Endoglin: A New Target of Therapy for Heart Failure

这项新的早期研究人员RO1提案探索了调控心脏纤维化的新机制，心脏纤维化是一种主要的 心力衰竭(HF)患者的发病率和死亡率的原因基于令人兴奋的新数据 在NIH-KO8计划的支持下，我们将探索一种新的机制来发挥endoglin的作用，一个辅助 促纤维化细胞因子转化生长因子β受体(TGFb1)作为适应不良的媒介 心脏重塑。PI是一位高级HF专家，其实验室研究分子机制 使用心衰和人体组织的临床前模型调节TGFb1和endoglin的活性。卡普尔实验室 最近报道，endoglin促进TGFb1介导的左、右室(LV和RV)纤维化，以及 此外，Endoglin表达的减少改善了LV和RV衰竭模型的存活率。更新的数据 支持内皮细胞通过骨形态发生蛋白9(BMP9)传递信号需要endoglin， 然而，BMP9在心力衰竭中的作用还没有被探索。当前的提案应用了内在化方面的专业知识 生物学、血流动力学和心力衰竭涉及TGFb介导的心肌纤维化领域，目前尚无特效治疗方法 目前存在。这项提议检验了新的假设，即内源性通过负性作用促进心脏纤维化。 调节心脏成纤维细胞中一种新的内源性抑制TGFb1介导的胶原合成的BMP9 此外，降低endoglin活性选择性地增加BMP9的丰度，从而限制心脏 肝纤维化和提高心衰存活率。提案中包括的初步数据显示，1)endoglin和 BMP9在心脏的非心肌细胞群中高度表达，2)endoglin负性调节 BMP9在人心脏成纤维细胞中的表达，3)BMP9抑制TGFb1介导的胶原合成 HCF，4)BMP9丢失促进TAC后左室纤维化，5)Enoglin活性降低增加BMP9丰度 6)中和内源性可以逆转已建立的心肌纤维化。的创新之处 建议包括：(A)使用HCF进行体外研究，(B)专门为研究而开发的转基因小鼠 Endoglin和BMP9在HF中，(C)研究成分和机械性能的开创性技术 细胞外基质，以及d)测试靶向endoglin和BMP9活性的翻译潜力的研究 高频。为了验证这一假说，提出了三个目标：(SA1)确定内吞的潜在机制-- BMP9信号在HCF中的依赖调节；(SA2)决定了内分泌的机制。 心衰患者适应性不良重构的依赖性调节；(SA3)检测靶向endoglin/BMP9的有效性 逆转心力衰竭已建立的心肌纤维化的活性。这一提议探索了一个范式转换假说，即 有巨大的潜力影响我们对心脏成纤维细胞生理学的基本理解，TGFb超家族 信号转导和心脏重构对不断增长的心力衰竭患者具有重要意义。

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.