Asporin, an extracellular protein, regulates cardiac remodeling

阿孢菌素是一种细胞外蛋白，调节心脏重塑

• 批准号: 10441587
• 负责人: Sarah J Parker
• 金额: $ 41.75万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10441587
• 关键词: Address; Anabolism; Angiotensin II; Autophagocytosis; Binding; Biological; Biology; Blood flow; Cardiac; Cardiac Myocytes; Cell Death; Cell Survival; Cells; Cicatrix; Core Protein; Degenerative polyarthritis; Deposition; Economics; Exhibits; Extracellular Matrix; Extracellular Matrix Proteins; Extracellular Protein; Fibrillar Collagen; Fibroblasts; Fibrosis; Functional disorder; Genes; Glycosaminoglycans; Glycosphingolipids; Goals; Grant; Health; Heart; Heart Block; Heart Injuries; Heart failure; Hypertrophy; Hypoxia; In Vitro; Infarction; Investigation; Knockout Mice; Leucine; Ligands; Link; Malignant Neoplasms; Mediating; Metabolic; Modification; Morbidity - disease rate; Mus; Myocardial Ischemia; Operative Surgical Procedures; Osteoporosis; Pathologic; Pathway interactions; Patients; Peptides; Play; Process; Proteins; Proteoglycan; Public Health; Pyrimidine; Recombinants; Regulation; Reperfusion Injury; Research; Role; Signal Transduction; Stress; Testing; Therapeutic Intervention; Transforming Growth Factor beta; Treatment Efficacy; asporin; base; biglycan; cell behavior; cell type; coronary fibrosis; decorin; design; heart function; improved; in vivo; inhibitor; innovation; insight; ischemic injury; macrophage; metabolic profile; metabolome; mortality; mouse model; novel; novel therapeutic intervention; novel therapeutics; peptide drug; pleiotropism; pressure; prevent; protective effect; public health relevance; purine metabolism; receptor; response; therapeutic evaluation; therapeutic target; therapeutically effective

Project Summary Extracellular matrix (ECM) is critical during cardiac remodeling in altering the cell’s response. Recently, class I small leucine rich proteoglycans (SLRPs) showed enormous impact on the heart’s function during ischemic injury or cardiac remodeling. Adverse cardiac remodeling stimulates fibrotic scar deposition due to increased TGFβ activity on fibroblasts. In the last decade, a non-conventional class I SLRP protein, asporin (ASPN), has been shown to play a role in regulating TGFβ signaling and cell viability in cancer and osteoporosis. The biological impact of ASPN in regulating TGFβ and cell viability in heart is unknown. Our long-term goal is to dissect the detailed mechanisms regulating ASPN activity and its impact on fibroblasts and cardiomyocytes, particularly in the setting of cardiac remodeling. These discoveries will facilitate design of effective ASPN-based therapies for heart failure. The objective of this grant is to characterize the role of ASPN in fibrosis and cardiomyocyte cell viability. Our central hypothesis is that ASPN is released by fibroblasts during cardiac stress and inhibits TGFβ signaling to reduce fibrosis during cardiac remodeling. Further, released ASPN acts on cardiomyocytes to upregulate autophagy and prevent cell death. Our rationale is that identification of the mechanisms to stimulate ASPN-protective effects in cardiac remodeling will offer new therapeutic opportunities. This project will further test therapeutic peptide delivery as well as AAV9-mediated delivery of ASPN gene for efficacy in mitigating reperfusion injury and cardiac remodeling. Our specific aims will test the following hypotheses: (Aim 1) ASPN inhibits fibrosis to maintain cardiac function and prevents adverse cardiac remodeling; (Aim 2) ASPN induces autophagy in cardiomyocytes; (Aim 3) ASPN regulates cardiomyocyte cell death in the setting of ischemia- reperfusion injury. Upon conclusion, we will better understand the role of novel role of ASPN in inhibiting fibrosis and activating autophagy for beneficial cardiac remodeling. This contribution is significant since it will establish the several pathways targeted by ASPN from ECM to fibroblasts and cardiomyocytes. Furthermore, current therapies, while promising in limiting ischemic injury, fail to address the key issue of adverse cardiac remodeling in heart failure patients. The proposed research is innovative as we will investigate the effects of ASPN in regulating fibrosis and cardiomyocyte cell death, an unexamined process to date. Insight into the mechanisms of ASPN activity will pave the way for ASPN-based therapies to benefit cardiac remodeling.

项目总结