Liver Cell Membrane Protein-Expression and Function

总体描述（由申请人提供）： 这是一个继续研究特定肝细胞膜蛋白的功能和运输的计划项目。四个项目，涉及15名教师调查代表6个学术部门提出。这些项目分享想法、技术和经常见面的调查人员，包括正式和非正式的。拟议的研究代表了肝脏病理生物学中几个基本问题的多学科方法，包括特定细胞骨架元件上膜蛋白的运输机制（项目1），连接蛋白表达和运输的调节（项目2），内吞突变体中运输步骤的鉴定（项目3），以及自噬空泡和溶酶体的运输机制（项目4）。项目4是新项目，由于与现有三个项目的密切合作而被添加到该计划中。过去五年的主要成就包括：（项目1）在体外重建含有单纯疱疹病毒的早期和晚期内吞囊泡以及外吞囊泡的基于微管的运动性，并鉴定囊泡相关的马达和调节因子;（项目2）鉴定和表征连接蛋白32的蛋白质结合伴侣，其可以调节连接蛋白32向质膜和从质膜的运输;（项目3）发现潜在的分选热休克蛋白异源复合物与磷酸化脱唾液酸糖蛋白受体胞质结构域的缔合是由新的酪蛋白激酶2 α亚基CK 2介导的（“.该项目还包括三个核心设施。行政和支助服务核心（核心A）提供秘书、簿记和共用设备职能。分子细胞学核心（核心B）提供最先进的显微镜和成像服务。基于四个项目中每个项目对该技术的大量使用，增加了一个新的蛋白质组学核心（核心C）。所有四个项目都涉及肝细胞膜生物学和病理生物学的相关领域，每个拟议的项目都代表了独立研究者之间的合作努力。项目内部和项目之间的合作将个人的专业知识扩展到肝脏病理学的重要领域，否则无法进行有效的研究。跟踪记录表明，参与的调查人员能够在本计划的框架内协同工作和互动，以促进思想，方法和资源的共享。最终，在该计划中进行的研究将导致对理解和治疗或预防各种获得性和遗传性肝脏疾病至关重要的基本见解。

DESCRIPTION, OVERALL (provided by applicant): This is a Program Project to continue investigation of the functions and trafficking of specific liver cell membrane proteins. Four projects involving 15 faculty investigators representing 6 academic departments are proposed. These projects share ideas, techniques, and investigators who meet often, both formally and informally. The proposed studies represent multidisciplinary approaches to several fundamental questions in liver pathobiology including mechanisms of trafficking of membrane proteins on specific cytoskeletal elements (Project 1), the regulation of expression and trafficking of connexins (Project 2), the identification of trafficking steps in endocytosis mutants (Project 3), and mechanisms of trafficking to autophagic vacuoles and lysosomes (Project 4). Project 4 is new and was added to the Program because of strong collaborations that developed with the existing three Projects. Major accomplishments over the past 5 year period include: (Project 1) reconstitution in vitro of the microtubule-based motility of early and late endocytic vesicles as well as exocytosing vesicles that contain Herpes simplex virus and identification of vesicle-associated motors and regulatory factors; (Project 2) identification and characterization of protein binding partners for connexin 32 that may regulate its trafficking to and from the plasma membrane; (Project 3) discovery that the association of a potential sorting heat shock protein heterocomplex with the phosphorylated asialoglycoprotein receptor cytoplasmic domain is mediated by a novel casein kinase 2 alpha subunit, CK2(". This Program also includes three Core facilities. The Administrative and Supporting Services Core (Core A) provides secretarial, bookkeeping, and common equipment functions. The Molecular Cytology Core (Core B) provides state-of-the-art microscopy and imaging services. A new Proteomics Core (Core C) has been added based upon the substantial use of this technology by each of the four Projects. All four Projects are concerned with interrelated areas of hepatocyte membrane biology and pathobiology, and each proposed project represents collaborative efforts between independent investigators. Collaborations within and between projects lead to extensions of an individual's expertise into important areas of liver pathobiology that could not otherwise be effectively investigated. The track record demonstrates the ability of the investigators involved to work together and interact synergistically within the framework of this Program to promote the sharing of ideas, methodology, and resources. Ultimately, the studies performed in this Program will lead to fundamental insights that should be important for understanding and treating or preventing various acquired and inherited disorders of the liver.