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.

项目概要/摘要 心肌细胞分裂的调节是心脏正常发育所必需的，并且与先天性心脏病有关 心脏病。心脏的神经支配调节心率，从而影响心肌细胞增殖。 此外，神经元释放神经肽，这是促进细胞增殖的关键因素。最近的证据 表明神经支配来自交感神经和副交感神经系统（外在神经支配） 心脏的作用促进出生后小鼠的心肌细胞增殖。 Ciona Robusta 是一种密切相关的 脊索动物，已记录了诸如心脏内神经元（固有神经元）等保守特征。 与出生后不久就停止增殖的哺乳动物心脏不同，海鞘心脏在发育过程中增殖 并进入成年期。与玻璃海鞘心脏相关的神经元是肽能的，表明神经肽是 由这些神经元分泌。速激肽是一个保守的神经肽家族，包括 P 物质、 它与心脏病有关，由脊椎动物中支配心脏的神经分泌。这 Ciona 的神经支配功能尚不清楚，但我们有初步数据表明 神经肽速激肽可促进发育中和成年 Ciona 心脏的心脏增殖。唯一文章 尚未对 Ciona 心脏神经支配进行记录，因此我们调查了是否有 Ciona 心脏中存在未被认识到的外在神经支配。我们发现大脑中神经元的证据 （外在）海鞘神经支配心脏的内在神经元。我们假设神经元输入促进 发育中的 Ciona 心脏的增殖。我们的初步数据支持了这一假设，即发展中国家 海鞘心脏由外在和内在神经元支配。此外，我们的数据表明速激肽信号传导 促进发育中和成年动物的心脏增殖。最后，我们初步的单细胞 RNA-seq 数据 表明心脏中的内在神经元可以对速激肽做出反应。我们提出以下调查目标 我们的假设。 目标 I：表征 Ciona 心脏的神经元神经支配。我们将确定时间和空间的时间- Ciona 心脏的神经支配过程。我们将使用单细胞RNA-seq来识别所有细胞的标记 心脏中的类型，包括表达速激肽受体（神经激肽）的类型和神经元亚型。 目标 II：确定神经元信号传导是否调节心肌细胞增殖。我们将确定 速激肽激活心肌细胞增殖的发育时间点。接下来我们要预防 内在神经元或心肌细胞中的速激肽信号传导以确定速激肽作用的细胞类型。我们 将通过测试生长因子是否间接研究速激肽是否促进心肌细胞增殖 内在神经元释放的直接促进心肌细胞增殖。我的最终职业目标是学习 神经支配对本科院校心脏发育的作用。