Revealing the mechanisms of neural-mediated cardiac proliferation in Ciona robusta

揭示海鞘神经介导的心脏增殖机制

• 批准号: 10752178
• 负责人: Hannah Gruner
• 金额: $ 7.61万
• 依托单位: SWARTHMORE COLLEGE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10752178
• 关键词: Adult; Affect; Anatomy; Birth; Brain; Cardiac; Cardiac Myocytes; Catecholamines; Cause of Death; Cell Count; Cell Proliferation; Cells; Central Nervous System; Chordata; Data; Development; Embryo; Embryonic Development; Family; Goals; Growth; Growth Factor; Growth and Development function; Heart; Heart Arrest; Heart Diseases; Heart Rate; Human; Institution; Literature; Mediating; Modeling; Morphology; Mus; Myocardial; Nerve; Neurons; Neuropeptides; Neurophysiology - biologic function; Newborn Infant; Outcome; Parasympathetic Nervous System; Process; Proliferating; Regulation; Reiterated Genes; Research; Role; Signal Transduction; Sister; Substance P; Sympathetic Nervous System; Tachykinin; Tachykinin Receptor; Testing; Time; Tube; United States; Urochordata; Vertebrates; biomarker identification; cardiogenesis; career; cell type; congenital heart disorder; follow-up; heart cell; heart innervation; mature animal; nerve supply; neural; neuromechanism; neurotransmission; novel; pericardial sac; postmitotic; postnatal; prevent; release factor; single-cell RNA sequencing; undergraduate student

Project Summary/Abstract Regulation of cardiomyocyte division is required for proper heart development, and is implicated in congenital heart disease. Neural innervation of the heart regulates heart rate, which impacts cardiomyocyte proliferation. Furthermore, neurons release neuropeptides that are key factors in promoting cell proliferation. Recent evidence suggests neural innervation from the sympathetic and parasympathetic nervous system (extrinsic innervation) of the heart promotes cardiomyocyte proliferation in post-natal mice. Ciona robusta are a closely related chordate, which have documented conserved features such as neurons within the heart (intrinsic neurons). Unlike mammalian hearts that cease proliferating shortly after birth, Ciona hearts proliferate during development and into adulthood. The neurons associated with Ciona hearts are peptidergic, suggesting neuropeptides are secreted from these neurons. Tachykinin is a conserved family of neuropeptides that includes Substance P, which is implicated in cardiac disease, and is secreted from nerves that innervate the heart in vertebrates. The function of neural innervation in Ciona is not known, however we have preliminary data indicating the neuropeptide tachykinin promotes cardiac proliferation in the developing and adult Ciona heart. The sole article documenting Ciona heart innervation has not been followed up, and thus we investigated if there was unappreciated extrinsic innervation that exists in Ciona hearts. We find evidence of neurons from the brain (extrinsic) of Ciona innervating the intrinsic neurons of the heart. We hypothesize that neuronal input promotes proliferation in developing Ciona hearts. This hypothesis is supported by our preliminary data that the developing Ciona heart is innervated by extrinsic and intrinsic neurons. Furthermore, our data suggest tachykinin signaling promotes cardiac proliferation in developing and adult animals. Last, our preliminary single cell RNA-seq data suggest intrinsic neurons in the heart can respond to tachykinin. We propose the following aims to investigate our hypothesis. Aim I: Characterize neuronal innervation of the Ciona heart. We will determine the temporal and spatial time- course of neural innervation of the Ciona heart. We will use single cell RNA-seq to identify markers of all cell types in the heart including those expressing the tachykinin receptor (neurokinin) and subtypes of neurons. Aim II: Determine whether neuronal signaling regulates cardiac cell proliferation. We will identify the developmental time-point(s) which tachykinin activates cardiomyocyte proliferation. Next we will prevent tachykinin signaling in intrinsic neurons or cardiomyocytes to determine what cell type tachykinin acts on. We will investigate if tachykinin promotes cardiomyocyte proliferation indirectly by testing if the growth factors released by intrinsic neurons promote cardiomyocyte proliferation directly. My ultimate career goal is to study the role of neural innervation on cardiac development at a primarily undergraduate institution.

项目摘要/摘要 适当心脏发育需要对心肌细胞的调节，并与先天性有关 心脏病。心脏的神经神经神经支配调节心率，这会影响心肌细胞增殖。 此外，神经元释放神经肽是促进细胞增殖的关键因素。最近的证据 提出来自交感神经和副交感神经系统的神经神经（外部神经神经） 心脏促进产后小鼠的心肌细胞增殖。 Ciona Robusta是密切相关的 Chordate记录了保守特征，例如心脏内神经元（内在神经元）。 与出生后不久停止增殖的哺乳动物心脏不同，开发过程中ciona的心脏增殖 并成年。与ciona心脏相关的神经元是肽能，表明神经肽是 从这些神经元中分泌。 tachyinin是一个保守的神经肽家族，包括物质P， 这与心脏病有关，并从神经脊椎动物的心脏神经中分泌。这 ciona中神经神经的功能尚不清楚，但是我们有初步数据表明 神经肽旋转蛋白促进发育中和成年Ciona心脏的心脏增殖。唯一的文章 尚未记录记录ciona心脏神经的神经支配，因此我们调查了是否存在 塞奥纳心脏中存在的未欣赏外在神经。我们发现大脑神经元的证据 （外部）ciona支配心脏的内在神经元。我们假设神经元输入促进 发展中心心脏的扩散。我们的初步数据支持了这一假设 西奥纳心脏受外在和内在神经元的支配。此外，我们的数据表明速素信号传导 促进发展中动物和成年动物的心脏增殖。最后，我们的初步单细胞RNA-seq数据 建议心脏内固有的神经元可以对速素反应。我们建议以下目的调查 我们的假设。 目的I：表征Ciona心脏的神经元神经。我们将确定时间和空间时间 - 西奥纳心脏神经神经支配的过程。我们将使用单细胞RNA-seq识别所有单元的标记 心脏中的类型，包括表达速素受体（神经蛋白）和神经元亚型的类型。 AIM II：确定神经元信号是否调节心脏细胞增殖。我们将确定 速蛋白激活心肌细胞增殖的发育时间点。接下来，我们将防止 固有神经元或心肌细胞中的速素信号传导，以确定速激肽作用于哪种细胞类型。我们 将研究速素是否通过测试生长因子间接促进心肌细胞增殖 由固有神经元释放，直接促进心肌细胞增殖。我的最终职业目标是学习 神经神经在主要是本科机构心脏发展中的作用。