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Massive Cardiac Endocytosis and Ectosome Shedding

大量心脏内吞作用和外体脱落

基本信息

批准号：
9920758
负责人：
DONALD W HILGEMANN
金额：
$ 40.5万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-01 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9920758
关键词：
Acyl Coenzyme A Acylation Acyltransferase Affect Anoxia Cardiac Cardiac Myocytes Carnitine Caspase Cause of Death Cells Cessation of life Chronic Chronic Disease Clinical Coenzyme A Coupled Cytoskeleton Degenerative Disorder Development Diagnosis Disease Drug Targeting Endocytosis Endocytosis Pathway Enzymes Event Extracellular Space G2A receptor Generations Glyburide Heart Hepatitis Individual Intervention JUN gene Life Link Lipids Lymphocyte Lysophosphatidylcholines Malignant Neoplasms Mediating Membrane Membrane Proteins Metabolic stress Mitochondria Molecular Mus Muscle Cells NADPH Oxidase Neurodegenerative Disorders Nonesterified Fatty Acids Nucleotides Oxidative Stress Pathologic Pathway interactions Peptides Permeability Pharmaceutical Preparations Phase Phospholipase A2 Phospholipids Physiological Physiology Play Process Proteins Public Health Reaction Reactive Oxygen Species Reperfusion Injury Role Sarcolemma Second Messenger Systems Sepsis Signal Pathway Signal Transduction Surface Testing Variant Work acylcarnitine drug discovery fatty acid metabolism heart function inhibitor/antagonist insight lipid metabolism mitochondrial dysfunction mitochondrial metabolism mitochondrial permeability transition pore monolayer novel therapeutics oxidation palmitoylation platelet activating factor receptor prevent protein aggregation protein protein interaction receptor tool trait

项目摘要

ABSTRACT This project focuses on cardiac signaling pathways in which lipid metabolism, coupled to mitochondrial activity state, promote massive sarcolemma internalization via endocytosis (MEND) and/or massive ectosome shedding (MESS) to the extracellular space. The endocytosis pathway depends on fatty acid metabolism and the generation of cytoplasmic acyl-coenzyme A that is used to lipidate numerous sarcolemmmal proteins. The shedding pathway depends primarily on the generation of lysophosphatidylcholine, the activation of its receptors in the cardiac myocyte, and subsequent scrambling of sarcolemmal phospholipids between monolayers. Both mechanisms appear to depend on the generation of ordered membrane domains within the sarcolemma which then facilitate unique protein-protein interactions and functions. Both mechanisms are expected to play major roles in membrane remodeling that occurs in ischemia/reperfusion injury, as well as in major chronic, degenerative diseases involving oxidative stress. Using multiple mice lines with deficiencies in these pathways, as well as drugs to manipulate individual reactions, we will analyze the commonalities and distinctive traits of these pathways, identify the essential molecular players, factors that decisively push the sarcolemma to MEND or MESS, and define more precisely the physiological and pathological roles of MEND and MESS. The project will provide insight into fundamental cell regulatory mechanisms that have a high impact for an understanding of the leading causes of death in the developed world.

摘要