Endoglin: A New Target of Therapy for Heart Failure

内皮糖蛋白：心力衰竭治疗的新靶点

• 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
• 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

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RO 1提案探索了调节心脏纤维化的新机制，这是一个主要的 心力衰竭（HF）患者的发病率和死亡率的原因 在NIH-KO 8项目的支持下，我们将探索内皮素作用的新机制， 促纤维化细胞因子转化生长因子β（TGF β 1）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调节TGF β 1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TGF β 1介导的左和右心室（LV和RV）纤维化， 此外，内皮糖蛋白表达的降低提高了LV和RV衰竭模型的存活率。最近的数据 支持内皮糖蛋白是通过内皮中骨形态发生蛋白9（BMP 9）进行信号传导所需， 然而，尚未探索BMP 9在HF中的作用。目前的建议适用于内皮素的专业知识， 生物学、血液动力学和HF领域的TGF β介导的心脏纤维化，对此没有特异性治疗 目前存在。这项提议验证了内皮糖蛋白通过负性地调节心肌纤维化的新假设。 调节BMP 9，一种新的心脏成纤维细胞中TGF β 1介导的胶原合成的内源性抑制剂， 并且进一步地，降低内皮糖蛋白活性选择性地增加BMP 9丰度，从而限制心脏 纤维化和改善HF的存活率。提案中包括的初步数据显示，1）内皮糖蛋白和 BMP 9在心脏的非肌细胞群体中高度表达，2）内皮糖蛋白负调节BMP 9的表达。 BMP 9在人心脏成纤维细胞（hCF）中的表达，3）BMP 9抑制TGF β 1介导的胶原合成， hCF，4）TAC后BMP 9的损失促进LV纤维化，5）内皮糖蛋白活性降低增加BMP 9丰度 中和内皮糖蛋白可以逆转已建立的心脏纤维化。创新方面 建议包括：（a）使用hCF进行体外研究，（B）专门开发转基因小鼠来研究 （c）研究HF中内皮糖蛋白和BMP 9的组成和机械性能的开创性技术， d）测试靶向内皮糖蛋白和BMP 9活性在细胞外基质中的翻译潜力的研究， HF。为了验证这一假设，提出了三个目标：（SA 1）确定内皮糖蛋白的潜在机制， hCF中BMP 9信号传导的依赖性调节;（SA 2）确定内皮糖蛋白- HF中适应不良重塑的依赖性调节;（SA 3）测试靶向内皮糖蛋白/BMP 9的效用 逆转HF中已建立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，TGF β超家族的基本理解 信号传导和心脏重塑，对不断增长的HF患者群体具有重要意义。