Mechanisms of Endosomal Sorting

内体分选机制

• 批准号: 7010726
• 负责人: DAVID J KATZMANN
• 金额: $ 27.37万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-01 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7010726
• 关键词: Saccharomyces cerevisiae; biological signal transduction; chimeric proteins; genetic mapping; genetic regulatory element; genetic screening; growth factor receptors; intracellular transport; lipid transport; lysosomes; membrane transport proteins; protein degradation; protein protein interaction; protein structure function; protein transport; receptor expression; ubiquitin; vesicle /vacuole

DESCRIPTION (provided by applicant): The goal of this research proposal is to define the molecular mechanisms of cargo identification during the earliest event in the sorting of proteins into the multivesicular body (MVB) pathway. Function of the MVB pathway is critical for a number of cellular phenomena. For example, failure to target signaling growth factor receptors into the MVB pathway, for subsequent degradation in the lysosome ("downregulation"), results in prolonged signaling that can contribute to both tumorigenesis and defects in organismal development. Additionally, defects in downregulation of the epithelial sodium channel result in an inherited form of hypertension (Liddle's syndrome). Major Histocompatability Complex II (MHCII)-mediated immune response relies upon the function of an MVB-like structure, the MHCII-compartment. Aberrant trafficking of lipids through this pathway also contributes to a number of human disease states, including atherosclerosis. Finally, many of the functional components of the MVB pathway are usurped by certain viruses during their life cycle (e.g. HIV-1). We have chosen the model eukaryotic organism Saccharomyces cerevisiae to study the mechanism of cargo identification and sorting into the MVB pathway. We will utilize an ubiquitinindependent MVB cargo to identify cis- and trans-acting factors that coordinate this poorly understood mode of entry into the MVB pathway. Defining the molecular mechanisms that govern MVB cargo identification, a requisite step that dictates cargo entry into the MVB pathway, will yield significant contributions to the understanding of protein and lipid sorting in normal and disease states.

描述（由申请人提供）：本研究建议的目的是在最早将蛋白质分类为多卵形体（MVB）途径的最早事件中定义货物识别的分子机制。 MVB途径的功能对于许多细胞现象至关重要。例如，未能将信号传导生长因子受体靶向MVB途径，以使溶酶体（“下调”）的随后降解会导致延长信号传导，从而导致肿瘤发生和生物体发育的缺陷。另外，上皮钠通道下调的缺陷导致遗传的高血压形式（Liddle's综合征）。主要的组织兼容性复合物II（MHCII）介导的免疫反应依赖于MVB样结构的功能，即MHCII-Compartment。通过该途径对脂质的异常运输也有助于许多人类疾病状态，包括动脉粥样硬化。最后，MVB途径的许多功能成分在其生命周期中被某些病毒篡夺（例如HIV-1）。我们选择了酿酒酵母的真核生物模型进行研究 货物识别和分类为MVB途径的机制。我们将利用泛素独立的MVB货物来识别顺式和反式作用因子，以协调这种不理理解的进入MVB途径的方式。定义控制MVB货物识别的分子机制，这是决定货物进入MVB途径的必要步骤，将对正常和疾病状态中对蛋白质和脂质排序的理解产生重大贡献。