The Role of Neuregulin in Human Cardiac Remodeling and Heart Failure

神经调节蛋白在人类心脏重塑和心力衰竭中的作用

基本信息

批准号：
8494678
负责人：
Bonnie Ky
金额：
$ 14.08万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8494678
关键词：
Adult Adverse effects Animal Experimentation Animals Basic Science Biological Assay Biological Markers Biomechanics Biometry Breast Carcinoma Cardiac Cardiac Myocytes Cardiomyopathies Cardiovascular Diseases Cardiovascular system Cause of Death Cessation of life Chronic Kidney Insufficiency Clinical Clinical Data Cohort Studies Complex Data Development Development Plans Dilated Cardiomyopathy Echocardiography Enrollment Ensure Epidemiology Etiology Fetal Heart Foundations Functional disorder Funding Future Goals Growth Heart Heart Diseases Heart Transplantation Heart failure Hospitalization Human Hypertrophy Injury Kidney Knowledge Left Ventricular Remodeling Longitudinal Studies Maintenance Master of Science Measures Medicine Mentors Methods Monoclonal Antibodies Neuregulin 1 Neuregulins Outcome Pathway interactions Patients Pennsylvania Phenotype Physicians Play Population Predisposition Proteins Relative (related person)Research Research Personnel Research Proposals Resources Risk Roche brand of trastuzumab Role Scientist Secondary to Severities Signal Pathway Signal Transduction Stress Structure Testing Thick Time Training Translating Trastuzumab United States National Institutes of Health Universities Ventricular Remodeling cardiogenesis career development chemotherapeutic agent clinically relevant clinically significant cohort design experience heart function human data human subject improved novel novel strategies paracrine patient oriented patient oriented research prevent programs prospective public health relevance response therapeutic target time use

项目摘要

DESCRIPTION (provided by applicant): Dr. Ky is an adult cardiologist with advanced training in echocardiography and heart failure who is currently enrolled in the Master of Science in Epidemiology program at the University of Pennsylvania. Her long-term goal is to be an independent, patient-oriented physician scientist who will make significant contributions to the study of human cardiac remodeling and cardiovascular medicine. Her career development plan encompasses focused didactic coursework; first hand experience in patient-oriented research through the design and execution of a prospective cohort study and additional cohorts initiated by the candidate; advanced methods in epidemiology and biostatistics for use in two large prospective cohort studies; and a highly structured, cohesive mentoring program. The overall objective of this scientific proposal is to determine the clinical relevance of circulating neuregulin as it relates to ventricular remodeling and risk of adverse clinical outcomes across a broad range of human cardiac remodeling phenotypes. Basic science research has defined this pathway as critical in the maintenance of cardiac function, but whether these findings translate to humans is unknown. Preliminary evidence from the Penn Heart Failure Study (PHFS) suggests that circulating neuregulin-12 (NRG-12) levels may be independently predictive of future risk of death or cardiac transplantation, and this risk may differ significantly by heart failure etiology and severity. Under the direction of Primary mentor Dr. Stephen Kimmel and Co-mentor Dr. Thomas Cappola, Dr. Ky will definitively determine if NRG-12 is associated with clinical outcomes across different etiologies and severity of heart failure and quantify the relationship between NRG-12 and cardiac remodeling over time using two large prospective cohorts: PHFS and the Chronic Renal Insufficiency Cohort (CRIC). Together these cohorts span the entire spectrum of cardiac remodeling, with eccentric hypertrophy in PHFS, and all remodeling geometries, including normal and concentric hypertrophy, in CRIC. The aims of this proposal are to: 1) establish the strength and consistency of the relationship between NRG-12 levels and incident adverse cardiac outcomes in all PHFS patients with eccentric hypertrophy, stratified by etiology and severity; 2) determine the longitudinal relationship between NRG-12 and cardiac remodeling in CRIC; 3) determine the relationship between NRG-12 and incident cardiac outcomes in CRIC. This research will provide the first large scale, systematic data on circulating neuregulin in human heart disease, laying the foundation for this candidate's long-term goal of translating knowledge from basic science and clinical observations into new approaches to prevent and treat heart failure. The combination of advanced epidemiologic and biostatistical training and mentored, patient-oriented research will ensure Dr. Ky emerges as a highly successful independent investigator in translational cardiovascular research.

描述（由申请人提供）：Ky 博士是一位成人心脏病专家，接受过超声心动图和心力衰竭方面的高级培训，目前正在宾夕法尼亚大学攻读流行病学理学硕士项目。她的长期目标是成为一名独立的、以患者为中心的医师科学家，为人类心脏重塑和心血管医学的研究做出重大贡献。她的职业发展计划包括重点教学课程；通过设计和执行前瞻性队列研究以及候选人发起的其他队列，获得以患者为导向的研究的第一手经验；用于两项大型前瞻性队列研究的流行病学和生物统计学先进方法；以及高度结构化、有凝聚力的指导计划。该科学提案的总体目标是确定循环神经调节蛋白的临床相关性，因为它与心室重塑以及广泛的人类心脏重塑表型中不良临床结果的风险有关。基础科学研究已将这一途径定义为维持心脏功能的关键，但这些发现是否适用于人类尚不清楚。宾夕法尼亚心力衰竭研究 (PHFS) 的初步证据表明，循环神经调节蛋白-12 (NRG-12) 水平可以独立预测未来死亡或心脏移植的风险，并且这种风险可能因心力衰竭病因和严重程度而存在显着差异。在主要导师 Stephen Kimmel 博士和联合导师 Thomas Cappola 博士的指导下，Ky 博士将最终确定 NRG-12 是否与不同病因和心力衰竭严重程度的临床结果相关，并量化 NRG-12 之间的关系使用两个大型前瞻性队列：PHFS 和慢性肾功能不全队列 (CRIC) 随着时间的推移进行心脏重塑。这些队列一起涵盖了心脏重塑的整个范围，包括 PHFS 中的偏心肥大，以及 CRIC 中的所有重塑几何形状，包括正常和向心肥大。该提案的目的是：1) 确定所有患有偏心性肥大的 PHFS 患者中 NRG-12 水平与不良心脏结局事件之间关系的强度和一致性，并按病因和严重程度进行分层； 2）确定CRIC中NRG-12与心脏重构之间的纵向关系； 3) 确定CRIC中NRG-12与事件心脏结局之间的关系。这项研究将提供第一个关于人类心脏病中循环神经调节蛋白的大规模、系统数据，为该候选人将基础科学和临床观察知识转化为预防和治疗心力衰竭的新方法的长期目标奠定基础。先进的流行病学和生物统计学培训以及受指导的、以患者为导向的研究相结合，将确保 Ky 博士成为转化心血管研究领域非常成功的独立研究者。