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ATF6 is Required for ANP Secretion from the Heart

ATF6 是心脏分泌 ANP 所必需的

基本信息

批准号：
10219762
负责人：
Chris Glembotski
金额：
$ 34.54万
依托单位：
UNIVERSITY OF ARIZONA
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：
2018-12-15 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10219762
关键词：
ATF6 gene Acute Address Adult Affect Antioxidants Atrial Natriuretic Factor Biological Models Blood Pressure Blood Volume Calcium Cardiac Cardiac Myocytes Cardiovascular Physiology Cardiovascular system Cell Nucleus Cell membrane Cells Cessation of life Chronic Cleaved cell Coupled Cytoplasmic Granules Data Development Docking Elements Ensure Excretory function Foundations Gene Deletion Gene Expression Genes Goals Golgi Apparatus Growth Factor Receptors Heart Heart Atrium Heart failure Hormone secretion Hormones Hypertension Ion Channel Ischemia Link Mammalian Cell Mission Modeling Morbidity - disease rate Mus Muscle Cells Organ Oxidative Stress Pathologic Pathway interactions Plasma Play Proteins Public Health Quality Control Research Role Rough endoplasmic reticulum Route SNAP receptor SNAP23 gene Secretory Vesicles Site Stretching Time Tissues Transgenic Mice United States National Institutes of Health Vasodilation Ventricular base cardiovascular effects cell type design dietary endoplasmic reticulum stress gain of function hemodynamics in vivo innovation loss of function misfolded protein mortality mouse model novel novel strategies novel therapeutics peptide hormone pressure programs protein folding protein function protein misfolding salt sensitive hypertension small molecule transcription factor transcriptome

项目摘要

Project Summary ER protein misfolding is sensed in the rough ER by ATF6, which is expressed in all mammalian cells. We previously showed that in ventricular myocytes, in vivo, ischemia causes ER protein misfolding, which is sensed by ATF6, converting it to a transcription factor that induces antioxidant genes that were not known to be ATF6-regulated in any cell type. Our objective here is to study a new role for ATF6 as a critical element in regulated secretion, focusing on atrial natriuretic peptide (ANP), a peptide hormone made in the ER of atrial myocytes. Neither the function of ATF6 in the atria, nor its role in regulated hormone secretion has been studied. Therefore, this proposal addresses a novel role for ATF6 as a linchpin in regulated hormone secretion using a cardiac model system that we call the ATF6-ANP axis. Our preliminary data showed that under non- stressed conditions, in contrast to ventricular cell and tissue, activated ATF6 was found in atrial cell and tissue, even in the absence of ER stress. While activated ATF6 did not increase ANP gene expression in the atria, it was required for ANP secretion from atrial myocytes. Mechanistically, we found that ATF6 induced several secretory pathway proteins that were not previously known to be ATF6-regulated and have not been studied in the heart, including the SNARE protein, SNAP23. SNAP23 is known to enhance granule docking and secretion in other cell types. Based on this background and preliminary data, our hypothesis is that ATF6 is essential for the secretion and beneficial cardiovascular (CV) effects of ANP. SNAP23 is a mechanistic link between ATF6 and regulated ANP secretion. We will address this hypothesis in three specific aims, which are to: 1- examine the effects of AAV9- and small molecule-based ATF6 gain-of-function, and conditional ATF6 gene deletion maneuvers on ANP secretion from atrial myocytes and mouse hearts, 2-determine how ATF6 gain- and loss-of-function affects plasma ANP and hemodynamic parameters in mouse models of dietary high-salt- induced hypertension and pressure overload-induced heart failure, and 3-define the mechanistic role of the ATF6-inducible secretory granule docking protein, SNAP23, in ANP secretion from cultured atrial myocytes and mouse hearts.

项目总结