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

项目摘要 博士斯特拉顿，在系研究助理教授。俄亥俄州的生理学和细胞生物学教授 Wexner医学中心提出研究表观遗传阅读蛋白BRD4的作用， 与衰老相关的心力衰竭斯特拉顿博士此前曾担任个人NIH NRSA博士后 奖学金，并有一个强大的出版记录，从他的研究生和博士后培训，并致力于 作为学术研究领导者的职业生涯。该提案是为了指导研究科学家的发展 (K01)该奖项有助于促进向研究独立性的过渡。OSU的研究环境非常 在临床和基础研究方面都很强。斯特拉顿博士组建了一个强大的导师团队， 合作者，以帮助确保拟议的实验和斯特拉顿博士的成熟，成为一个 成功的独立调查员他的主要导师将是彼得·莫勒博士，主席部。生理学和 细胞生物学，副院长研究俄勒冈州立大学医学院。Timothy McKinsey博士，副教授 加州大学丹佛分校的翻译助理系主任和CFReT主任将担任正式的合作伙伴， 导师，也是斯特拉顿博士的博士后顾问。指导委员会的成员包括洛伦博士 沃尔德，心脏衰老专业知识;威廉亚伯拉罕博士，临床心脏病学专业知识，威廉马拉基博士， 和Federica Accornero博士的心脏纤维化专业知识。假设引导 该提案旨在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（舒张功能障碍），导致静脉和肺系统中的血容量增加。 HFpEF患者的发病率和死亡率与收缩功能不全患者相似， 已经发现治疗剂在HFpEF群体中有效。鉴于300万美国人 如果被诊断患有HFpEF，并且该疾病预计每年花费美国超过150亿美元，那么迫切需要 我们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 在炎症和衰老反应中，BRD4协同激活病理基因程序的假设 在心肌细胞和心脏成纤维细胞中，导致驱动HFpEF发病机制的纤维化。初步数据 表明病理刺激导致心肌细胞激活BRD中邻近的成纤维细胞4 依赖的方式。心肌细胞和成纤维细胞将被用于研究BRD4在激活前胶原中的作用。 心肌细胞内的纤维化基因表达以产生病理性成纤维细胞活化。年轻，中等 将使用老年大鼠和高龄大鼠来确定年龄对BRD4功能和BRD4依赖性的影响。 病理基因表达补充实验将在小鼠中进行，以测试BRD4在年龄中的作用。 相关的舒张功能障碍

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.