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: 8051817
• 负责人: LAWRENCE BRASS
• 金额: $ 46.25万
• 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/8051817
• 关键词: 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; 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：除了相互黏附和血管壁外，血小板还会导致血栓形成 通过释放生物活性分子，如ADP、TXA2和CD40L。在形成基础的研究中 在这一提议中，发现人和小鼠血小板表面表达IV类信号素， Sema4D或CD100，一种以其在B细胞/T细胞相互作用中的作用而闻名的蛋白质。还发现， 活化的血小板脱落了Sema4D的外区，这种脱落酶被鉴定为TnFa裂解 酵素，ADAM17。基于这些观察和初步研究，可溶性Sema4D对 对于血小板，我们提出了以下假设：1)Sema4D，无论是作为可溶性分子还是作为表面结合的， 通过与附近血小板上表达的受体结合来促进血小板激活，2)血小板来源 Sema4D还可以影响循环和血管壁内的血小板以外的细胞，以及3) 当发生病理性的血小板激活时，血浆中的可溶性Sema4D水平会升高。为了测试这些 假设，目标1将研究Sema4D在血小板激活中的作用。Aim#2将调查 调节Sema4D胞外区的脱落。目标3将研究CD72和丛状蛋白的作用- 作为血小板、单核细胞和内皮细胞中血小板衍生Sema4D的候选受体，并目的 #4将询问体内的血小板激活是否会导致血浆Sema4D水平的可测量增加，从而 与血小板活化的程度有关。AIMS#1-3将利用现有鼠标系列 缺乏Sema4D、CD72或ADAM17。目标4将使用来自两个临床试验的样本 预计会有血小板激活。第一项试验包括1000名接受体外循环的患者 在肝素诱导的血小板减少(HIT)试验中，该试验是项目1的一部分。 在体外循环中，个体应该有一过性的血小板激活。那些发展成HIT的人将会有 持续的血小板激活。第二项试验包括4000名动脉粥样硬化患者 心血管疾病，预计会发生血小板激活，但不那么明显。 总的来说，这些目标将解决血小板Sema4D及其受体的基本生物学问题，探索 当血小板被激活时释放Sema4D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。