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

BRD4，衰老相关舒张功能障碍的重要正调节因子

• 批准号: 9770739
• 负责人: Matthew Stratton
• 金额: $ 11.32万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9770739
• 关键词: Adult; Affect; Age; Aging; American; Animals; Apoptosis; Basic Science; Binding; Biochemistry; Biological Aging; Biology of Aging; Blood Volume; Cardiac; Cardiac Myocytes; Cardiology; Cell physiology; Cellular biology; ChIP-seq; Chemicals; Chromatin; Chronic; Clinic; Clinical; Clinical Research; Collagen; DOCA; Data; Deposition; Development; Diagnosis; Diastolic heart failure; Disease; EFRAC; Elderly; Ensure; Environment; Epigenetic Process; Exercise; Failure; Fellowship; Fibroblasts; Fibrosis; Functional disorder; Gene Expression; Genes; Genetic; Growth; Head; Heart; Heart Hypertrophy; Heart failure; Histology; Hypertension; Hypertrophy; IL6 gene; Impairment; Individual; Inflammaging; Inflammation; Inflammatory; Investigation; Lead; Learning; Left ventricular structure; Link; Lung; Measurement; Mediating; Mediator of activation protein; Medical center; Medicine; Mentored Research Scientist Development Award; Mentors; Modeling; Morbidity - disease rate; Mus; Muscle Cells; National Research Service Awards; Ohio; Organism; Pathogenesis; Pathologic; Pathology; Patients; Physiological; Physiology; Population; Process; Proteins; Publications; Rattus; Reader; Regulation; Relaxation; Reporting; Research; Research Assistant; Research Personnel; Role; Scientist; Signal Transduction; Stress; Structure; Sum; System; Systolic heart failure; TNF gene; Testing; Therapeutic; Transcription Factor AP-1; Transforming Growth Factor beta; Translations; Treatment Efficacy; United States National Institutes of Health; Universities; Venous; Ventricular; Work; Wound Healing; age effect; age related; career; college; coronary fibrosis; cost; effective therapy; experimental study; innovation; loss of function; member; mid-career faculty; middle age; mortality; outcome forecast; post-doctoral training; preservation; prevent; professor; programs; protein complex; protein expression; recruit; response; success; therapeutic target; transcription factor; transcriptome sequencing

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.

项目摘要 俄亥俄州立大学生理学和细胞生物学系的研究助理教授Stratton博士 大学（OSU）韦克斯纳医学中心（OSU）建议研究表观遗传读取器蛋白BRD4的作用 在衰老相关的心力衰竭中。 Stratton博士以前曾担任过单独的NIH NRSA博士后 奖学金，并在他的毕业生和博士后培训中有很强的出版记录，并致力于 作为学术研究领袖的职业。该提案是针对受过指导的研究科学家发展的 （K01）奖励有助于促进对独立研究的过渡。 OSU的研究环境非常 临床和基础研究都很强。斯特拉顿博士组建了一个强大的导师团队， 合作者有助于确保拟议的实验的成功以及Stratton博士的成熟 成功的独立研究员。他的主要导师将是生理学系主任彼得·莫勒（Peter Mohler）博士 细胞生物学和研究OSU医学院研究副院长。副教授蒂莫西·麦肯锡博士 丹佛分校的CFRET助理部门负责人和CFRET主任将担任正式共同 导师，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 Wold，用于心脏老化专业知识；威廉·亚伯拉罕（William Abraham）博士，《临床心脏病学专业知识》，威廉·马拉基（William Malarkey）博士， 用于老化专业知识的生物学和Federica Accornero博士，用于心脏纤维化专业知识。假设指导 提案旨在理解病理基因表达程序被激活的机制 对衰老和炎症的反应。舒张期心力衰竭或心力衰竭，并保留了射血分数 （HFPEF）与高龄和炎症密切相关。在HFPEF中，心脏的左心室没有 正确放松（舒张功能障碍），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的患者相似，但是 已经发现治疗剂在HFPEF人群中有效。鉴于300万美国人是 被诊断出患有HFPEF和该疾病的预计将使美国每年损失超过150亿美元的损失，这是紧急的 需要了解有关该疾病的更多信息，并向诊所提供有效的疗法。这项工作将测试 假设在响应炎症和衰老时，BRD4协调激活病理基因程序 在心肌细胞和心脏成纤维细胞中，导致纤维化驱动HFPEF发病机理。初步数据 表明病理刺激会导致心肌细胞激活BRD4中相邻的成纤维细胞 依赖方式。心肌细胞和成纤维细胞将用于研究BRD4在激活促疾病中的作用 心肌细胞内的纤维化基因表达，以产生病理成纤维细胞激活。年轻，中间 老年大鼠的年龄和高年级大鼠将用于确定年龄对BRD4功能和BRD4依赖性的影响 病理基因表达。将在小鼠中进行互补实验，以测试BRD4在年龄中的作用 相关的舒张功能障碍。