Investigating the role of the complement system in cardiac regeneration

研究补体系统在心脏再生中的作用

• 批准号: 9760060
• 负责人: Niranjana Natarajan
• 金额: $ 6.16万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9760060
• 关键词: Acute; Address; Adult; Ambystoma; Animal Model; Antibodies; Apical; C5a anaphylatoxin receptor; Cardiac; Cardiac Myocytes; Cell Proliferation; Cell division; Cicatrix; Complement; Complement 3a; Complement 5a; Complement Activation; Complement Receptor; Complement component C5; Data; Dominant-Negative Mutation; Embryo; Event; Excision; Exhibits; G-Protein-Coupled Receptors; GTP-Binding Protein alpha Subunits, Gs; Gene Transfer; Generations; Genes; Heart; Heart Diseases; Heart Injuries; Heart failure; Hour; IL6 gene; Immune response; Impairment; Infarction; Inflammatory; Inflammatory Response; Injury; Innate Immune System; Isotopes; Knockout Mice; Laboratories; Lead; Life; Limb structure; Liver; Mammals; Mass Spectrum Analysis; Mediating; Modeling; Molecular; Mouse Cell Line; Mus; Myocardial; Myocardial Infarction; Myocardium; Natural regeneration; Neonatal; Newts; Pathway interactions; Peptides; Pharmacology; Receptor Activation; Receptor Signaling; Regenerative response; Resources; Retina; Role; Signal Transduction; Testing; Thrombin; Tissues; United States; Up-Regulation; Zebrafish; cardiac regeneration; complement pathway; complement system; deep sequencing; experimental study; injured; macrophage; mortality; receptor; receptor expression; receptor function; regenerative; repaired; response; tool; transcriptome sequencing; transcriptomics

Project summary: The mammalian heart has a limited regenerative potential due to the low proliferation rate of adult cardiomyocytes. However, a narrow regenerative window has been identified in the neonatal murine heart, wherein mice are able to successfully regenerate their hearts both at the tissue and functional level following injury. In a cross-species transcriptomic screen in the Lee laboratory, inflammatory response genes including complement receptors were upregulated in a conserved manner in the regenerating heart of three model organisms – axolotl, mouse and zebrafish. The most-upregulated inflammatory response genes include G-protein coupled receptors (GPCR) for complement proteins, complement 5a receptor (C5aR1) and complement 3a receptor (C3aR). The complement system is part of the innate immune system and enhances the ability of antibodies and macrophages to clear foreign material. Activation of an early immune response is a shared feature observed in the regenerating heart of several model organisms, consistent with the upregulation of C5aR1 and C3aR observed. C5aR1 is a GPCR that functions as a complement receptor for C5a, generated by proteolytic cleavage of complement component 5. Pharmacologic inhibition of C5aR1 after apical resection results in an impaired cardiomyocyte proliferative response in axolotl, mouse and zebrafish. I propose to investigate the role of complement activation in murine cardiac regeneration. Furthermore, I will elucidate the molecular mechanisms that initiate effective repair and cardiomyocyte proliferation in the mammalian heart following injury. I will utilize C5aR1 deletion models in zebrafish and mouse for my studies. I will examine downstream signaling components of the C5aR1 pathway that initiate cardiomyocyte proliferation following injury. To understand the cellular basis of C5aR1 signaling, I will employ a cardiomyocyte-specific deletion model of C5aR1 in mice. Furthermore, I propose to assess cardiomyocyte proliferation in C5aR1 wild-type and knock-out mice to understand the sequence of molecular events in the injured heart that initiate cardiomyocyte proliferation and effective regeneration. These studies will likely define a mechanistic pathway of early events critical for the initiation of cardiomyocyte proliferation in the myocardium.

项目概要： 哺乳动物的心脏具有有限的再生潜力，这是由于心脏的低增殖率。 成年心肌细胞然而，在本发明中已经确定了狭窄的再生窗口。 新生鼠心脏，其中小鼠能够成功地使它们的心脏再生， 组织和功能水平。在一个跨物种的转录组筛选中， 在实验室中，包括补体受体在内的炎症反应基因在 在三种模式生物-蝾螈，小鼠和 斑马鱼上调最多的炎症反应基因包括G蛋白偶联基因， 补体蛋白受体（GPCR）、补体5a受体（C5 aR 1）和补体 3a受体（C3 aR）。补体系统是先天免疫系统的一部分， 系统，并增强抗体和巨噬细胞清除异物的能力。 早期免疫反应的激活是在再生心脏中观察到的共同特征 几种模式生物，与观察到的C5 aR 1和C3 aR的上调一致。 C5 aR 1是一种GPCR，作为C5 a的补体受体，通过蛋白水解产生， 补体成分5的裂解。根尖切除术后C5 aR 1的药理学抑制 导致美西螈、小鼠和斑马鱼的心肌细胞增殖反应受损。我 提出研究补体激活在小鼠心脏再生中的作用。 此外，我将阐明启动有效修复的分子机制， 哺乳动物心脏损伤后心肌细胞增殖。我将利用C5 aR 1基因缺失 斑马鱼和老鼠的模型。我会检查下游信号 C5 aR 1通路的组分，其在损伤后启动心肌细胞增殖。到 为了理解C5 aR 1信号传导的细胞基础，我将采用心肌细胞特异性缺失 小鼠C5 aR 1模型。此外，我建议评估心肌细胞增殖， C5 aR 1野生型和基因敲除小鼠，以了解C5 aR 1基因敲除小鼠中的分子事件序列。 损伤的心脏，启动心肌细胞增殖和有效再生。这些研究 可能会定义一个早期事件的机制途径，这些事件对心肌细胞的启动至关重要。 心肌细胞增殖。