Regulated exocytosis is a fundamental and critical cell biological process during which specialized secretory cells release cargo proteins in response to specific stimuli. This process has broad implications for human health, as dysfunction of regulated exocytosis results in many disorders, including the conspicuous example of impaired insulin secretion in diabetes mellitus. Developmental growth disorders, asthma, and thyroid dysfunction are also caused by abnormalities in regulated exocytosis. However, despite this critical importance for human health, major steps in the regulated exocytosis pathway remain poorly understood. There is a particular lack of understanding of mechanisms regulating maturation of cargo-carrying secretory granules, a step that is critical to render these specialized organelles competent for exocytosis and to ensure that the secreted cargo is biologically active. Progress has been inhibited largely because of a lack of a genetic context in which to study secretory granule maturation; previous studies have relied largely on visual observations via electron microscopy (EM) and biochemical separation and purification of secretory granules. Importantly, we have identified a novel, highly-conserved regulator of secretory granule maturation, named hobbit, with associated severe defects in regulated exocytosis in both neuroendocrine and epithelial cells. The long-term goal of this project is to identify and characterize novel proteins, including hobbit, that are required for regulated exocytosis. The overall objective of this application is to understand the function of hobbit and hobbit-dependent granule maturation during regulated exocytosis. Our central hypothesis is that hobbit, a novel component of the regulated exocytosis pathway, cooperates with the ESCRT machinery and Rab proteins to regulate the progression of secretory granules through the process of maturation. We intend to test the central hypothesis and accomplish the overall objective of this proposal by pursuing the following two specific aims: 1) What is the function of hobbit in regulated exocytosis; and 2) Define the molecular pathway in which hobbit functions. The focus of Aim 1 is to uncover the function of hobbit in secretory granule maturation. The focus of Aim 2 is to identify critical members of the hobbit-dependent secretory pathway, and to identify other new regulators of regulated exocytosis. Our contribution is significant because we have identified a previously uncharacterized regulator of secretory granule maturation, allowing us to genetically dissect the molecular pathway regulating this process. We expect this work to provide new mechanistic insights into the regulated exocytosis pathway, which will have important implications for our understanding of the etiology of secretion-related diseases, including diabetes.
The proposed research is relevant to public health because regulated exocytosis has been linked with a growing number of human pathologies, including diabetes mellitus, pituitary, thyroid, salivary, and adrenal gland dysfunction, asthma, chronic obstructive pulmonary disease (COPD), and hormone-related cancers. The new knowledge gained from our efforts will provide novel insights and a new framework for developing rationally-designed therapies to combat diseases that currently devastate millions of lives.
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