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

描述（由申请人提供）：本申请涉及广泛的挑战领域（04）、临床研究和特定的挑战主题04-HL-103：评估白细胞与血小板、红细胞和内皮细胞相互作用在心脏、肺和血液疾病发病机制中的作用。我们的提案探索了分子信号传导和细胞-细胞相互作用的新范式，该范式与人类血栓性和炎症性疾病广泛相关，并且除了提供该领域的新知识外，还具有产生新的治疗策略和药物的潜力。该项目联合了一个由成熟的研究人员组成的团队，该团队非常适合研究与止血和炎症病理生物学相关的临床适用和基本问题，建立在我们最近取得的新发现的基础上，并提出了可以通过我们合作小组的专业知识和技术能力迅速解决的重点目标。因此，该项目已准备好进行快速翻译研究，并可能快速申请。这些特点使其成为挑战赠款计划的理想选择。血栓形成和炎症在急性冠状动脉综合征、中风、脓毒症、急性肺损伤和各种其他破坏性人类疾病的发病机制中错综复杂地联系在一起。虽然我们已经知道了很多，但在我们关于整合健康中的炎症和止血信号传导以及介导疾病中的失调信号传导的分子途径和细胞事件的知识中仍然存在重大差距。我们已经发现了一个以前未被认识的途径，具有这些关键特征。脑信号蛋白-丛蛋白D1信号传导最近已确定在神经系统中的细胞引导中的作用，但不知道其影响体内血小板活化、血小板-白细胞相互作用或止血和炎症事件。我们的初步数据产生强有力的证据表明，脑信号蛋白-丛蛋白D1信号轴直接影响每一个这些，因此，它可能是一个新的分子干预的目标。由于我们目前的证据表明，脑信号蛋白-丛蛋白D1信号通过修饰细胞内检查点和受体介导的细胞活化远端的细胞骨架组织来改变活化血小板的血栓前反应，因此靶向该途径的新治疗剂可能单独使用或与其他抗血栓治疗剂联合使用，包括环氧合酶抑制剂（阿司匹林）、噻吩并吡啶（氯吡格雷）和抗凝剂（肝素、华法林）。我们提出的相互关联的具体目标采用体外研究信息的人类细胞模型，在体内模型精心选择的临床前相关性和相关性与体外实验，和患者样本的分析，并将迅速推进我们的基本，翻译，和临床的理解semaphorin-plexin信号在止血，炎症和血管疾病。该项目还将为未来在许多其他实验模型和各种人类综合征中的研究奠定基础。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，并将影响不同科学和翻译社区的范式。因此，我们的建议是直接响应挑战赠款的目标和任务。 公共卫生相关性：本提案中概述的研究将涉及导致血栓形成和炎症性疾病的细胞和生化机制，这些疾病是主要的公共卫生问题。不受控制的血栓形成（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”）、急性肺损伤和许多其他破坏性人类疾病。我们对这些疾病和病症的理解仍然存在许多差距，限制了我们开发新的和改进的疗法和预防措施的能力。我们已经发现并将在本提案中检查的分子途径是新的和新颖的分子疗法的潜在靶点。我们的研究还将提供宝贵的新信息，说明凝块形成和炎症如何在健康状态下得到控制，并在疾病中变得不受控制和有害。

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.