Myeloid TLR4 epigenetic regulation and signaling in accelerating venous thrombus resolution

髓系 TLR4 表观遗传调控和信号传导加速静脉血栓溶解

• 批准号: 10328266
• 负责人: Andrea Tara Obi
• 金额: $ 16.95万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10328266
• 关键词: Acquired Immunodeficiency Syndrome; Acute; Address; Agonist; Anticoagulant therapy; Biology; Blood; Blood Vessels; Blood coagulation; Bone Marrow; Caring; Cells; Cessation of life; Chromatin; Chronic; Clinic; Clinical; Coagulation Process; Cytokine Gene; Data; Data Analyses; Deep Vein Thrombosis; Development; Ensure; Enzymes; Epigenetic Process; Fellowship; Foundations; Functional disorder; Funding; Gene Expression; Goals; Health; Hemorrhage; Human; IL6 gene; Immune; Immunologics; Immunology; Inflammatory; Injury; Innate Immune Response; Innate Immune System; Kinetics; Knowledge; Knowledge acquisition; Lead; Leg; Leukocytes; Life; Ligands; Limb structure; Mediating; Mediator of activation protein; Mentorship; Microbiology; Mixed-Lineage Leukemia; Modeling; Modernization; Modification; Molecular; Molecular Target; Morbidity - disease rate; Mus; Myelogenous; Natural Immunity; Operative Surgical Procedures; Pain; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Pharmacology; Play; Postdoctoral Fellow; Postphlebitic Syndrome; Process; Production; Program Development; Pulmonary Embolism; Recurrence; Research; Research Design; Research Proposals; Residual state; Resolution; Risk; Role; Scientist; Signal Pathway; Signal Transduction; Source; Surgeon; Swelling; TLR4 gene; Talents; Techniques; Testing; Therapeutic; Thinness; Thrombolytic Therapy; Thrombosis; Thrombus; Time; Training; Training Programs; Translating; Ulcer; United States; Up-Regulation; Veins; Venous; Venous Thrombosis; base; career; chronic thromboembolic pulmonary hypertension; clinical care; cytokine; deep field survey; epigenetic regulation; experience; histone methyltransferase; immunothrombosis; improved; innovation; insight; macrophage; malignant breast neoplasm; monocyte; mouse model; programs; response; skills; stem cells; success; thrombotic; undergraduate education

PROJECT ABSTRACT This proposal describes the 5-year training program for development of a research career in vascular biology, with focus on thrombosis. The candidate, Dr. Andrea Obi, has the long-term goals of becoming an independently funded surgeon-scientist, advancing understanding of immunothrombosis and reducing the morbidity from deep venous thrombosis (DVT). Dr. Obi has a strong foundation with advanced undergraduate education in Microbiology and Immunology, training in microsurgical venous thrombosis models during a T32 post-doctoral fellowship, and completion of a clinical fellowship in Vascular Surgery. A talented and experienced mentorship team provides a detailed plan of skill and scientific knowledge acquisition, and longitudinal professional development to ensure her success in developing an independent research program at the intersection of innate immunity and thrombosis. Dr. Obi's immediate goal is to leverage the K08 protected time and mentorship to develop expertise in advanced immunologic experimental techniques, solidify her scientific skill set in investigating epigenetic modifications, and to advance her knowledge in myeloid cellular signaling pathways, that will aid in developing immune based non-anticoagulant therapies for the treatment of DVT. Clinically, the presence of persistent residual venous thrombi following an episode of DVT is associated with valvular dysfunction, recurrent thrombosis and post thrombotic syndrome. Experimentally, innate immune cells, primarily monocytes/macrophages, play a central role in resolving the thrombus. In a translational mouse model we demonstrate that TLR4 is an essential mediator of thrombus resolution. Within the enclosed proposal we plan to address a major gap in clinic care, namely a lack of non-anticoagulant molecular targets for thrombus resolution, by evaluating the central hypothesis that that myeloid TLR4-mediated thrombus resolution is mechanistically driven by epigenetic changes that occur in bone marrow derived monocytes in response to acute venous thrombosis and determines the subsequent local cytokine and fibrinolytic response. This will be accomplished via three specific aims: (1) to examine the ligands, kinetics and cellular source of TLR4 and requirement for myeloid TLR4 signaling during thrombus resolution; (2) to examine the role of chromatic modifying enzyme MLL1 on postthrombotic TLR4 expression and molecular mediators of thrombus resolution; (3) to determine the feasibility of myeloid specific TLR4 agonism as a strategy to accelerate thrombus resolution and assess impact on vein wall injury.

项目摘要 该提案描述了为期5年的研究生物学研究职业的培训计划， 专注于血栓形成。候选人Andrea Obi博士的长期目标是成为独立的目标 资助的外科医生科学家，促进对免疫栓塞的理解，并降低了深度的发病率 静脉血栓形成（DVT）。 Obi博士在高级本科教育中拥有坚实的基础 微生物学和免疫学，在T32博士后训练微型外科静脉血栓形成模型 研究金，并完成血管外科临床研究金。有才华和经验丰富的指导 团队提供了详细的技能和科学知识获取计划以及纵向专业人员 开发以确保她成功地在先天的交集中制定独立研究计划 免疫力和血栓形成。 Obi博士的近期目标是利用K08受保护的时间和指导来发展高级专业知识 免疫学实验技术巩固了她在研究表观遗传修饰方面的科学技能， 为了促进她在髓样细胞信号通路中的知识，这将有助于发展基于免疫的 用于DVT治疗的非癌症疗法。临床上，存在持续残留静脉 DVT发作后的血栓与瓣膜功能障碍，复发性血栓形成和后 血栓综合征。在实验上，先天性免疫细胞（主要是单核细胞/巨噬细胞）的中心 在解决血栓上的作用。在翻译鼠标模型中，我们证明TLR4是必不可少的介体 血栓分辨率。在封闭的提案中，我们计划解决临床护理中的主要差距 缺乏通过评估中心假设的非通态分子分子靶标的 髓样TLR4介导的血栓分辨率在机械上是由发生在 骨髓响应急性静脉血栓形成而衍生的单核细胞，并确定随后的局部 细胞因子和纤溶反应。这将通过三个特定目标来完成：（1）检查配体， TLR4的动力学和细胞来源以及血栓分辨率期间髓样TLR4信号的需求； （2） 检查色度修饰酶MLL1对锁骨后TLR4表达和分子的作用 血栓分辨率的介体； （3）确定髓样特异性TLR4激动剂作为一种策略的可行性 加速血栓分辨率并评估对静脉壁损伤的影响。