The Role of Neuregulin in Human Cardiac Remodeling and Heart Failure

描述（由申请人提供）：Ky博士是一名成人心脏病专家，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，以患者为导向的医生科学家，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和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;以及高度结构化，有凝聚力的指导计划。 这项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，因为它与心室重塑和广泛的人类心脏重塑表型中不良临床结局的风险有关。基础科学研究已经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。来自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）水平可能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显着不同。在主要导师Stephen Kimmel博士和共同导师托马斯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局相关，并使用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与心脏重塑之间随时间推移的关系。这些队列涵盖了心脏重塑的整个范围，PHFS中有离心性肥大，CRIC中有所有重塑几何形状，包括正常和向心性肥大。本提案的目的是：1）在所有偏心性肥大PHFS患者中，根据病因和严重程度分层，确定NRG-12水平与事件不良心脏结局之间关系的强度和一致性; 2）在CRIC中确定NRG-12与心脏重塑之间的纵向关系; 3）在CRIC中确定NRG-12与事件心脏结局之间的关系。 这项研究将提供关于人类心脏病中循环神经调节蛋白的第一个大规模，系统的数据，为该候选人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的长期目标奠定基础。先进的流行病学和生物统计学培训与指导，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中非常成功的独立研究者。 公共卫生相关性： Neuregulin是一种天然存在的蛋白质，对心脏有有益的影响，在维持动物心脏功能方面起着关键作用。然而，缺乏人类数据。这项拟议的研究是同类研究中的第一项，将通过定义neuregulin与两个大型人类受试者队列的心脏功能和结果之间的关系，将引人注目的动物研究转化为人类的直接相关发现。 (End（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. 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)