Role of TLR2 in angiogenesis

抽象的。 先天免疫和Toll样受体(TLRs)在血管发育和发育中的临床重要性 疾病，发现由脂质氧化产生的内源性TLRs新配体及其扩展 TLRs(特别是TLR2)在人类病理中的作用强调其在心血管和肺中的重要性 与炎症相关的疾病和血管病变，如视网膜老化疾病和糖尿病。 TLR2的表达不限于免疫系统；它在其他细胞上也有功能，包括内皮和 可被细菌和内源性配体激活，即脂质过氧化产物。关于…的知识 内皮细胞TLR2仅限于使用抑制剂或随处可见的TLR2 KO的研究。因此，我们建议设立 使用出生后和发育模型研究内皮细胞TLR2在血管生成中的作用。我们将对此进行测试 内皮细胞TLR2通过两种机制调节血管生成：直接通过整合素介导的迁移和 间接地，通过促进髓系细胞的招募。依赖TLR2的血管生成在 存在外源细菌TLR2配体和内源TLR2配体，即CEP，特别是在 其内源性配体高度普遍存在的组织(即视网膜)。我们的具体目标是：目标1.明确 内皮特异性(CDH5-CreERT)KO小鼠体内TLR2对血管内皮细胞的自主作用 出生后(创伤、肿瘤)模型和发育(视网膜)血管生成。目的2.评估TLR2的作用-- 依赖髓系细胞在血管生成中的募集。确立欧共体TLR2和我们一样的角色 使用KO(CX3CR1-CreERT)的髓系TLR2在出生后和发育过程中髓系细胞的募集 血管生成。目的3.确定内源性和外源性TLR2激活的促血管生成通路 内皮细胞中的配体。我们将讨论TLR2/CD36复合体的调控功能和机制。 TLR2/MyD88/TIRAP/IRAK3/4/TRAF6和Src家族激酶在血管生成原整合素调控中的作用 将建立功能，即激活、粘连和迁移。TLR2途径在EC中的新靶点 生物学，例如TRAF6，将使用新的试剂在体内进行验证。这些研究将首次建立一个 内皮细胞TLR2在血管生成中的直接作用，并将连接先天免疫和血管形成，特别是在 与感染、炎症和氧化应激相关并加剧的病理。

ABSTRACT. Emerging clinical importance of innate immunity and Toll-like receptors (TLRs) in vascular development and diseases, and discoveries of new endogenous TLRs ligands generated by lipid oxidation and their expanding functions in human pathologies underscore importance of TLRs (TLR2 in particular) in cardiovascular and lung diseases and vascular pathologies associated with inflammation, such as retinal diseases of aging and diabetes. TLR2 expression is not restricted to immune system; it is functional on other cells, including endothelium and can be activated by bacterial and endogenous ligands, i.e. products of lipid peroxidation. The knowledge of endothelial TLR2 is limited to studies with inhibitors or ubiquitous TLR2 KO. Accordingly, we propose to establish a role for endothelial TLR2 in angiogenesis using postnatal and developmental models. We will test that endothelial TLR2 regulates angiogenesis by two mechanisms: directly by integrin-mediated migration and indirectly, by promoting recruitment of myeloid cells. TLR2-dependent angiogenesis is augmented in the presence of exogenous bacterial TLR2 ligands as well as endogenous TLR2 ligands, i.e. CEP, especially in tissues where its endogenous ligand is highly prevalent (i.e. in retinas). Our specific Aims are: Aim 1. To define the cell autonomous function of TLR2 on endothelium by using endothelial-specific (Cdh5-CreERT) KO mice in postnatal (wound, tumors) models and developmental (retinal) angiogenesis. Aim 2. To assess the role of TLR2- dependent myeloid cells recruitment in angiogenesis. To establish the role of EC TLR2 as we as the role of myeloid TLR2 using KO (CX3CR1-CreERT) in myeloid cells recruitment during postnatal and developmental angiogenesis. Aim 3. To define the proangiogenic pathways activated by endogenous and exogenousTLR2 ligands in endothelial cells. The regulatory function and mechanism of TLR2/CD36 complex will be addressed. Role for TLR2/Myd88/TIRAP/IRAK3/4/TRAF6 and Src family kinases in regulation of proangiogenic integrin functions, i.e. activation, adhesion and migration will be established. Main targets of TLR2 pathway novel to EC biology, e.g. TRAF6 will be verified in vivo using novel reagents. These studies will establish for the first time a direct role of endothelial TLR2 in angiogenesis and will link innate immunity and vascularization, especially in pathologies associated and exacerbated by infection, inflammation and oxidative stress.