Excitation-contraction coupling in human ventricle development

人心室发育中的兴奋-收缩耦合

• 批准号: 8258341
• 负责人: MARY B WAGNER
• 金额: $ 46.46万
• 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 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8258341
• 关键词: Adenylate Cyclase; Adrenergic Agents; Adult; Age; Animal Model; 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（由申请方提供）：哺乳动物心脏的出生后变化使得难以将药理学和手术治疗从成人外推至婴儿。兴奋-收缩偶联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，我们将研究出生后的变化，兴奋收缩耦合在人类心室。作为先天性心脏病手术修复的一部分，心室组织可能会被切除。我们将比较从左心发育不良综合征儿童（新生儿）中取出的小于一周的活检组织与从法洛四联症儿童（婴儿）中取出的3-12个月的心室活检组织的性质。更好地了解婴儿的收缩调节可能会建议更适合儿科人群的治疗方法。SA 1：增加收缩强度对于治疗心脏缺陷儿童非常重要。我们发现，新生儿心室，婴儿相比，有一个钝的反应，增加起搏频率，以及减少反应交感神经刺激。我们将通过比较参与收缩调节的分子靶点和检查不同药物治疗的收缩来确定这些差异的机制。SA2：我们假设，细胞内钙瞬变是不均匀的新生儿，并成为更均匀的第一年的生活，这些变化与单个心室细胞的形态。SA3：我们将确定收缩所需的钙源是否主要是通过细胞外间隙或细胞内储存的钙流入，以及这种来源是否随发育年龄而变化。SA4：我们将通过检验钠钙交换在新生儿心室中最大并随年龄增长而减少，从而对钙瞬变做出更多贡献的假设，来检查参与兴奋-收缩偶联的其他途径。此外，我们假设，在生命的第一年发生的转变，更依赖于钙电流（伊卡）作为触发收缩。SA5：我们假设，新生心室细胞有较小的伊卡和不太敏感的异丙肾上腺素比婴儿细胞，并提出这些发展变化与抑制性G蛋白水平。这些发现将有助于澄清是否有出生后的变化，在人类心室的兴奋-收缩耦合，并可能建议更合适的治疗儿童患者。这项研究通过比较出生不到一周和3-12个月大的患者的心脏组织的性质来检查出生后心脏收缩的变化。虽然在动物模型中研究了心脏发育，但在人类中知之甚少。这项研究可能会改善儿童心脏病的治疗方法。

项目成果

Non-genetic Purification of Ventricular Cardiomyocytes from Differentiating Embryonic Stem Cells through Molecular Beacons Targeting IRX-4.

• DOI: 10.1016/j.stemcr.2015.10.021
• 发表时间: 2015-12-08
• 期刊: Stem cell reports
• 影响因子: 5.9
• 作者: Ban K;Wile B;Cho KW;Kim S;Song MK;Kim SY;Singer J;Syed A;Yu SP;Wagner M;Bao G;Yoon YS
• 通讯作者: Yoon YS

Purification of cardiomyocytes from differentiating pluripotent stem cells using molecular beacons that target cardiomyocyte-specific mRNA.

• DOI: 10.1161/circulationaha.113.004228
• 发表时间: 2013-10-22
• 期刊: Circulation
• 影响因子: 37.8
• 作者: Ban K;Wile B;Kim S;Park HJ;Byun J;Cho KW;Saafir T;Song MK;Yu SP;Wagner M;Bao G;Yoon YS
• 通讯作者: Yoon YS

Electrically Induced Calcium Handling in Cardiac Progenitor Cells.

• DOI: 10.1155/2016/8917380
• 发表时间: 2016
• 期刊: Stem cells international
• 影响因子: 4.3
• 作者: Maxwell JT;Wagner MB;Davis ME
• 通讯作者: Davis ME