The Role Of SEMA4D/CD100 And Its Receptors In Platelet Biology And Thrombosis

SEMA4D/CD100 及其受体在血小板生物学和血栓形成中的作用

• 批准号: 7808880
• 负责人: LAWRENCE BRASS
• 金额: $ 45.18万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7808880
• 关键词: Abnormal Platelet; Address; Affect; Atherosclerosis; B-Lymphocytes; Behavior; Binding; Biology; Blood Circulation; Blood Platelets; Bypass; CD100 antigen; CD72 gene; Cardiopulmonary Bypass; Cell Communication; Cells; Cleaved cell; Clinical Trials; Collaborations; Collagen; Cytoplasmic Granules; Development; Endothelial Cells; Enzymes; Event; Extracellular Domain; Generations; Heparin; Homeostasis; Human; Individual; Integral Membrane Protein; Ligands; Lymphocyte; Measurable; Mediating; Mediator of activation protein; Metalloproteases; Mus; Patients; Plasma; Platelet Activation; Proteins; Recruitment Activity; Role; Sampling; Semaphorins; Surface; T-Lymphocyte; TNF-alpha converting enzyme; TNFSF5 gene; Testing; Thrombin; Thrombocytopenia; Thrombosis; Thrombus; axon guidance; base; in vivo; monocyte; novel; plexin; prospective; receptor; semaphorin IV

Project 5: In addition to adhering to each other and to the vessel wall, platelets contribute to thrombotic events by releasing bioactive molecules such as ADP, TxA2 and CD40L. In studies that form the basis for this proposal, human and mouse platelets were found to express on their surface the class IV semaphorin, sema4D or CD 100, a protein best known for its role in B-cell/T-cell interactions. It was also found that activated platelets shed the exodomain of sema4D and the "sheddase" was identified as the TNFa cleaving enzyme, ADAM17. Based on these observations and preliminary studies on the effects of soluble sema4D on platelets, we have developed the following hypotheses: 1) sema4D, either as a soluble molecule or surfacebound, contributes to platelet activation by binding to receptors expressed on nearby platelets, 2) plateletderived sema4D can also affect cells other than platelets within the circulation and the vessel wall, and 3) plasma levels of soluble sema4D will increase when pathological platelet activation occurs. To test these hypotheses, Aim #1 will examine the role of sema4D in platelet activation. Aim #2 will investigate the regulated shedding of the sema4D extracellular domain. Aim #3 will examine the role of CD72 and plexin- Bl as candidate receptors for platelet-derived sema4D in platelets, monocytes and endothelial cells, and Aim #4 will ask whether platelet activation in vivo causes a measurable increase in plasma sema4D levels that correlates with the extent of platelet activation. Aims #1-3 will take advantage of existing mouse lines lacking sema4D, CD72 or ADAM17. Aim #4 will make use of samples from two clinical trials in which platelet activation is expected. The first trial includes the 1,000 patients undergoing cardiopulmonary bypass in the prospective heparin-induced thrombocytopenia (HIT) trial that is part of Project #1. All of these individuals should have transient platelet activation while on bypass. Those that develop HIT will have persistent platelet activation. The second trial includes 4,000 patients with well-characterized atherosclerotic cardiovascular disease, a setting where platelet activation is predicted to occur, but be less pronounced. Collectively, these aims will address the basic biology of platelet sema4D and its receptors, explore the consequences of sema4D release when platelets are activated, and begin to assess the role of soluble sema4D as a contributor to thrombotic events in vivo.

项目 5：除了相互粘附和粘附在血管壁上之外，血小板还有助于血栓形成 通过释放 ADP、TxA2 和 CD40L 等生物活性分子来发生事件。在构成基础的研究中 根据该提议，人类和小鼠血小板被发现在其表面表达 IV 类信号蛋白， sema4D 或 CD 100，一种以其在 B 细胞/T 细胞相互作用中的作用而闻名的蛋白质。还发现 活化的血小板脱落 sema4D 的外域，“脱落酶”被鉴定为 TNFa 裂解 酶，ADAM17。基于这些观察和可溶性 sema4D 对 血小板，我们提出了以下假设：1）sema4D，作为可溶性分子或表面结合， 通过与附近血小板上表达的受体结合来促进血小板活化，2) 血小板衍生的 sema4D 还可以影响循环系统和血管壁内血小板以外的细胞，3) 当病理性血小板活化发生时，血浆中可溶性 sema4D 水平会增加。为了测试这些 假设，目标 #1 将检查 sema4D 在血小板激活中的作用。目标 #2 将调查 sema4D 胞外结构域的调控脱落。目标 #3 将检查 CD72 和丛蛋白的作用 Bl作为血小板、单核细胞和内皮细胞中血小板衍生的sema4D的候选受体，以及Aim #4 将询问体内血小板活化是否会导致血浆 sema4D 水平显着增加，从而导致 与血小板活化程度相关。目标 #1-3 将利用现有的鼠标线 缺少 sema4D、CD72 或 ADAM17。目标 #4 将利用两项临床试验的样本，其中 预计血小板会被激活。第一项试验包括 1,000 名接受体外循环的患者 在前瞻性肝素诱导血小板减少症 (HIT) 试验中，该试验是项目 #1 的一部分。所有这些 个体在搭桥时应该有短暂的血小板活化。那些开发HIT的人将拥有 持续的血小板活化。第二项试验包括 4,000 名患有明确动脉粥样硬化的患者 心血管疾病，预计会发生血小板激活，但不太明显。 总的来说，这些目标将解决血小板 sema4D 及其受体的基础生物学问题，探索 血小板激活时 sema4D 释放的后果，并开始评估可溶性 sema4D 的作用 作为体内血栓形成事件的贡献者。