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novel therapeutic intervention; postnatal; preservation; pressure; prevent; programs; promoter; receptor; response; unpublished works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.

项目概要 心脏纤维化是一种常见的不良心肌重塑事件，会加重慢性心力衰竭引起的心力衰竭。 心室压力超负荷和其他心脏病，例如射血分数保留的心力衰竭。 由于我们对心脏纤维化的发病机制了解不完全，目前尚无特异性抗纤维化治疗方法 存在，受影响的患者通常通过心脏移植进行治疗，这种疗法有很多局限性。 受这一临床问题的推动，我们的研究最近发现了心脏调节的新见解 胶原含量和纤维化，并且在本应用中，我们建议扩展这项工作以获得进一步的成果 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 SLIT3（一种与 ROBO 受体结合的分泌型糖蛋白）的表达会导致心脏功能显着下降。 胶原蛋白含量，改善成年小鼠的舒张功能，减少心脏纤维化并提高生存率 由横主动脉缩窄（TAC）引起的左心室（LV）压力超负荷后。我们还发现 SLIT3 在体外刺激心脏成纤维细胞功能、细胞内信号传导和胶原蛋白生成。总的来说， 这些结果支持 SLIT3 和胶原蛋白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 SLIT3 全局敲除小鼠， SLIT3 敲除可能影响发育程序，SLIT3 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。新初步 使用 SLIT3 floxed 小鼠和诱导型 Cre 启动子的数据，我们发现 SLIT3 周细胞或成纤维细胞，在出生后状态下在体外和体内调节胶原蛋白表达，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 在以下条件下通过 ROBO1 调节成纤维细胞活化和功能 体内平衡和压力超负荷。因此，我们提出以下目标： (1) 描述 SLIT3 的作用 调节体内成人心脏成纤维细胞功能。 (2)确定SLIT3/ROBO1如何调节的细节 体内和体外成人心脏成纤维细胞的活化和功能。 (3) 表征心脏周细胞的作用 和成纤维细胞介导的 SLIT3 对左心室压力期间心脏成纤维细胞 ROBO1 依赖性反应的影响 体内超载。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 并将进一步推进我们对心脏纤维化发病机制的理解。本研究结果 可能为靶向 SLIT3-ROBO1 减轻压力超负荷引起的心脏纤维化提供理论依据， 从而使心力衰竭和其他形式的心脏病患者受益。