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: 10210235
• 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/10210235
• 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; Prognosis; 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; United States National Institutes of Health; Universities; Venous; Ventricular; Work; age effect; age related; career; college; coronary fibrosis; cost; effective therapy; experimental study; innovation; loss of function; member; mid-career faculty; middle age; mortality; post-doctoral training; preservation; prevent; professor; programs; protein complex; protein expression; recruit; response; success; therapeutic target; therapeutically effective; transcription factor; transcriptome sequencing; wound healing

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.

项目概要 斯特拉顿博士，俄亥俄州立大学生理学和细胞生物学系研究助理教授 大学 (OSU) Wexner 医学中心提议研究表观遗传读取蛋白 BRD4 的作用， 与衰老相关的心力衰竭。 Stratton 博士此前曾获得 NIH NRSA 个人博士后学位 研究员，并在研究生和博士后培训中拥有良好的发表记录，并致力于 学术研究领导者的职业生涯。该提案旨在指导研究科学家的发展 (K01) 奖项旨在帮助促进向研究独立性的过渡。 OSU 的研究环境非常好 临床和基础研究实力雄厚。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以及斯特拉顿博士的成熟 成功的独立调查员。他的主要导师是生理学系系主任 Peter Mohler 博士， 细胞生物学，俄勒冈州立大学医学院研究副院长。蒂莫西·麦肯锡博士，副教授 加州大学丹佛分校翻译系助理主任兼 CFReT 主任将作为正式的合作伙伴 导师，也是斯特拉顿博士的博士后导师。指导委员会成员包括Loren博士 Wold，针对心脏老化的专业知识； William Abraham 博士，临床心脏病学专业知识，William Malarkey 博士， 获得衰老生物学专业知识，Federica Accornero 博士获得心脏纤维化专业知识。以假设为指导 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，但没有 已发现治疗方法对 HFpEF 人群有效。鉴于 300 万美国人 如果被诊断出患有 HFpEF，并且该疾病预计每年给美国造成超过 150 亿美元的损失，那么迫切需要 需要更多地了解这种疾病并向临床提供有效的治疗方法。这项工作将测试 假设为了应对炎症和衰老，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，从而驱动 HFpEF 发病机制。初步数据 表明病理刺激导致心肌细胞激活 BRD4 中邻近的成纤维细胞 依赖方式。心肌细胞和成纤维细胞将用于研究 BRD4 在激活前体细胞中的作用 心肌细胞内的纤维化基因表达产生病理性成纤维细胞激活。年轻、中年 老年和高龄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。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。