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到血管壁外，血小板还有助于血栓形成。 通过释放生物活性分子如ADP、TxA 2和CD 40 L来引发事件。在研究中， 根据这一提议，发现人和小鼠血小板在其表面上表达IV类脑信号蛋白， sema 4D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sema 4D的胞外结构域，并且“脱落酶”被鉴定为TNF α裂解酶。 酶，ADAM 17。基于这些观察结果和对可溶性sema 4D对细胞增殖的影响的初步研究， 血小板，我们已经开发了以下假设：1）sema 4D，作为可溶性分子或表面结合的， 通过与附近血小板上表达的受体结合来促进血小板活化，2）血小板衍生的 sema 4D还可以影响循环和血管壁内除血小板以外的细胞，以及3） 当病理性血小板活化发生时，可溶性Sema 4D的血浆水平将增加。测试这些 假设，目标#1将检查sema 4D在血小板活化中的作用。目标#2将调查 调节sema 4D胞外结构域的脱落。目的#3将检查CD 72和丛蛋白的作用- B1作为血小板、单核细胞和内皮细胞中血小板源性sema 4D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sema 4D水平的可测量增加， 与血小板活化程度相关。目标#1-3将利用现有的鼠标线 缺乏sema 4D、CD 72或ADAM 17。目标4将使用来自两项临床试验的样本，其中 预期血小板活化。第一次试验包括1,000名接受心肺转流术的患者 在前瞻性肝素诱导的血小板减少症（HIT）试验中，该试验是项目#1的一部分。所有这些 个体在旁路时应该有短暂的血小板活化。那些发展HIT的人将有 持续性血小板活化。第二项试验包括4,000名具有良好特征的动脉粥样硬化患者， 心血管疾病，一种预计会发生血小板活化但不太明显的情况。 总的来说，这些目标将解决血小板sema 4D及其受体的基础生物学，探索 血小板活化时sema 4 D释放的结果，并开始评估可溶性sema 4 D的作用。 作为体内血栓形成事件的贡献者。