PYRIN PROTEINS AS REGULATORS OF INNATE IMMUNE PATHWAYS

描述(申请人提供)：含有吡咯结构域(PYD)的蛋白质最近成为重要的信号分子，通过激活炎症介质途径参与细胞内对病原体的天然免疫。吞噬细胞中的信号由细胞内含有PYD的病原体识别受体启动，这些受体称为PAN、PYPAF、NALP、NOD或卡特彼勒蛋白。PAN受体的激活需要对细胞内病原体的特异性识别，这导致了含有PYD的中央适配蛋白ASC的结合和寡聚化。ASC将病原体识别与下游效应通路的激活联系在一起，包括caspase-1和NF-βB。PYD信号的调节异常与许多系统性自身炎症疾病有关。本申请中提出的研究的目的是在ASC水平上定义控制PYD介导的信号转导激活从而导致效应性介质产生的调节机制。我们的中心假设基于强有力的初步发现，即PYD介导的信号转导在很大程度上依赖于中央适配器蛋白ASC，即ASC的可获得性是一种限制性事件，因此对PAN受体激活后下游效应器的激活具有调节作用，并且多个调节因子起着控制效应器激活的作用。我们计划测试我们的中心假设，并通过追求以下具体目标来实现这项应用的总体目标：1)确定炎症引发的ASC重新分布的机制。2)阐明限制PYD依赖信号转导的调控途径。3)确定调节ASC依赖信号的分子途径。我们这项研究的基本原理是，了解PYD介导的信号转导通路的调控机制，最终将有助于确定潜在的策略来干预这一途径，以治疗PYD介导的全身炎症。与此同时，有关PYD蛋白的基本新信息有望促进我们对先天免疫和宿主防御的理解。这项研究与公共卫生的相关性在于，参与对病原微生物的先天免疫反应的细胞通路的不受控制的激活会产生许多不利影响，导致自体炎症和自身免疫性疾病。一旦了解了这些途径，就有可能开发新的药物来干扰这些炎症途径，以更好地治疗这些疾病。

DESCRIPTION (provided by applicant): 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.