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 调节心肌细胞分裂是心脏正常发育所必需的，并与先天性心脏病有关。 心脏病。心脏的神经支配调节心率，从而影响心肌细胞的增殖。 此外，神经元释放神经肽，神经肽是促进细胞增殖的关键因素。最近的证据 提示来自交感和副交感神经系统的神经支配(外源性神经支配) 心脏的功能可促进出生后小鼠的心肌细胞增殖。乔纳·罗布斯塔是一位密切相关的 脊索，它记录了保守的特征，如心脏内的神经元(内在神经元)。 与出生后不久停止增殖的哺乳动物心脏不同，乔纳心脏在发育过程中会增殖 并进入成年期。与Ciona心脏相关的神经元是多肽能的，这表明神经肽是 从这些神经元中分泌出来。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，由脊椎动物支配心脏的神经分泌。这个 免疫球蛋白的神经支配功能尚不清楚，但我们有初步数据表明 神经肽速激肽促进发育中和成人心脏的心脏增殖。唯一的一篇文章 关于Ciona心脏神经支配的记录没有得到跟进，因此我们调查了是否有 乔纳心脏中存在的未被赏识的外在神经。我们发现了来自大脑的神经元的证据 (外在的)支配心脏内部神经元的乔纳。我们假设神经元的输入促进了 在发育中的乔纳心脏中增殖。这一假设得到了我们的初步数据的支持，即 心脏由外源性神经元和内源性神经元共同支配。此外，我们的数据表明速激肽信号 促进发育中和成年动物的心脏增殖。最后，我们的初步单细胞rna-seq数据 表明心脏内的固有神经元可以对速激肽做出反应。我们提出以下目的来调查 我们的假设。 目的I：表征心脏的神经元神经支配。我们将确定时间和空间时间- 乔纳心的神经支配过程。我们将使用单细胞rna-seq来识别所有细胞的标记。 心脏中的类型包括那些表达速激肽受体(神经激动素)的类型和神经元的亚型。 目的II：确定神经元信号是否调节心肌细胞的增殖。我们将确定 速激肽激活心肌细胞增殖的发育时间点(S)。接下来，我们将防止 在内源性神经元或心肌细胞中传递速激肽信号，以确定速激肽作用于什么细胞类型。我们 将通过测试生长因子是否间接促进心肌细胞增殖来研究速激肽是否会间接促进心肌细胞的增殖 由内源性神经元释放，直接促进心肌细胞增殖。我的最终职业目标是学习 神经支配在主要本科院校心脏发育中的作用。