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Proteins important for dense-core vesicle function

对致密核心囊泡功能重要的蛋白质

基本信息

批准号：
10337224
负责人：
Michael Ailion
金额：
$ 30.33万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-02-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10337224
关键词：
Affect Animals Attention deficit hyperactivity disorder Behavior Beta Cell Binding Biochemical Biogenesis Biogenic Amines Biological Biological Assay Biological Process Biology Blood Glucose Caenorhabditis elegans Calcium Cell Line Cells Chemicals Complex Data Defect Dense Core Vesicle Development Diabetes Mellitus Disease Drug Addiction Eating Disorders Endocrine Endocrine System Diseases Event Functional disorder Genetic Genetic Screening Goals Golgi Apparatus Growth Factor Hormone secretion Hormones Human In Vitro Knowledge Lead Mediating Medicine Membrane Mental Depression Mental disorders Metabolic Diseases Molecular Monomeric GTP-Binding Proteins Mood Disorders Nematoda Nerve Neuroendocrine Cell Neurons Neuropeptides Obesity Organelles Pathway interactions Peptides Phenotype Process Property Proteins Proteolytic Processing Role Schizophrenia Set protein Signaling Molecule Sorting - Cell Movement Structure Synaptic Vesicles Synaptic plasticity System Testing Work base biophysical properties blood glucose regulation experimental study golgin in vivo insight mutant nervous system disorder neuron development neuronal survival novel novel therapeutics pain sensation peptide hormone rab GTP-Binding Proteins response trafficking trans-Golgi Network vesicular release

项目摘要

The dense-core vesicle is an organelle that releases peptide hormones, growth factors, and biogenic amines from neurons and neuroendocrine cells in response to increases in calcium. Dense-core vesicle cargos regulate a variety of biological processes including neuronal survival and development, pain sensation, blood glucose homeostasis, and synaptic plasticity. As a consequence, numerous diseases such as mood disorders, obesity, and diabetes are caused by defects in neuropeptide and hormone secretion. Thus, it is important to determine the molecular machinery and mechanisms that orchestrate the biogenesis and release of these vesicular carriers. However, in comparison to other vesicular compartments such as synaptic vesicles, little is known about the molecular mechanisms of dense-core vesicle biogenesis, trafficking, and release. Dense-core vesicles are generated at the trans-Golgi and gain their compartmental identity in a poorly defined maturation process that occurs post-Golgi, but few molecules have been identified that function in these processes. Cargo sorting to dense-core vesicles remains a puzzle. The long-term goal of this project is to understand the molecular mechanisms by which dense-core vesicles are formed, sort cargos, and gain their compartmental identity. A first step towards this goal is to identify molecules required for dense-core vesicle biogenesis. We performed a genetic screen in the nematode C. elegans for mutants defective in dense-core vesicle function and identified a number of new proteins that act in dense-core vesicle biogenesis, including the small GTPase RAB-2 and CCCP-1, a RAB-2 effector, as well as the EARP endosomal trafficking complex. In this project, we will test how RAB-2 and its effectors interact with EARP to mediate cargo sorting to dense-core vesicles. In Aims 1 and 2, we will use genetic, biochemical and cell biological approaches in C. elegans and in the mammalian insulin-secreting cell line INS-1 832/13 to determine how and where the RAB-2 and EARP complexes are localized, whether they physically and functionally interact, and determine their precise roles in the sorting, processing, and secretion of dense-core vesicle cargos. In Aim 3, we will use a combination of in vitro biochemical approaches and in vivo functional assays to determine how the golgin-like coiled-coil protein CCCP-1 binds membranes and functions to mediate dense-core vesicle biogenesis. These studies will advance our understanding of how dense-core vesicles are generated and sort cargos, and provide general insights into mechanisms of membrane trafficking and cargo sorting controlled by multisubunit complexes that mediate trafficking between endosomal compartments and the trans-Golgi network.

密核囊泡是一种释放肽激素、生长因子和生物胺的细胞器