Endoglin: A New Target of Therapy for Heart Failure

内皮糖蛋白：心力衰竭治疗的新靶点

基本信息

批准号：
9158433
负责人：
Navin Kumar Kapur
金额：
$ 43.75万
依托单位：
TUFTS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-15 至 2021-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9158433
关键词：
ACVRL1 gene Accounting Activins Adult Affect Attenuated Biology Bone Morphogenetic Proteins Cardiac Cardiac Myocytes Cells Collagen Collagen Type I Complex Congestive Heart Failure Data Echocardiography Endoglin Endothelial Cells Endothelium Extracellular Matrix Failure Fibroblasts Fibrosis Glycoproteins Heart Heart failure Human Hypertrophy Hypoxia In Vitro Individual Knowledge Laboratories Laboratory Study Left Left Ventricular Function Ligand Binding Measures Mechanics Mediating Mediator of activation protein Modeling Molecular Morbidity - disease rate Mus Muscle Cells Myocardial Nature Pathway interactions Patients Phosphorylation Phosphotransferases Physiologic intraventricular pressure Physiology Population Pre-Clinical Model Property Proteins Public Health Receptor Signaling Regulation Reporting Research Personnel Role Signal Pathway Signal Transduction Specialist Staging System TGFB1 gene Techniques Testing Therapeutic Tissues Transforming Growth Factor beta Transgenic Mice Transgenic Model United States National Institutes of Health Ventricular Wild Type Mouse base bone morphogenetic protein 9 coronary fibrosis cytokine design gain of function hemodynamics human tissue improved inhibitor/antagonist innovation insight loss of function mortality mouse model neutralizing antibody new therapeutic target novel novel strategies novel therapeutics patient population programs receptor recombinant peptide response targeted treatment therapeutic development

项目摘要

This new early stage investigator RO1 proposal explores new mechanisms regulating cardiac fibrosis, a major cause of morbidity and mortality for patients with heart failure (HF) Based on exciting new data generated with support from the NIH-KO8 program, we will explore a new mechanism for the role of endoglin, an auxiliary receptor for the pro-fibrogenic cytokine transforming growth factor beta (TGFb1), as a mediator of maladaptive cardiac remodeling. The PI is an advanced HF specialist, whose laboratory studies molecular mechanisms regulating TGFb1 and endoglin activity using preclinical models of HF and human tissue. The Kapur laboratory recently reported that endoglin facilitates TGFb1-mediated left and right ventricular (LV and RV) fibrosis, and further, that reduced endoglin expression improves survival in models of LV and RV failure. More recent data support that endoglin is required for signaling via bone morphogenetic protein 9 (BMP9) in endothelium, however a role for BMP9 in HF has not been explored. The current proposal applies expertise in endoglin biology, hemodynamics, and HF to the field of TGFb-mediated cardiac fibrosis, for which no specific therapy currently exists. This proposal tests the novel hypothesis that endoglin promotes cardiac fibrosis by negatively regulating BMP9, a new endogenous inhibitor of TGFb1-mediated collagen synthesis in cardiac fibroblasts, and further that reducing endoglin activity selectively increases BMP9 abundance, thereby limiting cardiac fibrosis and improving survival in HF. Preliminary data included in the proposal shows that 1) endoglin and BMP9 are highly expressed by non-myocyte cell populations in the heart, 2) endoglin negatively regulates BMP9 expression in human cardiac fibroblasts (hCF), 3) BMP9 inhibits TGFb1 mediated collagen synthesis in hCF, 4) loss of BMP9 promotes LV fibrosis after TAC, 5) reduced endoglin activity increases BMP9 abundance in the LV, and 6) neutralizing endoglin can reverse established cardiac fibrosis. Innovative aspects of the proposal include: (a) the use of hCF for in vitro studies, (b) transgenic mice developed specifically to study endoglin and BMP9 in HF, (c) pioneering techniques to study composition and mechanical properties of the extracellular matrix, and d) studies to test the translational potential of targeting endoglin and BMP9 activity in HF. To test this hypothesis three aims are proposed: (SA1) Determine the mechanisms underlying endoglin- dependent regulation of BMP9 signaling in hCF; (SA2) Determine the mechanisms underlying endoglin- dependent regulation of maladaptive remodeling in HF; (SA3) Test the utility of targeting endoglin/BMP9 activity to reverse established cardiac fibrosis in HF. This proposal explores a paradigm shifting hypothesis that has tremendous potential to impact our basic understanding of cardiac fibroblast physiology, TGFb superfamily signaling, and cardiac remodeling with important implications for the growing population of patients with HF.

这项新的早期研究者 RO1 提案探索了调节心脏纤维化的新机制，心脏纤维化是一个主要的疾病心力衰竭 (HF) 患者发病和死亡的原因基于以下令人兴奋的新数据在NIH-KO8计划的支持下，我们将探索内皮糖蛋白（endoglin）作用的新机制。促纤维化细胞因子转化生长因子β（TGFb1）的受体，作为适应不良的介质心脏重塑。 PI 是一位高级 HF 专家，其实验室研究分子机制使用 HF 和人体组织的临床前模型调节 TGFb1 和内皮糖蛋白活性。卡普尔实验室最近报道内皮糖蛋白促进 TGFb1 介导的左心室和右心室（LV 和 RV）纤维化，并且此外，内皮糖蛋白表达的减少可以提高左心室和右心室衰竭模型的生存率。更多最新数据支持内皮因子通过内皮细胞中的骨形态发生蛋白 9 (BMP9) 发出信号需要内皮糖蛋白，然而，BMP9 在心力衰竭中的作用尚未被探索。目前的提案应用了内皮糖蛋白方面的专业知识生物学、血流动力学和心力衰竭对 TGFb 介导的心脏纤维化领域的影响，目前尚无具体治疗方法目前存在。该提案测试了内皮糖蛋白通过负向促进心脏纤维化的新假设调节 BMP9，一种新型内源性抑制剂，抑制心脏成纤维细胞中 TGFb1 介导的胶原蛋白合成，进一步说，降低内皮糖蛋白活性选择性地增加 BMP9 丰度，从而限制心脏纤维化并提高心力衰竭患者的生存率。该提案中包含的初步数据表明 1) 内皮糖蛋白和 BMP9 在心脏中的非肌细胞细胞群中高表达，2) 内皮糖蛋白负调节 BMP9 在人心脏成纤维细胞 (hCF) 中的表达，3) BMP9 抑制 TGFb1 介导的胶原合成 hCF，4) TAC 后 BMP9 缺失促进左室纤维化，5) 内皮糖蛋白活性降低增加 BMP9 丰度 6) 中和内皮糖蛋白可以逆转已形成的心脏纤维化。的创新方面提案包括：(a) 使用 hCF 进行体外研究，(b) 专门开发用于研究的转基因小鼠 HF 中的内皮糖蛋白和 BMP9，(c) 研究内皮糖蛋白和 BMP9 的组成和机械性能的开创性技术细胞外基质，以及 d) 测试靶向内皮糖蛋白和 BMP9 活性的翻译潜力的研究高频。为了检验这一假设，提出了三个目标：（SA1）确定内皮糖蛋白的潜在机制 hCF 中 BMP9 信号传导的依赖性调节； (SA2) 确定内皮糖蛋白的潜在机制心衰中适应不良重塑的依赖性调节； (SA3) 测试靶向内皮糖蛋白/BMP9的效用逆转心力衰竭中已形成的心脏纤维化的活性。该提案探讨了一种范式转变假设具有巨大的潜力影响我们对心脏成纤维细胞生理学、TGFb 超家族的基本理解信号传导和心脏重塑对不断增长的心力衰竭患者群体具有重要意义。