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.
Prompt clearance of dying corpses in tissues is essential for preventing induction of inflammation. A key step in apoptotic cell removal is the release of nucleotide find-me signals via the pannexin channels, attracting phagocytes to facilitate clearance. This proposal addresses how the pannexin channels and the cell clearance process influence the onset and progression of atherosclerosis and lung inflammation. The proposed studies will also help identify selective and beneficial pharmacological targeting of pannexins in specific diseases.
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