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.

这个新的早期研究者RO1提案探讨了调节心脏纤维化的新机制，这是一个主要的基于带有令人兴奋的新数据的心力衰竭（HF）的发病率和死亡率的原因 NIH-KO8计划的支持，我们将探索一种新的机制，以实现Endoglin（辅助）的角色促纤维化细胞因子转化生长因子β（TGFB1）的受体，作为适应不良的介体心脏重塑。 PI是高级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来调节TGFB1和内源活性。卡普尔实验室最近报道说，内聚元促进TGFB1介导的左右心室（LV和RV）纤维化，以及此外，降低的内聚糖表达可改善LV和RV衰竭模型中的生存。最新数据通过骨形态发生蛋白9（BMP9）在内皮中进行信号传导所必需的支持，但是，尚未探索BMP9在HF中的作用。当前的提案在内糖林中应用专业知识生物学，血流动力学和HF到TGFB介导的心脏纤维化领域，没有特定的治疗目前存在。该提案检验了新的假设，即内og以否定性地促进心脏纤维化调节BMP9是一种新的TGFB1介导的胶原蛋白合成的内源性抑制剂，在心脏成纤维细胞中，此外，减少内核活动有选择地增加BMP9的丰度，从而限制心脏 HF中的纤维化和改善生存率。提案中包含的初步数据表明1）Endoglin和 BMP9由心脏中的非肌细胞细胞种群高度表达人类心脏成纤维细胞中的BMP9表达（HCF），3）BMP9抑制TGFB1介导的胶原蛋白合成 HCF，4）BMP9的损失促进了TAC后的LV纤维化，5）降低的内聚糖活性增加了BMP9的丰度在LV中，和6）中和内尾可以逆转确定的心脏纤维化。创新方面建议包括：（a）使用HCF进行体外研究，（b）专门研究的转基因小鼠 HF中的Endoglin和BMP9，（C）研究组成和机械性能的开创性技术细胞外基质和d）研究以测试靶向内源和BMP9活性的翻译潜力 HF。为了检验该假设，提出了三个目标：（SA1）确定内og的机制 HCF中BMP9信号的依赖调节；（sa2）确定内糖林的基础机制 HF中适应不良重塑的依赖调节；（SA3）测试靶向内og/bmp9的效用在HF中逆转了建立的心脏纤维化的活性。该提案探讨了一个范式转移假设具有影响我们对心脏成纤维细胞生理学的基本理解的巨大潜力，TGFB超家族信号传导和心脏重塑对不断增长的HF患者人群的重要意义。