PYRIN domain (PYD) containing proteins have recently emerged as important signaling molecules involved in the development of innate immunity to intracellular pathogens through activation of inflammatory mediator pathways. Signals are initiated in phagocytic cells by intracellular PYD-containing pathogen recognition receptors, known as PAN, PYPAF, NALP, Nod, or Caterpiller proteins. Activation of PAN receptors requires specific recognition of intracellular pathogens, which leads to association with, and oligomerization of the central PYD-containing adaptor protein ASC. ASC links pathogen recognition to activation of downstream effector pathways, including caspase-1 and NF-?B. Dysregulation of PYD signaling has been associated with a number of systemic autoinflammatory disorders. The objective of the research proposed in this application is to define the regulatory mechanisms at the level of ASC that control activation of PYD- mediated signal transduction leading to the production of effector mediators. Our central hypothesis, based on strong preliminary findings showing that PYD-mediated signal transduction depends critically on the central adaptor protein ASC, is that availability of ASC is a limiting, and therefore regulating, event essential for activation of downstream effectors upon activation of PAN receptors, and that multiple regulators serve to control effector activation. We plan to test our central hypothesis and accomplish the overall objective of this application by pursuing the following specific aims: 1) Identify mechanisms responsible for inflammation-triggered redistribution of ASC. 2) Elucidate regulatory pathways that restrict PYD-dependent signaling. 3) Determine molecular pathways that regulate ASC dependent signaling. Our rationale for this research is that an understanding of the mechanisms by which PYD-mediated signal transduction pathways are regulated, will ultimately allow the identification of potential strategies to intervene with this pathway for therapeutic purposes in treating PYD-mediated systemic inflammation. At the same time, the fundamental new information obtained about PYD proteins is expected to advance our understanding of innate immunity and host defense. The relevance of this research to public health is that the uncontrolled activation of the cellular pathways involved in the innate immune response to pathogenic microorganisms has many adverse effects that contribute to autoinflammatory and autoimmune diseases. Once the pathways are understood, it will be possible to develop new drugs to interfere with these inflammatory pathways to better treat these disorders. ? ? ? ?
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