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: 10658863
• 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/10658863
• 关键词: Address; Anabolism; Angiotensin II; Autophagocytosis; Binding; Biological; Biology; Blood flow; Cardiac; Cardiac Myocytes; Cell Death; Cell Death Induction; 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; Macrophage; 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; biglycan; cell behavior; cell type; coronary fibrosis; decorin; design; heart function; improved; in vivo; inhibitor; innovation; insight; ischemic injury; 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; Address; Anabolism; Angiotensin II; Autophagocytosis; Binding; Biological; Biology; Blood flow; Cardiac; Cardiac Myocytes; Cell Death; Cell Death Induction; 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; Macrophage; 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; biglycan; cell behavior; cell type; coronary fibrosis; decorin; design; heart function; improved; in vivo; inhibitor; innovation; insight; ischemic injury; 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.

项目摘要 在心脏重塑过程中，细胞外基质（ECM）在改变细胞的反应时至关重要。最近，第一级 富含亮氨酸的小蛋白聚糖（SLRP）在缺血性损伤过程中对心脏的功能显示出巨大影响 或心脏重塑。不良心脏重塑刺激TGFβ增加的纤维化疤痕沉积 成纤维细胞的活性。在过去的十年中，非常规I类SLRP蛋白Asporin（ASPN）已经是 证明在调节癌症和骨质疏松症中的TGFβ信号传导和细胞活力中发挥作用。生物学 ASPN在调节TGFβ和心脏中细胞活力中的影响尚不清楚。我们的长期目标是剖析 调查ASPN活性及其对成纤维细胞和心肌细胞的影响的详细机制，尤其是在 心脏重塑的设置。这些发现将有助于设计有效的基于ASPN的疗法 心脏衰竭。该赠款的目的是表征ASPN在纤维化和心肌细胞中的作用 生存能力。我们的中心假设是ASPN在心脏应激期间由成纤维细胞释放并抑制TGFβ 信号传导以减少心脏重塑期间的纤维化。此外，释放的ASPN作用于心肌细胞 上调自噬并防止细胞死亡。我们的理由是识别刺激机制 心脏重塑中的ASPN保护作用将提供新的治疗机会。这个项目将进一步 测试治疗肽的递送以及AAV9介导的ASPN基因的递送，以降低效率 再灌注损伤和心脏重塑。我们的具体目的将检验以下假设：（目标1）ASPN 抑制纤维化以维持心脏功能并防止心脏不良重塑； （目标2）ASPN影响 心肌细胞自噬； （AIM 3）ASPN在缺血的情况下调节心肌细胞细胞死亡 再灌注损伤。总结一下，我们将更好地了解ASPN新作用在抑制纤维化中的作用 并激活自噬以进行有益心脏重塑。这种贡献很重要，因为它将建立 ASPN从ECM到成纤维细胞和心肌细胞靶向的几种途径。此外，当前 疗法虽然有限制性缺血损伤有望解决，但无法解决不良心脏重塑的关键问题 在心力衰竭患者中。拟议的研究具有创新性，因为我们将研究ASPN的影响 调节纤维化和心肌细胞死亡，这是迄今为止的意外过程。洞悉机制 ASPN活性的OF将为基于ASPN的疗法铺平道路，以使心脏重塑受益。