The Role of Neuregulin in Human Cardiac Remodeling and Heart Failure

描述（由申请人提供）：Dr. Ky是一名成人心脏病专家，在超声心动图和心力衰竭方面接受过高级培训，目前就读于宾夕法尼亚大学流行病学硕士课程。她的长期目标是成为一名独立的、以患者为导向的内科科学家，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由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；流行病学和生物统计学的先进方法用于两项大型前瞻性队列研究；以及一个结构严密、凝聚力强的指导项目。这项科学建议的总体目标是确定循环神经调节蛋白的临床相关性，因为它与广泛的人类心脏重塑表型的心室重塑和不良临床结果的风险有关。基础科学研究已经确定这一途径对维持心脏功能至关重要，但这些发现是否适用于人类尚不清楚。宾夕法尼亚大学心力衰竭研究（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，而这种风险可能因心力衰竭的病因和严重程度而有显著差异。在主要导师Stephen Kimmel博士和共同导师Thomas Cappola博士的指导下，Ky博士将明确确定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，并通过两个大型前瞻性队列：PHFS和慢性肾功能不全队列（CRIC）量化NRG-12与心脏重塑之间的关系。总之，这些队列跨越了整个心脏重构的频谱，PHFS中有偏心肥大，CRIC中有所有重构几何形状，包括正常和同心肥大。本研究的目的是：1)在所有PHFS偏心型肥厚患者中，按病因和严重程度分层，建立NRG-12水平与不良心脏结局之间的强度和一致性关系；2)确定NRG-12与CRIC心脏重构的纵向关系；3)确定NRG-12与CRIC心脏事件结局的关系。这项研究将提供第一个大规模的、系统的关于人类心脏疾病循环神经调节蛋白的数据，为该候选人的长期目标奠定基础，将基础科学和临床观察的知识转化为预防和治疗心力衰竭的新方法。先进的流行病学和生物统计学培训与指导相结合，以患者为导向的研究将确保Ky博士在转化心血管研究中成为一名非常成功的独立研究者。

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. PUBLIC HEALTH RELEVANCE: Neuregulin is a naturally occurring protein that has beneficial effects on the heart and plays a key role in maintaining heart function in animals. However, human data are lacking. This proposed study, the first of its kind, will translate the compelling animal research to directly relevant findings in humans, by defining the relationships between neuregulin and heart function and outcomes in two large cohorts of human subjects. (End of Absrtract)