Substance P: A central mediator of cardiac fibrosis and diastolic dysfunction

P物质：心脏纤维化和舒张功能障碍的中心介质

• 批准号: 9308567
• 负责人: WILLIAM BRYSON CAMPBELL
• 金额: $ 35.48万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9308567
• 关键词: Adverse effects; Amino Acids; Angiotensin II; Biological Process; Biological Response Modifier Therapy; CCR5 gene; Cardiac; Cardiac Myocytes; Cardiac development; Cells; Chymase; Coronary; Coronary artery; Development; Dissection; EFRAC; Endothelial Cells; Endothelin; Endothelin-1; Failure; Fibroblasts; Fibrosis; Functional disorder; Future; Goals; Heart; Heart Rate; Heart failure; Human; In Vitro; Infiltration; Infusion procedures; Length; MMP14 gene; Mediating; Mediator of activation protein; Molecular; Mus; Myocardial; Myofibroblast; Necrosis; Nerve; Neuropeptides; Nociception; Pathway interactions; Peptide Hydrolases; Phenotype; Physiological; Population; Process; Protein Isoforms; Receptor Activation; Regulation; Role; Small Interfering RNA; Stimulus; Stream; Stress; Substance P; Substance P Receptor; Tail; Testing; Therapeutic; Tryptase; Vasodilation; WNT Signaling Pathway; afferent nerve; beta catenin; coronary fibrosis; gene therapy; hemodynamics; in vivo; innovation; knock-down; macrophage; mast cell; novel; pressure; receptor; response; therapeutic target

We recently demonstrated that the sensory nerve neuropeptide substance P (SP) is required for the development of cardiac fibrosis in response to elevations in myocardial stress, specifically pressure overload (PO). Due to its localization to sensory nerves projecting to coronary arteries, SP is likely one of the first mediators released in response to changes in coronary pressure/flow. We believe that this places SP up- stream of multiple pro-fibrotic cascades, and we have identified several cell-specific effects initiated by SP in response to PO. Therefore, targeting SP holds real therapeutic potential, however, dissection of these cell- specific pathways is firstly required. What makes SP an even more attractive therapeutic target is the existence of two isoforms of its receptor, the neurokinin-1 receptor (NK-1R). We believe that the full length NK-1R mediates the physiological actions of SP, while the truncated isoform mediates the pro-fibrotic effects. Thus, it may be possible to selectively target the adverse effects of SP, while leaving the physiological actions intact. This proposal will examine the role of these NK-1R isoforms in mediating the cell-specific actions of SP on multiple pathways involved in cardiac fibrosis: 1) focal cardiomyocyte necrosis and the subsequent macrophage response; 2) SP/endothelin-1 interactions at the level of the cardiac fibroblast; and 3) mast cell- specific proteases. Our overall hypothesis is that SP acts via the truncated NK-1R to modulate cell-specific molecular pathways to promote cardiac fibrosis and diastolic dysfunction. Specific aim 1 will examine the extent to which SP activation of the NK-1R on sympathetic nerves initiates focal cardiomyocyte necrosis, a known stimulus for fibrosis. Further, the contribution to fibrosis of SP activated macrophages in response to focal necrosis will also be examined. Specific aim 2 will examine the synergistic actions of SP and endothelin-1 on cardiac fibroblast phenotype and function. This includes investigating truncated NK-1R activation of the membrane type 1 matrix metalloproteinase/TGF-β1 pathway in vitro. Myofibroblast-specific NK-1R-deficient mice will be used to examine the role of myofibroblast-specific NK-1Rs in vivo under conditions of PO. Specific aim 3 will identify the importance of mast cell-specific NK-1Rs in mediating the release of mast cell-derived pro-fibrotic molecules including tryptase and chymase. This proposal is significant and innovative because it will establish a neuropeptide as a mediator of cardiac fibrosis and diastolic dysfunction, as well as identifying cell-specific mechanisms by which SP promotes fibrosis. Of high significance is the existence of the two NK-1R isoforms, of which we believe the truncated isoform mediates the pro-fibrotic actions of SP. Thus, this proposal will identify a unique, actionable therapeutic target for diastolic dysfunction since antagonists, biologics, or gene therapy approaches specific to the truncated NK-1R could be developed.

我们最近证明，感觉神经肽P物质（SP）是需要的， 心肌应激升高（特别是压力超负荷）引起的心脏纤维化 （采购订单）。由于其定位于投射到冠状动脉的感觉神经，SP可能是最早的一种。 响应于冠状动脉压力/流量的变化而释放的介质。我们相信这会让SP上涨- 流的多个促纤维化级联反应，我们已经确定了几个细胞特异性的影响，启动SP在 回复PO因此，靶向SP具有真实的治疗潜力，然而，这些细胞的解剖- 首先需要具体的路径。是什么使SP成为一个更有吸引力的治疗目标是存在的 它的两种受体亚型，神经激肽-1受体（NK-1 R）。我们认为，全长NK-1 R 介导SP的生理作用，而截短的同种型介导促纤维化作用。因此 有可能选择性地针对SP的不利影响，同时保持生理作用不变。 该建议将研究这些NK-1 R亚型在介导SP对细胞的特异性作用中的作用。 心肌纤维化涉及多个途径：1）局灶性心肌细胞坏死和随后的 巨噬细胞反应; 2）SP/内皮素-1在心脏成纤维细胞水平的相互作用;和3）肥大细胞- 特异性蛋白酶我们的总体假设是，SP通过截短的NK-1 R调节细胞特异性 分子途径促进心脏纤维化和舒张功能障碍。具体目标1将审查 交感神经上NK-1 R的SP激活引发局灶性心肌细胞坏死的程度， 已知纤维化刺激物。此外，SP激活的巨噬细胞对纤维化的贡献是响应于 还将检查局灶性坏死。具体目标2将检查SP和内皮素-1的协同作用 对心脏成纤维细胞表型和功能的影响。这包括研究截短的NK-1 R活化， 膜1型基质金属蛋白酶/TGF-β1通路的体外研究。肌成纤维细胞特异性NK-1 R缺陷型 小鼠将用于检查PO条件下肌成纤维细胞特异性NK-1 R在体内的作用。具体 目的3将确定肥大细胞特异性NK-1 R在介导肥大细胞源性 促纤维化分子，包括类胰蛋白酶和糜蛋白酶。这一建议具有重要意义和创新性，因为它 将建立一种神经肽作为心脏纤维化和舒张功能障碍的介质，以及识别 SP促进纤维化的细胞特异性机制。重要的是两个NK-1 R的存在 同种型，其中我们认为截短的同种型介导SP的促纤维化作用。 将为舒张功能障碍确定一个独特的、可行的治疗靶点，因为拮抗剂、生物制剂或 可以开发对截短的NK-1 R特异的基因治疗方法。