BRD4, a Crucial Positive Regulator of Aging-Associated Diastolic Dysfunction

项目摘要 斯特拉顿博士，系研究助理教授。俄亥俄州立大学生理学和细胞生物学 沃克斯纳医学中心建议研究表观遗传阅读器蛋白BRD4的作用， 与衰老相关的心力衰竭。斯特拉顿博士之前曾在NIH NRSA获得个人博士后学位 在他的研究生和博士后培训中有很好的发表记录，并致力于 作为学术研究领袖的职业生涯。这项提议是为了建立一个有指导的研究科学家发展 (K01)奖，以帮助促进向研究独立的过渡。俄亥俄州立大学的研究环境非常好 具有较强的临床和基础研究能力。斯特拉顿博士组建了一支强大的导师团队 合作者帮助确保拟议实验的成功和斯特拉顿博士成熟为 成功的独立调查员。他的主要导师将是主席部门的彼得·莫勒博士。生理学和生理学 细胞生物学，俄亥俄州立大学医学院研究部副院长。Timothy McKinsey博士，副教授 加州大学丹佛分校翻译部助理主任兼CFReT主任将担任正式联合 他是斯特拉顿博士的博士后导师。指导委员会的成员包括罗伦博士 Wold，心脏老化专业知识；William Abraham博士，临床心脏病学专业知识，William Malarkey博士， 衰老生物学专业知识，费德里卡·埃科罗博士心脏纤维化专业知识。假设被引导 一项提案试图了解病理基因表达程序被激活的机制 对衰老和炎症的反应。舒张性心力衰竭或射血分数保留的心力衰竭 (HFpEF)与高龄和炎症密切相关。在HFpEF中，心脏的左心室不 适当放松(舒张期功能障碍)，导致静脉和肺系统的血容量增加。 HFpEF患者的发病率和死亡率与收缩功能障碍患者相似，然而， 治疗方法已被发现在HFpEF人群中有效。鉴于300万美国人 被诊断出患有HFpEF，这种疾病预计每年给美国造成超过150亿美元的损失，有一个紧迫的问题 需要更多地了解这种疾病，并为临床提供有效的治疗方法。这项工作将考验 假设BRD4对炎症和衰老作出反应，协同激活病理基因程序 在心肌细胞和心脏成纤维细胞中，导致纤维化，从而推动HFpEF的发病。初步数据 表明病理性刺激导致BRD4中的心肌细胞激活邻近的成纤维细胞 依赖的态度。心肌细胞和成纤维细胞将被用来研究BRD4‘S在激活蛋白原中的作用。 纤维化基因在心肌细胞内的表达，以产生病理性成纤维细胞的激活。年轻，中年 老年和高龄大鼠将被用来确定年龄对BRD4功能和BRD4依赖的影响 病理基因表达。将在小鼠身上进行补充实验，以测试BRD4的S在年龄中的作用 相关的舒张期功能障碍。

Project Summary Dr. Stratton, a Research Assistant Professor in the Dept. of Physiology and Cell Biology at The Ohio State University (OSU) Wexner Medical Center, proposes to investigate the role of an epigenetic reader protein, BRD4, in aging-associated heart failure. Dr. Stratton has previously held an individual NIH NRSA Postdoctoral Fellowship and has a strong publication record from his graduate and postdoctoral training and is committed to a career as an academic research leader. The proposal is for a Mentored Research Scientist Development (K01) award to help facilitate a transition to research independence. The research environment at OSU is very strong in both clinical and basic research. Dr. Stratton has assembled a strong team of mentors and collaborators to help ensure success of the proposed experiments and the maturation of Dr. Stratton into a successful independent investigator. His primary mentor will be Dr. Peter Mohler, Chair Dept. of Physiology and Cell Biology, and Vice Dean for Research OSU College of Medicine. Dr. Timothy McKinsey, Associate Professor and Assistant Department Head for Translation and Director of CFReT at UC Denver will serve as a formal co- mentor, and was Dr. Stratton's postdoctoral advisor. Members of the mentoring committee include Dr. Loren Wold, for cardiac aging expertise; Dr. William Abraham, for clinical cardiology expertise, Dr. William Malarkey, for biology of aging expertise, and Dr. Federica Accornero, for cardiac fibrosis expertise. The hypothesis guided proposal seeks to understand the mechanism by which pathologic gene expression programs are activated in response to aging and inflammation. Diastolic heart failure or heart failure with preserved ejection fraction (HFpEF) is strongly linked with advanced age and inflammation. In HFpEF, the heart's left ventricle does not relax properly (diastolic dysfunction), leading to increased blood volume in the venous and pulmonary systems. HFpEF patients suffer similar morbidity and mortality as patients with systolic dysfunction however, no therapeutics have been found to be effective in the HFpEF population. Given that 3 million Americans are diagnosed with HFpEF and the disease is projected to cost the US over $15 billion annually, there is an urgent need to learn more about this disease and deliver effective therapies to the clinic. This work will test the hypothesis that in response to inflammation and aging, BRD4 coordinately activates pathologic gene programs in cardiomyocytes and cardiac fibroblasts, resulting in fibrosis that drives HFpEF pathogenesis. Preliminary data indicate that pathologic stimulation causes cardiomyocytes to activate neighboring fibroblasts in a BRD4 dependent manner. Cardiomyocytes and fibroblasts will be used to investigate BRD4's role in activation of pro- fibrotic gene expression within the cardiomyocyte to generate pathologic fibroblast activation. Young, middle aged, and advanced aged rats will be used to determine the effect of age on BRD4 function and BRD4 dependent pathologic gene expression. Complementary experiments will be conducted in mice to test BRD4's role in age associated diastolic dysfunction.