Role of platelets for tissue remodelling - modulation of angiogenesis, inflammation and apoptosis

血小板在组织重塑中的作用 - 调节血管生成、炎症和细胞凋亡

• 批准号: 208707263
• 负责人: Professor Dr. Harald Langer
• 金额: --
• 依托单位: I. Medizinische Klinik: Kardiologie, Angiologie, Pneumologie, Intensivmedizin
• 依托单位国家: 德国
• 项目类别: Clinical Research Units
• 财政年份: 2011
• 资助国家: 德国
• 起止时间: 2010-12-31 至 2018-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/208707263?language=en
• 关键词: Role; platelets; tissue; remodelling; modulation

After tissue injury, diverse processes contribute to restoration of integrity and function of the injured organ. These processes include inflammation, apoptosis and angiogenesis. During tissue injury, platelets accumulate rapidly at the site of vascular lesions, immediately after the vascular wall - the barrier between intra- and extravascular - is breached. In this locally and temporally defined segment, an intersection point between injury and regeneration exists, where the initial steps for restoration and preservation of an intact and functinal tissue are taken.From the first period of the KFO we know that platelet adhesions receptors as well as released mediators can modulate angiogenesis. Further preliminary work indicates that also other processes contributing to tissue remodelling such as apoptosis can be tailored by platelets, e.g. via mebrane expressed death receptor Fas-L. Furthermore, platelet derived receptors of innate immunity including anaphylatoxin receptors (C5aR) may modulate angiogenesis, but also platelet function. Accordingly, different mechanisms of tissue remodelling such as angiogenesis, apoptosis and inflammation are modulated by platelets. Not only the anaphylatoxins being part of our complement system, but also opsonising complement components C1q and C3 are of relevance. For instance, recent data implicate that the platelet adhesion receptor GPIb mediates an interaction of platelets with active C3. (Verschoor et al., 2011). As apoptotic cells bind complement, this could represent one potential mechanism, how platelets interact with the injured tissue. Moreover, various connection points between platelet activation and the complement system are obvious (Verschoor und Langer, 2013). Thus, the goal of this TP is to define the differential role of platelets for modulation of the aforementioned processes in the different in vivo settings (e.g, hind limb ischemia, myocardial infarction) and to characterize them on a mechanistic level towards mediating platelet effectors such as receptors for apoptosis or inflammation as well as paracrine mediators such as the anti-angiogenic platelet factor 4 (PF-4) elicited from our preliminary work. Translationally, we will also validate candidate proteins originating from results of our patient cohort during the first period of the KFO.

组织损伤后，不同的过程有助于损伤器官的完整性和功能的恢复。这些过程包括炎症、细胞凋亡和血管生成。在组织损伤期间，血管壁--血管内和血管外的屏障--被打破后，血小板会立即在血管损伤部位迅速积聚。在这个局部和时间上定义的节段，损伤和再生之间存在一个交叉点，在这里采取了恢复和保存完整和功能组织的初始步骤。从KFO的第一阶段我们知道，血小板黏附受体以及释放的介质可以调节血管生成。进一步的初步工作表明，其他有助于组织重塑的过程，如细胞凋亡，也可以由血小板来调节，例如通过膜表达的死亡受体Fas-L。此外，包括过敏性毒素受体(C5aR)在内的先天免疫的血小板衍生受体不仅可以调节血管生成，还可以调节血小板功能。相应地，不同的组织重塑机制，如血管生成、细胞凋亡和炎症，都受到血小板的调节。不仅过敏毒素是我们补体系统的一部分，而且调理补体成分C1q和C3也是相关的。例如，最近的数据表明，血小板黏附受体GPIB介导了血小板与活性C3的相互作用。(Verschor等人，2011年)。由于凋亡细胞与补体结合，这可能代表了一种潜在的机制，即血小板如何与受损组织相互作用。此外，血小板活化和补体系统之间的各种连接点也很明显(Verschor und Langer，2013)。因此，本研究的目的是明确在不同的活体环境(如后肢缺血、心肌梗死)中，血小板在调节上述过程中的不同作用，并从机制水平上表征它们在介导血小板效应因子(如凋亡或炎症受体)以及旁分泌介质(如我们前期工作中产生的抗血管生成血小板因子4(PF-4))方面的作用。在翻译上，我们还将在KFO的第一阶段验证来自我们患者队列结果的候选蛋白质。

项目成果

Interruption of classic CD40L-CD40 signalling but not of the novel CD40L-Mac-1 interaction limits arterial neointima formation in mice

• DOI: 10.1160/th13-08-0653
• 发表时间: 2014-03
• 期刊: Thrombosis and Haemostasis
• 影响因子: 6.7
• 作者: F. Willecke;Shilpa Tiwari;Benjamin Rupprecht;D. Wolf;S. Hergeth;N. Hoppe;B. Dufner;Lisa Schulte;N. Michel;N. Bukosza;T. Marchini;Markus Jäckel;P. Stachon;I. Hilgendorf;Katharina Zeschky;Rebecca Schleicher;H. Langer;C. von zur Muhlen;C. Bode;K. Peter;A. Zirlik