Pannexin 1 in Regulation of Adipose Tissue Inflammation

在几乎所有的组织中，通常通过细胞凋亡过程，存在细胞的持续更新。健康 在组织中，垂死的细胞很快被吞噬细胞识别和清除。然而，未能及时清除 凋亡细胞导致其继发性坏死，释放有毒的细胞质内容物， 组织中该项目的基础源于Ravichandran实验室的初步观察， 凋亡细胞通过称为“发现我信号”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作为一种类型的“寻找我信号”，对体内凋亡细胞的清除至关重要 （Elliott等人，Nature 2009）。随后，与P01的另外两名项目负责人（Doug Bayliss和Brant Isakson），我们发现泛连接蛋白通道在早期凋亡过程中“开放”，导致 以释放核苷酸，建立find-me信号梯度以吸引吞噬细胞（Chekeni等人，Nature 2010）。 人类的PANX 1基因与心脏病、动脉粥样硬化以及气道炎症有关， 呼吸道疾病这一提议将直接检验泛连接蛋白通道有助于有效的细胞内信号传导的假设。 凋亡细胞清除，帮助限制组织炎症，以及与动脉粥样硬化相关的病理学， 气道炎症在目标1中，我们将测试泛连接蛋白通道介导的核苷酸释放是否通过死亡而被抑制。 巨噬细胞（例如动脉粥样硬化病变）影响单核细胞向血管病变的募集， 这是否影响动脉粥样硬化进展和斑块稳定性。我们还将测试具体的候选人小 我们已经确定为Panx 1通道的潜在抑制剂/修饰剂的分子。在目标2中，通过全球和 细胞类型特异性条件性Panx 1敲除小鼠，我们将讨论Panx 1在气道炎症中的作用， 基于我们最近的观察（Juncadella等人，Nature，2012）。总的来说，这些研究应该产生新的 死亡细胞和吞噬细胞之间通讯的知识，与动脉粥样硬化的直接关系 和气道炎症。这些研究还可以为将Panx 1通道视为一种 用于治疗开发合适靶点和可能鉴定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.