Minority Predoctoral Fellowship Program

少数族裔博士前奖学金计划

基本信息

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
项目类别：
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

项目摘要

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）：心脏薄丝调节蛋白的突变，肌钙蛋白T，最近与家族性肥厚性心肌病有关，这是年轻人突然死亡的原因。该疾病的严重程度与肥大程度无关，并且更有可能是由于细胞水平的心血管生理学改变所致。实验室中的先前工作已经确定，整个器官水平的各种表型取决于薄丝中的突变特异性变化。具体而言，TNT的N末端部分的灵活性改变会影响细丝功能，并改变下游的心肌信号通路。 Ca2+动力学的变化也有助于发病机理。可以假设CTNT突变经历机制，其中薄丝蛋白相互作用可能会因柔韧性变化而导致生理信号变化而破坏，从而驱动不同的表型。将研究CTNT的灵活性及其对薄丝功能的影响的变化。 CTNT突变（ARG92TRP）中力学和Ca2+体内稳态的变化将被表征，这是由于受影响的心肌信号通路（β-肾上腺素能和钙调蛋白激酶II活性）的结果，并且时间模式也正在研究中。