Defining the Role of TREM-Like Transcript-1 in Platelet Aggregation

定义 TREM 样 Transcript-1 在血小板聚集中的作用

• 批准号: 7289943
• 负责人: A. Valance Washington
• 金额: $ 10.27万
• 依托单位: UNIVERSIDAD CENTRAL DEL CARIBE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-30 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7289943
• 关键词: Address; Affect; Alpha Granule; Apolipoprotein E; Arterial Fatty Streak; Atherosclerosis; Basophilic leukemia; Blood Platelets; Blood Vessels; Cardiovascular Diseases; Cardiovascular system; Cell model; Cessation of life; Chimeric Proteins; Clot retraction; Co-Immunoprecipitations; Confocal Microscopy; Cues; Cytoplasmic Granules; Cytoplasmic Tail; Disease; Enzyme-Linked Immunosorbent Assay; Extracellular Domain; Fibrin; Fibrinogen; Fibrinolysis; Flow Cytometry; Glutathione S-Transferase; Goals; Growth; Hemorrhage; Hemostatic Agents; Hemostatic function; Homozygote; Human; Immunofluorescence Immunologic; Immunoglobulin Fragments; Immunoglobulin G; Knockout Mice; Laboratories; Lead; Ligands; Lip structure; Mass Spectrum Analysis; Mediating; Megakaryocytes; Molecular; Morbidity - disease rate; Mus; Myeloid Cells; Myocardial Infarction; Nature; Patients; Pharmacia brand of estropipate; Platelet Activation; Platelet aggregation; Play; Positioning Attribute; Proteins; Rattus; Receptor Aggregation; Receptor Signaling; Regulation; Reporting; Role; Secondary to; Serum; Signal Pathway; Stroke; Surface; Testing; Therapeutic Intervention; Thrombin; Thrombocytopenia; Thrombosis; Thrombus; Transcript; acute coronary syndrome; ilium; in vivo; in vivo Model; mortality; mouse model; polyclonal antibody; receptor; research study; response; success

DESCRIPTION (provided by applicant): Cardiovascular disease (CVD) remains our largest cause of mortality and morbidity. Although there are several causes, platelet thrombus formation and fibrinolysis play a central role in the initiation and progression of various facets of these CVDs. Therefore, it is important to understand the cues that cause the breakdown of the regulation of platelet activation. It is my long-term goal to identify and understand the key molecular components involved in proper platelet function and subsequently to develop treatments for patients with acute coronary syndromes. We discovered the platelet surface receptor called "triggering receptor expressed in myeloid cells" (TREM) like transcript-1 or TLT-1 that is found in mice and humans. TLT-1 is abundant, specific to platelets and megakaryocytes, and up-regulated from the alpha-granules upon stimulation with thrombin or LPS to the platelet surface. After platelet activation, a TLT-1 soluble fragment is found in serum. These results suggest that TLT-1 plays a unique role in hemostasis and/or thrombosis. Using single chain antibody fragments (scFv) specific to TLT-1, we are able block thrombin-mediated platelet aggregation and delay clot retraction, suggesting that TLT-1 enhances thrombin-mediated aggregation and is a pro-thrombotic molecule. Clot retraction in platelets is mediated by the CD41/CD61 interaction with its ligand fibrin(ogen). Therefore, the delay in clot retraction implies a possible interaction with CD41/CD61 or its ligand, fibrin(ogen). This project will address the hypothesis that TLT-1 functions as an aggregation receptor secondary to CD41/CD61 whose function is to potentiate the activation of CD41/CD61 and subsequent platelet aggregation. Consequently, TLT-1 plays an early role in the formation and growth of an atherosclerotic plaque. To test this hypothesis, we propose three specific aims that address the mechanisms of TLT-1 involvement in platelet activation and examine TLT-1 function in vivo. Aim 1: To characterize TLT-1 involvement in clot retraction. Aim 2: Identify proteins that interact with the TLT-1 cytoplasmic domain. Aim 3: To elucidate the mechanisms of TLT-1 function and evaluate TLT-1 involvement in the advancement of CVD in an in vivo model. Our discovery and initial characterization of the TLT-1 and its potential role in thrombosis and hemostasis places our laboratory in a unique position to examine this interaction in detail.

描述（由申请人提供）：心血管疾病（CVD）仍然是我们死亡率和发病率的最大原因。虽然有多种原因，血小板血栓形成和纤维蛋白溶解在这些心血管疾病的各个方面的发生和发展中起着核心作用。因此，了解导致血小板活化调节崩溃的线索是很重要的。我的长期目标是识别和了解血小板正常功能的关键分子成分，并随后开发急性冠状动脉综合征患者的治疗方法。我们发现了血小板表面受体，称为“髓样细胞中表达的触发受体”（TREM），如在小鼠和人类中发现的转录-1或TLT-1。TLT-1含量丰富，对血小板和巨核细胞具有特异性，在凝血酶或LPS刺激下从α -颗粒上调至血小板表面。血小板活化后，在血清中发现TLT-1可溶性片段。这些结果表明，TLT-1在止血和/或血栓形成中起着独特的作用。使用TLT-1特异性的单链抗体片段（scFv），我们能够阻断凝血酶介导的血小板聚集和延迟凝块收缩，这表明TLT-1增强了凝血酶介导的聚集，是一种促血栓形成的分子。血小板中的凝块收缩是由CD41/CD61与其配体纤维蛋白（原）相互作用介导的。因此，凝块收缩的延迟意味着可能与CD41/CD61或其配体纤维蛋白（原）相互作用。

项目成果

Clinical studies support a role for trem-like transcript-1 during the progression of sepsis.

临床研究支持 trem 样转录物 1 在脓毒症进展过程中的作用。

• 发表时间: 2010
• 期刊: Boletin de la Asociacion Medica de Puerto Rico
• 作者: Esponda,Omar;Morales,Jessica;Aguilar,Alexandra;Gomez,Michael;Washington,AValance
• 通讯作者: Washington,AValance