Minority Predoctoral Fellowship Program

少数族裔博士前奖学金计划

• 批准号: 7485839
• 负责人: Guinto J Pia
• 金额: $ 5.86万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-09 至 2009-08-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7485839
• 关键词: Address; Adrenergic Agents; Affect; Amino Acids; Ca(2+)-Calmodulin Dependent Protein Kinase; Cardiac; Cardiovascular Physiology; Cardiovascular system; Clinical; Complex; Decompression Sickness; Disease; Exhibits; Familial Hypertrophic Cardiomyopathy; Fellowship; Fellowship Program; Heart; Heart failure; Homeostasis; Human; Hypertrophy; In Vitro; Individual; Investigation; Kinetics; Lead; Link; Measures; Mechanics; Methodology; Minority; Modeling; Motion; Mus; Muscle Cells; Mutation; Myocardium; Myopathy; N-terminal; Names; Organ; Pathogenesis; Pattern; Peptides; Phenotype; Phosphorylation; Physiological; Physiology; Pliability; Property; Proteins; Regulation; Role; SERCA2a; Severities; Signal Pathway; Signal Transduction; Staging; Structure; Sudden Death; Tail; Testing; Therapeutic Intervention; Thin Filament; Time; Transfection; Transgenic Mice; Troponin; Troponin T; Ventricular; Work; adrenergic; cell motility; genetic regulatory protein; molecular dynamics; mutant; novel therapeutics; phospholamban; pre-doctoral; protein protein interaction; response; uptake

DESCRIPTION (provided by applicant): Mutations in cardiac thin filament regulatory protein, Troponin T, have recently been linked to Familial Hypertrophic Cardiomyopathy, a cause of sudden death in young people. The severity of the disorder is not related to the degree of hypertrophy and is more likely to be due to alterations in cardiovascular physiology at the cellular level. Prior work in the lab has established that varied phenotypes at the whole-organ level are determined by distinct mutation-specific alterations in the thin filament. Specifically, altered flexibility in the N- terminal portion of TnT affects thin filament function and alters downstream myocellular signaling pathways. Changes in Ca2+ kinetics also contribute to pathogenesis. It can be hypothesized that cTnT mutations undergo mechanisms in which thin-filament protein interactions may be disrupted due to changes in flexibility resulting in altered physiologic signaling, which drives distinct phenotypes. The changes in flexibility of cTnT and its effects on thin filament function will be investigated. Changes in mechanics and Ca2+ homeostasis in cTnT mutation (Arg92Trp) will be characterized, which are a result of affected myocellular signaling pathways (beta-adrenergic and calmodulin kinase II activity) and temporal patterns also under investigation.

描述（由申请人提供）：心脏细丝调节蛋白（肌钙蛋白T）的突变最近与家族性肥厚性心肌病（一种导致年轻人猝死的疾病）有关。这种疾病的严重程度与肥大程度无关，更可能是由于细胞水平上心血管生理学的改变。先前的实验室工作已经确定，整个器官水平上的不同表型是由细丝中不同的突变特异性改变决定的。具体来说，TnT N端柔韧性的改变会影响细丝功能并改变下游心肌细胞信号通路。Ca2+动力学的变化也有助于发病。可以假设cTnT突变的机制是，由于柔韧性的改变导致生理信号的改变，薄丝蛋白的相互作用可能被破坏，从而导致不同的表型。研究了cTnT柔韧性的变化及其对细丝功能的影响。cTnT突变（Arg92Trp）的机制和Ca2+稳态的变化将被表征，这是受影响的心肌细胞信号通路（β -肾上腺素能和钙调蛋白激酶II活性）和时间模式的结果，也正在研究中。