Pannexin 1 in Regulation of Adipose Tissue Inflammation

在几乎所有的组织中，细胞都有不断的更替，通常是通过细胞凋亡的过程。在健康中 在组织中，垂死的细胞被吞噬细胞迅速识别和清除。然而，未能及时清理 凋亡的细胞导致继发性坏死，释放有毒的胞浆内容物，并在 纸巾。这个项目的基础来自拉维坎德兰实验室的初步观察 凋亡细胞通过被称为“Find-Me信号”的可溶性因子吸引吞噬细胞。我们的工作确定了 核苷酸ATP和UTP作为一种“Find-Me信号”在体内清除凋亡细胞 (Elliott等人，《自然》，2009年)。随后，与本P01的另外两个项目负责人合作(Doug Bayliss和Brant Isakson)，我们发现在早期的细胞凋亡过程中，pAnnexin通道被“打开”，导致 为了释放核苷酸，建立了Find-Me信号梯度来吸引吞噬细胞(Chekeni等人，自然，2010年)。 人类的Panx1基因与心脏病、动脉粥样硬化以及呼吸道炎症和 呼吸道疾病。这一提议将直接检验PAnnexin通道有助于提高效率的假设 细胞凋亡清除，有助于限制组织炎症，以及与动脉粥样硬化和 呼吸道发炎。在目标1中，我们将测试pAnnexin通道是否通过DISTING介导的核苷酸释放 巨噬细胞(例如在动脉粥样硬化病变中)会影响单核细胞对血管病变的募集，并且 这是否会影响动脉粥样硬化的进展和斑块的稳定性。我们还将测试特定的候选人小 我们已经确定为Panx1通道的潜在抑制剂/修饰物的分子。在目标2中，通过全局和 细胞类型特异性条件性Panx1基因敲除小鼠，我们将讨论Panx1在呼吸道炎症中的作用， 基于我们最近的观察(Juncadella等人，《自然》，2012年)。总的来说，这些研究应该会产生新的 死亡细胞和吞噬细胞之间的通讯知识对动脉粥样硬化的直接影响 和呼吸道炎症。这些研究还可以为将Panx1通道视为 适合于治疗开发的靶点，并可能识别用于这种靶向的新的小分子。

In nearly all tissues, there is a continual turnover of cells, usually by the process of apoptosis. In healthy tissues, the dying cells are quickly recognized and cleared by phagocytes. However, failure to promptly clear apoptotic cells leads to their secondary necrosis, release of toxic cytoplasmic contents, and inflammation within tissues. The basis for this project stems from the initial observations by the Ravichandran laboratory that apoptotic cells via soluble factors termed ‘find-me signals’ attract phagocytes. Our work identified the nucleotides ATP and UTP as one type of ‘find-me signal’ and critical for clearance of apoptotic cells in vivo (Elliott et al., Nature 2009). Subsequently, in collaboration with two other Project leaders on this P01 (Doug Bayliss and Brant Isakson), we showed that pannexin channels are ‘opened up’ during early apoptosis, leading to release of nucleotides, setting up a find-me signal gradient to attract phagocytes (Chekeni et al., Nature 2010). PANX1 gene in humans has been linked to heart disease, atherosclerosis, as well as airway inflammation and airway disease. This proposal will directly test the hypothesis that pannexin channels contribute to efficient apoptotic cell clearance, helping limit tissue inflammation, and pathologies associated with atherosclerosis and airway inflammation. In Aim 1, we will test whether pannexin channel-mediated nucleotide release by dying macrophages (e.g. in atherosclerotic lesions) influences monocyte recruitment to the vascular lesions, and whether this affects atherosclerosis progression, and plaque stability. We will also test specific candidate small molecules that we have identified as potential inhibitors/modifiers of Panx1 channels. In Aim 2, via global and cell type specific conditional Panx1 knockout mice, we will address the role of Panx1 in airway inflammation, based on our recent observations (Juncadella et al., Nature, 2012). Collectively, these studies should yield new knowledge on communication between dying cells and phagocytes, with direct implications for atherosclerosis and airway inflammation. These studies can also provide a rationale for considering Panx1 channels as a suitable target for therapeutic development and possibly identify new small molecules for such targeting.