PYRIN PROTEINS AS REGULATORS OF INNATE IMMUNE PATHWAYS

描述（由申请人提供）：最近，含有PYRIN结构域（PYD）的蛋白质作为重要的信号分子出现，其通过激活炎症介质途径参与对细胞内病原体的先天免疫的发展。信号在吞噬细胞中由细胞内含有PYD的病原体识别受体（称为PAN、PYPAF、NALP、Nod或Caterpiller蛋白）引发。PAN受体的激活需要细胞内病原体的特异性识别，这导致与含有PYD的中央衔接蛋白ASC的关联和寡聚化。ASC链接病原体识别激活下游效应途径，包括caspase-1和NF-？B。PYD信号传导的失调与许多系统性自身炎症性疾病相关。本申请中提出的研究的目的是确定ASC水平的调节机制，其控制PYD介导的信号转导的激活，导致效应介质的产生。我们的中心假设，基于强有力的初步研究结果表明，PYD介导的信号转导关键取决于中央衔接蛋白ASC，是ASC的可用性是一个限制，因此调节，事件必不可少的激活下游效应后激活PAN受体，和多个监管机构用于控制效应激活。我们计划通过追求以下具体目标来测试我们的中心假设并实现本申请的总体目标：1）鉴定负责炎症触发的ASC再分布的机制。2)阐明限制PYD依赖性信号传导的调控途径。3)确定调节ASC依赖性信号传导的分子途径。我们进行这项研究的基本原理是，了解PYD介导的信号转导通路的调节机制，最终将允许确定潜在的策略来干预该通路，以治疗PYD介导的全身性炎症。与此同时，获得的关于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具有许多导致自身炎症和自身免疫性疾病的不良影响。一旦这些途径被理解，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.