Regulation of Cardiac Collagen Content by SLIT3

SLIT3 对心脏胶原蛋白含量的调节

• 批准号: 10647783
• 负责人: Ming-Sing Si
• 金额: $ 62.72万
• 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/10647783
• 关键词: Acute; Adult; Affect; Binding; Blood capillaries; Cardiac; Cells; Chronic; Clinical; Collagen; Cytoplasm; Data; Defect; Deposition; Development; Diabetes Mellitus; EFRAC; Event; Extracellular Matrix; Eye; Fibroblasts; Fibrosis; Functional disorder; Glycoproteins; Goals; Hand; Heart Diseases; Heart Transplantation; Heart failure; Homeostasis; In Vitro; Injury; Ischemia; 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; Rupture; SRGAP2 gene; Signal Transduction; Smooth Muscle Myocytes; Stress; Testing; Transgenic Organisms; Vascular Smooth Muscle; Ventricular Remodeling; Wild Type Mouse; Work; amphiphysin; antifibrotic treatment; aorta constriction; congenital heart disorder; coronary fibrosis; heart function; improved; in vivo; inducible Cre; insight; interstitial; knockout animal; mouse model; multidisciplinary; novel; novel therapeutic intervention; postnatal; preservation; pressure; prevent; programs; promoter; receptor; response; unpublished works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 心脏纤维化是一种常见的不良心肌重塑事件，其导致慢性心力衰竭。 心室压力超负荷和其它心脏病如射血分数保持的心力衰竭。 由于我们对心脏纤维化发病机制的认识不完全，没有特异性的抗纤维化治疗 存在，并且受影响的患者通常通过心脏移植治疗，这种治疗具有许多局限性。 受这一临床问题的启发，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，并且，在本申请中，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，我们发现全球缺乏 SLIT 3是一种分泌型糖蛋白，与ROBO受体结合，导致心脏活动显著减少。 胶原蛋白含量，改善成年小鼠的舒张功能，减少心脏纤维化，提高存活率 在由横向主动脉缩窄（TAC）引起的左心室（LV）压力超负荷后。我们还发现 SLIT 3刺激体外心脏成纤维细胞功能、细胞内信号传导和胶原蛋白产生。总的来说， 这些结果支持了在正常心脏发育过程中SLIT 3和胶原沉积之间的发育联系， 稳态和病理应激。然而，由于这些研究依赖于SLIT 3全球敲除小鼠， SLIT 3基因敲除可能影响发育程序，更具体的是，SLIT 3基因的出生后功能。 以及细胞和分子信号的细节-在成年状态下仍然不确定。新的初步 使用SLIT 3 floxed小鼠和诱导型Cre启动子的数据，我们发现，由心脏产生的SLIT 3 周细胞或成纤维细胞，在体外和体内在出生后状态下调节胶原蛋白表达，最有可能的是， 通过ROBO 1发送信号。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SLIT 3通过ROBO 1调节成纤维细胞的活化和功能， 体内平衡和压力过载。因此，我们提出以下目标：（1）描述SLIT 3的作用 在体内调节成人心脏成纤维细胞功能。(2)确定SLIT 3/ROBO 1如何调节的细节 成体心脏成纤维细胞在体内和体外的活化和功能。(3)描述心脏周细胞的作用 和成纤维细胞介导的SLIT 3对左心室压力期间心脏成纤维细胞的ROBO 1依赖性反应的影响 体内过载。这项研究将揭示心脏成纤维细胞调节的新的细胞和分子概念 并将进一步推进我们对心脏纤维化发病机制的理解。这项研究成果 可能为靶向SLIT 3-ROBO 1以减轻压力超负荷诱导的心脏纤维化提供了基本原理， 从而有益于患有心力衰竭和其它形式的心脏病的患者。