Excitation-contraction coupling in human ventricle development

人心室发育中的兴奋-收缩耦合

• 批准号: 7807078
• 负责人: MARY B WAGNER
• 金额: $ 46.71万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-01 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7807078
• 关键词: Adenylate Cyclase; Adrenergic Agents; Adult; Age; Animal Model; Be++ element; Beryllium; Binding; Biopsy; Birth; Calcium; Cells; Child; Childhood; Climacteric; Congenital Heart Defects; Contractile Proteins; Contracts; Coupling; Data; Development; Electrophysiology (science); Elements; Extracellular Space; Frequencies; GTP-Binding Proteins; Goals; Heart; Heart Atrium; Human; Hypoplastic Left Heart Syndrome; Infant; Isoproterenol; Life; Measurement; Measures; Mediating; Messenger RNA; Methods; Molecular Biology; Molecular Target; Morphology; Muscle; Myocardial Contraction; Myocardium; Newborn Infant; Operative Surgical Procedures; Oryctolagus cuniculus; Pathway interactions; Patients; Pharmacological Treatment; Play; Population; Property; Protein Inhibition; Protein phosphatase; Proteins; Regulation; Relative (related person); Role; Sarcoplasmic Reticulum; Sodium; Source; System; Testing; Tetralogy of Fallot; Time; Tissues; Translating; Tubular formation; Ventricular; Work; adrenergic; base; cardiogenesis; heart electrical activity; improved; phosphatase inhibitor; phosphoric diester hydrolase; postnatal; receptor; repaired; response

DESCRIPTION (provided by applicant): Postnatal changes in the mammalian heart make it difficult to extrapolate pharmacological and surgical therapies from adults to infants. Excitation-contraction coupling is the method by which the electrical activity of the heart is translated into the contraction of the heart, with regulation of intracellular calcium playing an integral role. In this study, we will examine the postnatal changes in excitation contraction coupling in the human ventricle. As part of surgical repair of congenital heart defects, ventricular tissue may be removed. We will compare properties of biopsies removed at less than one week of age (newborns) from children with hypoplastic left heart syndrome to ventricular biopsies removed at 3-12 months (infants) of age from children with Tetralogy of Fallot. A better understanding of contraction regulation in infants may suggest therapies that are more appropriate for the pediatric population. SA1: Increasing the strength of contraction is important for treatment of children with heart defects. We show that newborn ventricle, compared to infant, has a blunted response to increases in pacing frequency as well as a diminished response to sympathetic stimulation. We will determine the mechanism of these differences by comparing molecular targets involved in regulation of contraction and examining the contraction with different pharmacological treatments. SA2: We hypothesize that intracellular calcium transients are inhomogeneous in the newborn and become more homogeneous in the first year of life and these changes correlate with the morphology of single ventricular cells. SA3: We will determine if the source of calcium required for contraction is primarily through influx of calcium from the extracellular space or if it is from the intracellular stores, and if this source changes with developmental age. SA4: We will examine other pathways involved in excitation-contraction coupling by testing the hypothesis that sodium-calcium exchange is largest in the newborn human ventricle and decreases with age, thus contributing more to the calcium transient. Furthermore, we hypothesize that the transformation to being more dependent on calcium current (ICa) as a trigger for contraction occurs during the first year of life. SA5: We hypothesize that newborn ventricular cells have smaller ICa and are less sensitive to isoproterenol than infant cells and propose these developmental changes correlate with inhibitory G protein levels. These findings will help to clarify if there are postnatal changes in human ventricle in terms of excitation-contraction coupling and may suggest more appropriate therapies for pediatric patients. This study examines how contraction of the heart changes after birth by comparing properties of heart tissue from patients less than one week old to those 3-12 months old. While heart development has been studied in animal models, very little is known in the human. This study may result in improved therapies for children with heart problems.

描述（由申请人提供）：哺乳动物心脏的出生后变化使得很难将药物和手术疗法从成人推断到婴儿。兴奋-收缩耦合是将心脏的电活动转化为心脏收缩的方法，其中细胞内钙的调节起着不可或缺的作用。在这项研究中，我们将检查人类心室兴奋收缩耦合的出生后变化。作为先天性心脏缺陷手术修复的一部分，心室组织可能会被切除。我们将比较在不到 1 周时从患有左心发育不良综合征的儿童（新生儿）中取出的活检组织与在 3-12 个月大时（婴儿）从患有法洛四联症的儿童中取出的心室活检组织的特性。对婴儿收缩调节的更好理解可能会建议更适合儿科人群的治疗方法。 SA1：增加收缩强度对于治疗患有心脏缺陷的儿童很重要。我们发现，与婴儿相比，新生儿心室对起搏频率增加的反应迟钝，对交感神经刺激的反应减弱。我们将通过比较参与收缩调节的分子靶点并检查不同药物治疗的收缩情况来确定这些差异的机制。 SA2：我们假设新生儿的细胞内钙瞬变是不均匀的，在生命的第一年变得更加均匀，这些变化与单心室细胞的形态相关。 SA3：我们将确定收缩所需的钙来源主要是来自细胞外空间的钙流入还是来自细胞内储存，以及该来源是否随着发育年龄而变化。 SA4：我们将通过测试以下假设来检查参与兴奋-收缩耦合的其他途径：钠-钙交换在新生儿心室中最大，并随着年龄的增长而减少，从而对钙瞬变的贡献更大。此外，我们假设在生命的第一年发生了更加依赖钙电流（ICa）作为收缩触发因素的转变。 SA5：我们假设新生心室细胞的 ICa 较小，对异丙肾上腺素的敏感性低于婴儿细胞，并提出这些发育变化与抑制性 G 蛋白水平相关。这些发现将有助于阐明人类心室在兴奋-收缩耦合方面是否存在产后变化，并可能为儿科患者提供更合适的治疗方法。这项研究通过比较 1 周以内的患者与 3-12 个月大的患者的心脏组织特性，探讨出生后心脏收缩的变化。虽然已经在动物模型中研究了心脏发育，但对人类的了解却很少。这项研究可能会改善患有心脏病的儿童的治疗方法。