New Pathways in Thrombosis and Inflammation Mediated by Semaphorin-Plexin Signali

信号蛋白-丛蛋白信号介导的血栓形成和炎症的新途径

• 批准号: 7827041
• 负责人: Guy A. Zimmerman
• 金额: $ 49.87万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7827041
• 关键词: Acute Lung Injury; Address; Adherence; Age; Anticoagulants; Area; Aspirin; Binding; Biochemical; Biological; Biological Models; Blood Platelets; Blood Vessels; Cardiovascular system; Cell Adhesion Molecules; Cell Communication; Cell model; Cells; Characteristics; Clinical; Clinical Research; Coagulation Process; Communication; Communities; Complex; Cues; Cyclooxygenase Inhibitors; Cytoskeletal Modeling; Data; Diagnosis; Disease; Distal; Endothelium; Erythrocytes; Event; Experimental Models; Family; Family member; Future; Gene Expression; Goals; Grant; Health; Heart; Hematological Disease; Hemostatic Agents; Hemostatic function; Heparin; Human; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Integrins; Intervention; Investigation; Knowledge; Lead; Leukocytes; Ligands; Link; Lung; Measures; Mediating; Mediator of activation protein; Messenger RNA; Mission; Molecular; Molecular Target; Mus; Myocardial Infarction; Nervous system structure; Neurons; Pathogenesis; Pathologic; Pathway interactions; Patients; Pattern; Pharmacologic Substance; Platelet Activation; Public Health; Recombinants; Research Personnel; Role; Sampling; Semaphorins; Sepsis; Septicemia; Severities; Signal Pathway; Signal Transduction; Signaling Molecule; Stroke; Syndrome; Technical Expertise; Testing; Therapeutic Agents; Thrombosis; Thrombus; Vascular Diseases; Warfarin; acute coronary syndrome; axon growth; base; clopidogrel; healthy volunteer; improved; in vivo; in vivo Model; meetings; neuronal guidance; novel; novel therapeutics; plexin; pre-clinical; preclinical study; protein expression; public health relevance; receptor; research study; response; septic; thienopyridine

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (04), Clinical Research, and specific Challenge Topic 04-HL-103: assess the role of leukocyte interaction with platelets, erythrocytes, and endothelium in the pathogenesis of heart, lung, and blood diseases. Our proposal explores a new paradigm in molecular signaling and cell-cell interactions that is broadly relevant to human thrombotic and inflammatory diseases, and has the potential to generate novel therapeutic strategies and agents in addition to providing new knowledge in the field. The project unites a team of established investigators that is uniquely well-suited to examine clinically-applicable and basic questions relevant to the pathobiology of hemostasis and inflammation, builds on new discoveries that we have recently made, and poses focused aims that can be addressed expeditiously with expertise and technical capabilities that are in place in our collaborative group. The project is thus poised for rapid translational investigation and, potentially, fast track application. These features make it ideal for the Challenge Grant initiative. Thrombosis and inflammation are intricately linked in the pathogenesis of acute coronary syndromes, stroke, sepsis, acute lung injury, and a variety of other devastating human disorders. While much is known, there remain major gaps in our knowledge regarding the molecular pathways and cellular events that integrate inflammatory and hemostatic signaling in health, and mediate dysregulated signaling in disease. We have discovered a previously-unrecognized pathway that has these critical characteristics. Semaphorin-plexin D1 signaling has recently-identified roles in cellular guidance in the nervous system, but was not known to influence platelet activation, platelet-leukocyte interactions, or hemostatic and inflammatory events in vivo. Our preliminary data yield strong evidence that the semaphorin-plexin D1 signaling axis directly influences each of these, and that it may therefore be a novel target for molecular intervention. Because our current evidence indicates that semaphorin-plexin D1 signaling alters prothrombotic responses of activated platelets by modifying intracellular checkpoints and cytoskeletal organization distal to receptor-mediated cellular activation, new therapeutic agents that target this pathway could potentially be used independently or in combination with other antithrombotic therapies including cyclooxygenase inhibitors (aspirin), thienopyridines (clopidogrel), and anticoagulants (heparin, warfarin). The inter-related specific aims that we propose employ in vitro studies in informative human cell models, in vivo models carefully chosen for preclinical relevance and correlation with the in vitro experiments, and analyses of patient samples, and will rapidly advance our basic, translational, and clinical understanding of semaphorin-plexin signaling in hemostasis, inflammation, and vascular disease. The project will also form the basis for future investigations in many other experimental models and a variety of human syndromes. Our studies will exploit scientific and clinical opportunities, have the potential for broad and major impact, and will influence paradigms in diverse scientific and translational communities. Our proposal is thus directly responsive to the Challenge Grant goals and missions. PUBLIC HEALTH RELEVANCE: The investigations outlined in this proposal will address cellular and biochemical mechanisms that contribute to thrombotic and inflammatory diseases, which are major public health problems. Unregulated thrombosis (clot formation, often occluding blood vessels) and inflammation contribute directly to heart attack, stroke, sepsis ("blood poisoning"), acute lung injury, and a host of other devastating human disorders. Many gaps in our understanding of these disease and disorders remain, limiting our ability to develop new and improved therapies and preventative measures. The molecular pathway that we have discovered and will examine in this proposal is a potential target for new and novel molecular therapies. Our studies will also provide invaluable new information on how clot formation and inflammation are controlled in health, and become uncontrolled and injurious in disease.

描述（由申请人提供）：本申请涉及广泛的挑战领域（04），临床研究和特定挑战主题04-HL-103：评估白细胞相互作用与血小板，红细胞和内皮的角色在心脏，肺和血液疾病的发病机理中的作用。我们的建议探讨了分子信号传导和细胞 - 细胞相互作用的新范式，该范式与人类血栓形成和炎症性疾病广泛相关，并且有可能产生新颖的治疗策略和药物，而除了提供新的知识外。该项目将一组成熟的研究人员团结起来，非常适合研究与止血和炎症的病理学相关的临床知识和基本问题，建立在我们最近做出的新发现的基础上，并以我们协作小组中有专业的和技术能力来迅速解决的新发现。因此，该项目有望进行快速翻译研究，并可能是快速的应用。这些功能使其成为挑战授予倡议的理想选择。血栓形成和炎症在急性冠状动脉综合征，中风，败血症，急性肺损伤和各种其他毁灭性的人类疾病的发病机理中复杂地联系在一起。虽然众所周知，但我们关于在健康中整合炎症和止血信号的分子途径和细胞事件的知识中仍然存在主要差距，并介导疾病中的信号失调。我们发现了具有这些关键特征的先前未认可的途径。 Semaphorin-Plexin D1信号在神经系统的细胞引导中具有最近鉴定的作用，但众所周知会影响血小板激活，血小板 - 白细胞相互作用，或者体内止血和炎症事件。我们的初步数据产生了有力的证据，表明闪光蛋白 - 封型D1信号轴直接影响其中的每一个，因此它可能是分子干预的新目标。因为我们目前的证据表明，标准蛋白 - 粘蛋白D1信号传导通过修改受体介导的细胞激活远端的细胞内检查点和细胞骨架组织来改变激活的血小板的凝血性反应，新的治疗剂，新的治疗药物，该途径的靶向可能与其他抗凝聚力均与其他抗链抗激素结合在内，包括该途径可能会独立地使用。硫吡啶（氯吡格雷）和抗凝剂（肝素，华法林）。我们提出的相互关联的特定目的是在内容丰富的人类细胞模型中采用体外研究，精心选择的体内模型，以临床前相关性和与体外实验的相关性以及对患者样本的分析，并将快速提高我们的基本，翻译和临床对敏锐的敏锐症和炎症性疾病的临床理解。该项目还将构成许多其他实验模型和各种人类综合征的未来研究基础。我们的研究将利用科学和临床机会，具有广泛和重大影响的潜力，并会影响各种科学和转化社区的范式。因此，我们的建议直接响应挑战赠款的目标和任务。 公共卫生相关性：该提案中概述的调查将解决导致血栓形成和炎症性疾病的细胞和生化机制，这是主要的公共卫生问题。不受管制的血栓形成（凝块形成，通常阻塞血管）和炎症直接导致心脏病发作，中风，败血症（“血液中毒”），急性肺损伤以及许多其他破坏性的人类疾病。我们对这些疾病和疾病的理解的许多差距仍然存在，从而限制了我们开发新的和改进的疗法和预防措施的能力。我们发现并将在此提案中检查的分子途径是新型和新分子疗法的潜在靶标。我们的研究还将提供有关凝块形成和炎症如何在健康中控制，并在疾病中不受控制和伤害的宝贵新信息。