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(申请人提供)：心脏细丝调节蛋白，肌钙蛋白T的突变，最近被认为与家族性肥厚性心肌病有关，这是导致年轻人猝死的原因之一。疾病的严重程度与肥厚程度无关，更有可能是由于细胞水平上的心血管生理变化。实验室之前的工作已经确定，整个器官水平上的不同表型是由细丝中独特的突变特异性变化决定的。具体地说，TnT N末端部分的灵活性改变影响了细丝功能，并改变了下游的心肌细胞信号通路。钙动力学的改变也参与了发病过程。可以假设，cTnT突变经历了一种机制，在这种机制中，细丝蛋白的相互作用可能会由于灵活性的变化而中断，从而导致生理信号改变，从而驱动不同的表型。将研究cTnT柔韧性的变化及其对细丝功能的影响。CTnT突变(Arg92Trp)的力学和钙稳态的变化将被描述，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)的结果，也在研究中。