CALCIUM REGULATION DURING HEART DEVELOPMENT

心脏发育过程中的钙调节

• 批准号: 6537344
• 负责人: Michael Artman
• 金额: $ 27.02万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-01 至 2003-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6537344
• 关键词: action potentials; calcium flux; cardiac myocytes; confocal scanning microscopy; heart contraction; histogenesis; human tissue; intracellular transport; laboratory rabbit; mathematical model; microtubules; muscle contraction; neuromuscular transmission; sarcolemma; sodium channel; voltage /patch clamp

Mechanisms of excitation-contraction (EC) coupling have not been defined in the developing heart. We hypothesize that transsarcolemmal Ca/2+ influx is the major source of activator Ca/2+ for contractions in the immature heart. Experiments will be performed using ventricular myocytes isolated from rabbits and humans at four different developmental stages. Confocal laser scanning microscopy will be used to define subcellular Ca/2+ distribution during myocyte contractions (fluo-3) and to quantitate postnatal T-tubule development (di-8-ANEPPS). Complementary approaches will be used to characterize various Ca/2+ transport pathways, including L- and T-type Ca/2+ channels, SR Ca/2+ release (triggered by Ca/2+ influx of depolarization), "reverse" Na+-Ca/2+ exchange and Ca/2+ entry through Na channels operating in slip mode conductance. A pharmacological approach will be used to individually block the respective Ca/2+ entry pathways (or SR function) while cells are voltage clamped with their own action potential as the command voltage (to eliminate changes in action potential duration). In a second approach, the absolute magnitudes of Ca/2+ influx by each relevant pathway will be established using experimental conditions highly optimized for each pathway (specific experimental solutions and square- step clamping protocols). Since transarcolemmal Ca/2+ influx and the shape of the Ca/2+ transients will be recorded in single myocytes using different action potentials and intracellular Na+ concentrations. Age- related differences in the magnitude and time course of Ca/2+ transients may be influenced by changes in cytosolic Ca/2+ buffering and therefore, Ca/2+ buffer power will be determined in separate experiments. Mathematical models of adult ventricular cells provide relatively accurate descriptions of action-potential configuration and Ca/2+ transients, but no such model exists for immature myocytes. We will construct a mathematical model to describe the electrophysiological and Ca/2+ dynamics of neonatal ventricular cells based on previous reports and new data from the present studies. Results from the proposed experiments will provide important new insights into fundamental aspects of the regulation of [Ca/2+]i and contractions in the immature heart. This new information will help fulfil the longer-term goal of understanding normal and pathological mechanisms involved in controlling contractility during cardiac development. These data will ultimately form the foundation for designing age-appropriate therapeutic strategies for infants and children with cardiac dysfunction.

激发-收缩（EC）耦合的机制尚未明确

项目成果

Paradoxical effect of dofetilide on action potential duration and calcium transient amplitude in newborn rabbit ventricular myocytes.

多非利特对新生兔心室肌细胞动作电位持续时间和钙瞬变幅度的矛盾作用。

• DOI: 10.1097/01.fjc.0000151896.57637.66
• 发表时间: 2005
• 期刊: Journal of cardiovascular pharmacology
• 影响因子: 3
• 作者: Srivastava,Shekhar;Collis,Leon;Go,Anita;Mancarella,Salvatore;Coetzee,WilliamA;Artman,Michael
• 通讯作者: Artman,Michael

Phospholemman expression is high in the newborn rabbit heart and declines with postnatal maturation.

Phospholemman 表达在新生兔心脏中较高，并随着出生后的成熟而下降。

• DOI: 10.1016/j.bbrc.2007.01.194
• 发表时间: 2007
• 期刊: Biochemical and biophysical research communications
• 影响因子: 3.1
• 作者: Srivastava,Shekhar;Cala,StevenE;Coetzee,WilliamA;Artman,Michael
• 通讯作者: Artman,Michael