The Contribution of Melanocyte-like Cells to Atrial Function and Development

黑素细胞样细胞对心房功能和发育的贡献

基本信息

批准号：
8848105
负责人：
Xiongwen Chen
金额：
$ 44.77万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-06-15 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8848105
关键词：
Action Potentials Adrenergic Receptor Affect Anatomy Animal Model Arrhythmia Atrial Fibrillation Atrial Function Biological Biology Calcium Carbachol Cardiac Cell Lineage Cells Characteristics Clinical Coupling Data Dermal Development Disease Dopachrome isomerase Elderly Electrophysiology (science)Engineering Enzymes Exhibits Gap Junctions Gated Ion Channel Gene Expression Profile Generations Genes Genetic Genetic Transcription Genetically Engineered Mouse Goals Heart Heart Atrium Heterozygote Human In Vitro Investigation Ions Knockout Mice Knowledge Laboratories Lead Manganese Superoxide Dismutase Maps Modeling Monophenol Monooxygenase Mus Muscarinic Acetylcholine Receptor Muscarinic Agonists Muscle Cells Mutant Strains Mice Myocardium Optics Oxidants Patch-Clamp Techniques Pathogenesis Pathologic Pattern Physiological Physiology Play Population Predisposition Property Proto-Oncogene Protein c-kit Publishing Pulmonary veins Reactive Oxygen Species Research Personnel Role Series Site Sodium-Calcium Exchanger Staging Stimulus Stress Techniques Testing Wild Type Mouse Work base design heart rhythm improved in vivo insight melanocyte mouse model novel oxidative damage receptor research study response voltage

项目摘要

DESCRIPTION (provided by applicant): We recently described a novel population of melanocyte-like cells in the pulmonary veins and atria of humans and mice. In the developing and mature heart, melanocyte-like cells are found in a pattern unlike that of any currently known cell lineage and are found in anatomic regions that often give rise to clinical atrial arrhythmia triggers. These cells express a unique transcription signature that is distinct from that of atrial myocytes or dermal melanocytes. Interestingly, isolated murine melanocyte-like cells are electrically excitable and generate atrial myocyte-like action potentials. We have found that genetic deletion of the enzyme dopachrome tautomerase (Dct), which is expressed by both human and murine cardiac melanocytes, unmasks a pathological state with action potential prolongation and afterdepolarizations in these cells. Furthermore, mature Dct knockout mice retain melanocyte-like cells and have structurally normal hearts, yet display increased susceptibility to atrial arrhythmias. While wild-type mice with melanocyte-like cells in their hearts do not have increased atrial arrhythmias at baseline, they do have more atrial arrhythmias when challenged with the muscarinic agonist carbachol compared to c-kit mutant mice that lack melanocyte-like cells in their hearts. In addition, Dct knockout mice have fewer atrial arrhythmias when treated with reactive oxygen species scavengers. Hence, melanocyte-like cells may contribute to atrial arrhythmias in response to increased stresses (i.e. autonomic stimulation or reactive oxygen species) that commonly induce clinical atrial arrhythmias. Despite our initial characterization, the function of melanocyte-like cells during normal physiologic and pathophysiologic states remains obscure. Furthermore, while we have some evidence melanocyte-like cells are excitable and may influence arrhythmogenesis; the underlying electrophysiologic characteristics of these cells require further investigation to understand their potential contribution to arrhythmias. Therefore, we are proposing a series of in vitro and in vivo experiments using genetically engineered mouse models to characterize the cellular electrophysiology of these cells and determine their contribution to atrial arrhythmias. The specific aims proposed include: 1) elucidating the voltage-dependent currents underlying the electrical excitability of isolated murine melanocyte-like cells and the direct contribution of melanocyte-like to atrial arrhythmia triggers, 2) determining the effects of autonomic stimulation upon Dct-positive melanocyte-like cellular excitability and their contribution atrial arrhythmias, 3) assessing the effects of reactive oxygen species upon the excitability of Dct-positive melanocyte-like cells and their influence upon atrial arrhythmias, and 4) investigating the role of melanocyte-like cells in the normal heart. The knowledge we will gain about the basic biology of melanocyte-like cells is likely to open new avenues in our understanding of atrial electrophysiology, with the potential for paradigm shifting insights into the pathogenesis of atrial arrhythmias.

描述（由申请人提供）：我们最近描述了人类和小鼠的肺静脉和心房中的新型黑素细胞样细胞。在发育中的和成熟的心脏中，与当前已知的细胞谱系不同的模式发现了黑色素细胞样细胞，并且在解剖区域中发现通常会引起临床心律不齐的触发因素。这些细胞表达了独特的转录特征，该特征与心肌细胞或真皮黑素细胞不同。有趣的是，孤立的鼠黑素细胞样细胞是电兴奋的，并产生心房肌细胞样作用电位。我们发现，由人和鼠心脏黑素细胞表达的酶多发性互变异酶（DCT）的遗传缺失揭示了这些细胞中具有动作潜在延长和过度过度化的病理状态。此外，成熟的DCT基因敲除小鼠保留了黑素细胞样细胞并具有结构正常的心脏，但表现出增加对心律不齐的敏感性。虽然野生型小鼠的心脏中有黑素细胞样细胞并没有增加基线的心律不齐，但与缺乏心脏中缺乏类似黑素细胞细胞的C-kit突变小鼠相比，在毒蕈碱激动剂卡巴醇中受到挑战时，它们确实具有更多的心律失常。此外，用活性氧气清除剂处理时，DCT敲除小鼠的心律不齐更少。因此，黑色素细胞样细胞可能会导致心律不齐，响应增加的应激（即自主刺激或活性氧），通常会诱导临床心律不齐。尽管我们最初的表征，但在正常生理和病理生理状态下，黑素细胞样细胞的功能仍然晦涩难懂。此外，尽管我们有一些证据表明黑素细胞样细胞是可激发的，并且可能影响心律不齐。这些细胞的潜在电生理特征需要进一步研究，以了解它们对心律不齐的潜在贡献。因此，我们提出了一系列使用基因工程小鼠模型来表征这些细胞的细胞电生理学的体外和体内实验，并确定它们对心房心律不齐的贡献。 The specific aims proposed include: 1) elucidating the voltage-dependent currents underlying the electrical excitability of isolated murine melanocyte-like cells and the direct contribution of melanocyte-like to atrial arrhythmia triggers, 2) determining the effects of autonomic stimulation upon Dct-positive melanocyte-like cellular excitability and their contribution atrial arrhythmias, 3)评估活性氧对DCT阳性黑色素细胞样细胞的兴奋性及其对心房心律不齐的影响，以及4）研究黑素细胞样细胞在正常心脏中的作用。我们将获得有关类似黑素细胞样细胞的基本生物学的知识，可能会在我们对房间生理学的理解中开辟新的途径，并有可能将范式转移到心房心律不齐的发病机理中。