核细胞中，预定用于细胞表面或外部环境的蛋白质首先易位到内质网（ER）中，在内质网中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需的。一级氨基酸序列的突变导致蛋白质错误折叠，并有助于疾病的发病机制。最近，我们对细胞机制的基本理解有了重大突破，这些细胞机制指导蛋白质折叠、修饰、运输、聚集和降解，以确保最终产物的保真度。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蛋白质的最终目的地。许多蛋白质伴侣已被确定为瞬时相互作用的折叠中间体和它们的作用，促进蛋白质折叠正在迅速阐明。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学，这些途径正在迅速得到阐明。本次会议将集中在一个新的遗传，生物化学和细胞生物学方法，以解开蛋白质折叠，加工和运输的复杂性在体内早期分泌途径。鉴定分泌中的限速步骤将提高从真核细胞以高水平产生复合蛋白的能力。一个研讨会将致力于阐明蛋白质伴侣蛋白在蛋白质折叠中的作用。了解野生型和突变蛋白如何折叠的基本过程可以被利用来开发治疗上有用的抑制剂或增效剂，用于这些过程，以靶向癌症，感染和免疫性疾病以及遗传疾病等病理。本次会议将重点关注新技术和方法来研究这个快速发展的领域，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.