The Role of Galectin-3 in Cardiac Remodeling and Heart Failure

描述（由申请人提供）：这是Jennifer Ho博士的K23奖申请，她是波士顿马萨诸塞州总医院的心脏病学研究员。何博士正在建立以患者为导向的心脏重塑和心力衰竭临床研究的职业生涯。K23奖将使何博士能够完成以下对她未来职业生涯至关重要的培训目标：(1)继续她在先进生物统计方法方面的培训；(2)获得先进的无创心脏和血管成像技术；(3)便于开展以患者为导向的心血管生理学干预研究；(4)建立独立的临床研究事业。为了实现这些目标，何博士将与她的指导团队密切合作，包括她的主要导师，马萨诸塞州总医院人类心血管生理和代谢项目主任Thomas Wang博士，以及她的两位共同导师，弗雷明汉心脏研究主任Daniel Levy博士和无创心血管成像和遗传性心肌病专家Carolyn Ho博士。何博士的长期目标是使用信息丰富的生物标志物和非侵入性成像来定义导致明显心力衰竭的亚临床疾病表型，从而通过针对潜在病理生理学的治疗来识别和潜在治疗高危个体。她提出的研究将集中在这样一个潜在的途径，半乳糖凝集素-3。实验证据表明半乳糖凝集素-3是心脏纤维化的重要介质，是心力衰竭病理生理的重要贡献者。作为一种生物标志物，半乳糖凝集素-3也能预测心衰患者的预后。初步数据显示半乳糖凝集素-3可预测社区心力衰竭事件的发生。何博士的研究将集中于阐明半乳糖凝集素-3与明显心力衰竭前的亚临床心血管表型的关系。具体来说，她将研究社区中与心室和血管功能的关系（Aim 1），以及半凝集素-3与肥厚性心肌病（一种以心脏纤维化为标志的疾病）中心脏表型的关系（Aim 2）。最后，何博士将进行一项随机安慰剂对照试验，研究半乳糖凝集素-3抑制对半乳糖凝集素-3水平升高的高血压患者胶原代谢和亚临床心血管表型的影响（目的3）。该研究和培训计划将构成在高危人群中进行生物标志物引导靶向治疗试验的基础，该试验将在K23授予结束前的R01拨款申请中提出。

DESCRIPTION (provided by applicant): This is an application for a K23 award for Dr. Jennifer Ho, a cardiology research fellow at Massachusetts General Hospital, Boston. Dr. Ho is establishing a career in patient-oriented clinical research in cardiac remodeling and heart failure The K23 award will enable Dr. Ho to accomplish the following training goals critical to her future career: (1) to continue her training in advanced biostatistical methods; (2) to gain expertise in advanced noninvasive cardiac and vascular imaging; (3) to become facile with patient-oriented intervention studies in cardiovascular physiology; and (4) to establish an independent clinical research career. In order to achieve these goals, Dr. Ho will work closely with her mentoring team, consisting of her primary mentor, Dr. Thomas Wang, Director of the Program in Human Cardiovascular Physiology and Metabolism at Massachusetts General Hospital, and her two co-mentors, Dr. Daniel Levy, Director of the Framingham Heart Study, and Dr. Carolyn Ho, an expert in noninvasive cardiovascular imaging and genetic cardiomyopathies. Dr. Ho's long-term goals are to define subclinical disease phenotypes that lead to overt heart failure using informative biomarkers and non-invasive imaging, allowing the identification and potential treatment of at-risk individuals with therapies targeted at the underlying pathophysiology. Her proposed research will focus on one such potential pathway, Galectin-3. Experimental evidence suggests that Galectin-3 is an important mediator of cardiac fibrosis, an important contributor to the pathophysiology of heart failure. As a biomarker, Galectin-3 also predicts prognosis in patients with heart failure. Preliminary data shows Galectin-3 to predict incident heart failure events in the community. Dr. Ho's research will focus on elucidating the relation of Galectin-3 to subclinical cardiovascular phenotypes that precede overt heart failure. Specifically, she will study the relation to ventricular and vascular function in the community (Aim 1), and the relation of Galectin-3 to cardiac phenotypes in hypertrophic cardiomyopathy, a condition marked by cardiac fibrosis (Aim 2). Lastly, Dr. Ho will conduct a pilot randomized placebo-controlled trial t study the effect of Galectin-3 inhibition on collagen metabolism and subclinical cardiovascular phenotypes in hypertensive individuals with elevated Galectin-3 levels (Aim 3). This research and training plan will form the basis of a biomarker-guided targeted therapy trial in an at-risk population, to be proposed in an R01 grant application before the end of the K23 award.