Regulation of Cardiac Collagen Content by SLIT3

SLIT3 对心脏胶原蛋白含量的调节

• 批准号: 10522302
• 负责人: Ming-Sing Si
• 金额: $ 64.89万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10522302
• 关键词: Acute; Adult; Affect; Binding; Blood capillaries; Cardiac; Cells; Chronic; Clinical; Collagen; Data; Defect; Deposition; Development; Diabetes Mellitus; EFRAC; Event; Extracellular Matrix; Eye; Fibroblasts; Fibrosis; Glycoproteins; Goals; Hand; Heart Diseases; Heart Transplantation; Heart failure; Homeostasis; In Vitro; Knock-out; Knockout Mice; Left ventricular structure; Link; LoxP-flanked allele; MADH3 gene; Mediating; Molecular; Mus; Myocardial; Myocardial Infarction; Obesity; Pathogenesis; Pathologic; Pathology; Patients; Pericytes; Perivascular Fibrosis; Phosphorylation; Physiologic intraventricular pressure; Population; Production; Proteins; Publishing; Regulation; Reporting; Research; Role; SRGAP2 gene; Signal Transduction; Smooth Muscle Myocytes; Stress; Testing; Transgenic Organisms; Vascular Smooth Muscle; Ventricular Remodeling; Work; antifibrotic treatment; base; congenital heart disorder; constriction; coronary fibrosis; heart function; improved; in vivo; insight; interstitial; knockout animal; mouse model; multidisciplinary; novel; postnatal; preservation; pressure; prevent; programs; promoter; receptor; response; treatment strategy; unpublished works

PROJECT SUMMARY Cardiac fibrosis is a common adverse myocardial remodeling event that worsens heart failure caused by chronic ventricular pressure overload and other cardiac pathologies such as heart failure with preserved ejection fraction. Due to our incomplete understanding of the pathogenesis of cardiac fibrosis, no specific antifibrotic therapy exists, and affected patients are usually treated by heart transplantation, a therapy that has many limitations. Motivated by this clinical problem, our research has recently uncovered new insights into the regulation of cardiac collagen content and fibrosis, and, in this application, we propose to extend this work to gain further understanding into cellular and molecular mechanisms. In our recent work, we discovered that global deficiency of SLIT3, a secreted glycoprotein which binds to the ROBO receptors, leads to a marked decrease in cardiac collagen content, improved diastolic function in adult mice, and decreased cardiac fibrosis and improved survival after left ventricle (LV) pressure overload induced by transverse aortic constriction (TAC). We also found that SLIT3 stimulates cardiac fibroblast function, intracellular signaling, and collagen production in vitro. Collectively, these results support a developmental link between SLIT3 and collagen deposition during both normal cardiac homeostasis and pathologic stress. However, as these studies relied on SLIT3 global knockout mice where SLIT3 knockout potentially affected developmental programs, the more specific, postnatal functions of SLIT3 - as well as the details of the cellular and molecular signaling - remain undefined in the adult state. New preliminary data using SLIT3 floxed mice and inducible Cre promoters, we find that SLIT3, generated by either cardiac pericytes or fibroblasts, regulates collagen expression in vitro and in vivo in the postnatal state, most likely, by signaling through ROBO1. Based on these results, our overarching hypothesis is that cardiac pericyte and fibroblast-mediated SLIT3 regulate fibroblast activation and function via ROBO1 during conditions of homeostasis and pressure overload. As such, we propose the following aims: (1) Characterize the role of SLIT3 in regulating adult cardiac fibroblast function in vivo. (2) Determine the details of how SLIT3/ROBO1 regulates adult cardiac fibroblast activation and function in vivo and in vitro. (3) Characterize the role of cardiac pericyte and fibroblast-mediated SLIT3 on the ROBO1-dependent response of cardiac fibroblasts during LV pressure overload in vivo. This research will reveal new cellular and molecular concepts of cardiac fibroblast regulation and will further advance our understanding of the pathogenesis of cardiac fibrosis. The results of this research may provide the rationale for targeting SLIT3-ROBO1 to mitigate pressure overload-induced cardiac fibrosis, thereby benefiting patients with heart failure and other forms of cardiac disease.

项目摘要 心脏纤维化是一个常见的不良心肌重塑事件，会使慢性造成的心力衰竭恶化 心室压力超负荷和其他心脏病理，例如心力衰竭，并保留了射血分数。 由于我们对心脏纤维化的发病机理不完全理解，因此没有特定的抗纤维化疗法 存在，受影响的患者通常通过心脏移植治疗，这种疗法有许多局限性。 由于这个临床问题的激励，我们的研究最近发现了对心脏调节的新见解 胶原蛋白含量和纤维化，在此应用中，我们建议扩展这项工作以进一步获得 了解细胞和分子机制。在我们最近的工作中，我们发现全球缺陷 SLIT3是一种与机器人受体结合的分泌的糖蛋白，导致心脏显着降低 胶原蛋白含量，成年小鼠的舒张功能提高，心脏纤维化降低并提高了生存率 左心室（LV）压力超负荷后，由横向主动脉收缩（TAC）引起。我们还发现 SLIT3刺激心脏成纤维细胞功能，细胞内信号传导和体外产生胶原蛋白的产生。共同 这些结果支持两个正常心脏期间的SLIT3和胶原蛋白沉积之间的发育联系 稳态和病理压力。但是，由于这些研究依赖于slit3全球敲除小鼠 SLIT3敲除潜在影响的发展计划，这是SLIT3-的更具体的产后功能 - 以及细胞和分子信号传导的细节 - 在成人状态下仍然不确定。新的初步 使用Slit3 Floxed小鼠和可诱导CRE启动子的数据，我们发现这两种心脏生成的slit3 周细胞或成纤维细胞，调节体外和体内胶原蛋白的表达，最有可能通过 通过Robo1发出信号。基于这些结果，我们的总体假设是心脏周细胞和 成纤维细胞介导的SLIT3在条件下通过ROBO1调节成纤维细胞激活和功能 稳态和压力超负荷。因此，我们提出以下目的：（1）表征slit3的作用 在体内调节成人心脏成纤维细胞功能。 （2）确定slit3/robo1调节的细节 成人心脏成纤维细胞激活和体内和体外功能。 （3）表征心脏周细胞的作用 和成纤维细胞介导的SLIT3在LV压力期间心脏成纤维细胞的ROBO1依赖性响应上 体内过载。这项研究将揭示心脏成纤维细胞调节的新细胞和分子概念 并将进一步提高我们对心脏纤维化发病机理的理解。这项研究的结果 可能提供靶向slit3-robo1的理由来减轻压力超负荷引起的心脏纤维化， 从而使心力衰竭和其他形式的心脏病患者受益。