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

基本信息

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
项目类别：
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

项目摘要

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血管生物学研究职业发展的 5 年培训计划，重点关注血栓形成。候选人 Andrea Obi 博士的长期目标是成为独立的资助外科医生科学家，增进对免疫血栓形成的了解并降低深部发病率静脉血栓（DVT）。 Obi 博士在以下领域拥有深厚的本科教育基础：微生物学和免疫学，T32博士后期间显微外科静脉血栓模型培训奖学金，并完成血管外科临床奖学金。才华横溢且经验丰富的导师团队提供详细的技能和科学知识获取计划，以及纵向专业发展，以确保她成功地在先天的交叉点上开发独立的研究计划免疫和血栓形成。 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，巩固她在研究表观遗传修饰方面的科学技能，并提高她在骨髓细胞信号通路方面的知识，这将有助于开发基于免疫的用于治疗 DVT 的非抗凝疗法。临床上，持续残留静脉的存在 DVT 发作后的血栓与瓣膜功能障碍、复发性血栓形成和术后血栓形成有关。血栓综合症。实验上，先天免疫细胞（主要是单核细胞/巨噬细胞）发挥着核心作用起到溶解血栓的作用。在翻译小鼠模型中，我们证明 TLR4 是重要的介质的血栓溶解。在随附的提案中，我们计划解决临床护理中的一个主要差距，即通过评估中心假设，缺乏血栓溶解的非抗凝分子靶标髓系 TLR4 介导的血栓消退在机制上是由发生在骨髓来源的单核细胞对急性静脉血栓形成的反应，并决定随后的局部细胞因子和纤溶反应。这将通过三个具体目标来实现：（1）检查配体， TLR4 的动力学和细胞来源以及血栓溶解过程中骨髓 TLR4 信号传导的需求； (2) 检查染色酶 MLL1 对血栓后 TLR4 表达和分子生物学的作用血栓溶解的介质； (3)确定骨髓特异性TLR4激动作为策略的可行性加速血栓溶解并评估对静脉壁损伤的影响。