Regulation of Fetal Myocyte Development

胎儿肌细胞发育的调节

• 批准号: 7745510
• 负责人: JEFFREY L SEGAR
• 金额: $ 36.88万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-01-01 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7745510
• 关键词: AGTR2 gene; Address; Adult; Affect; Age; Anemia; Angiotensin II; Angiotensin II Receptor; Angiotensin Receptor; Apoptosis; Apoptotic; Birth; Cardiac; Cardiac Myocytes; Cardiac Volume; Cardiovascular Diseases; Cell Count; Cell Death; Chronic; Development; Differentiation and Growth; Equilibrium; Event; Fetal Development; Fetal Heart; Fetus; Growth; Heart; Heart Hypertrophy; Human; Hyperplasia; Hypertrophy; Intervention; Lead; Life; Long-Term Effects; Measures; Mediating; Mitogen-Activated Protein Kinases; Modeling; Molecular; Morphology; Muscle Cells; Myocardium; Nuclear; Physiological; Play; Population; Pregnancy; Proteins; Regulation; Relative (related person); Renin-Angiotensin System; Research; Research Personnel; Role; Sheep; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Staging; Stress; Structure; Testing; Third Pregnancy Trimester; Time; Ventricular Dysfunction; Ventricular Function; Ventricular Remodeling; Work; Workload; design; fetal; hemodynamics; in utero; in vivo; inhibitor/antagonist; member; postnatal; programs; receptor; response

DESCRIPTION (provided by applicant): An intact renin-angiotensin system is not obligate for the development of load-induced cardiac hypertrophy in the adult, although ANG II plays an important role in myocardial remodeling. The response of the fetal heart to increased load and the role of the renin-angiotensin system in cardiac growth are poorly understood. In species like the human and sheep, most cardiomyocytes are terminally differentiated at birth, with postnatal growth of the heart occurring by hypertrophy and not by increasing cell number. Thus factors affecting the total number of myocytes present within the myocardium need to be identified. Intrauterine events that accelerate the rate of terminal differentiation of cardiomyocytes or increases the rate of cell death (apoptosis) will lead to a reduction in the total cardiomyocyte number. This proposal is designed to investigate in normal and pathological states (chronic fetal anemia induced volume overload) the role of angiotensin II in regulating growth, maturation and proliferation of cardiac myocytes during two stages of fetal development. Specifically, we intend to use a chronically-catheterized fetal sheep model to investigate (1) mechanisms regulating fetal cardiomyocyte hypertrophy, hyperplasia and apoptosis in responses to increased cardiac load in vivo; (2) the differential effects of selective angiotensin II receptor blockade on these responses and, (3) whether these interventions produce permanent alterations in cardiac morphology and function. Adaptive changes in cardiomyocyte growth, maturation and proliferation in utero could produce alterations in cardiac morphology and function that may ultimately program the heart for cardiovascular disease and ventricular function in adult life.

描述（由申请人提供）：尽管ANG II在心肌重塑中发挥重要作用，但完整的肾素-血管紧张素系统对于成人中负荷诱导的心脏肥大的发展并不必然。人们对胎儿心脏对负荷增加的反应以及肾素-血管紧张素系统在心脏生长中的作用知之甚少。在人类和绵羊等物种中，大多数心肌细胞在出生时就已终末分化，出生后心脏的生长是通过肥大而不是细胞数量增加来实现的。因此，需要确定影响心肌内存在的心肌细胞总数的因素。加速心肌细胞终末分化速率或增加细胞死亡（细胞凋亡）速率的宫内事件将导致心肌细胞总数减少。该提案旨在研究正常和病理状态（慢性胎儿贫血引起的容量超负荷）下血管紧张素II在胎儿发育两个阶段调节心肌细胞生长、成熟和增殖中的作用。具体来说，我们打算使用长期留置导管的胎羊模型来研究（1）体内心脏负荷增加时调节胎儿心肌细胞肥大、增生和凋亡的机制； (2) 选择性血管紧张素 II 受体阻断对这些反应的不同影响，(3) 这些干预措施是否会导致心脏形态和功能的永久性改变。子宫内心肌细胞生长、成熟和增殖的适应性变化可能会导致心脏形态和功能的改变，最终可能导致心脏在成年后发生心血管疾病和心室功能。