LPS Regulation of Macrophage Function

描述（由申请人提供）：先天免疫系统是抵御病原体的第一道防线。先天免疫细胞缺乏适应性免疫系统的精致特异性，但为了以一种可测量的方式作出反应，它们必须能够针对特定的病原体做出相应的反应。因此，这些细胞进化出模式识别受体，包括toll样受体（tlr），这些受体识别微生物特征的保守分子模式，而这些模式在宿主体内没有发现。虽然人们对tlr介导免疫反应的机制了解甚多，但仍有许多关键问题没有得到解答。其中的核心是对TLR信号通路的所有组成部分的完整了解，以及对这些组成部分的架构安排如何导致宿主防御的适当协调的理解。我们利用系统生物学的工具发现了Sharpin，这是TLR信号的一个新成分，我们对该蛋白的初步研究改变了我们对TLR通路结构的理解。我们已经证明Sharpin在含有nemo的IKK复合体水平上起作用，并控制TLR2/NF-？B途径是产生Th1细胞因子所必需的。在本提案中，我们将：1。确定Sharpin通过表观遗传修饰染色质结构和增强小体形成影响TLR依赖基因转录反应的机制。2. 描述Sharpin通过IKK复合体转导TLR2/MyD88信号调节转录反应的方式。3. 确定Sharpin在体内控制对细菌病原体的先天和适应性免疫反应中的作用。拟议的研究将推进我们对TLR2/MyD88通路，NF-？B活化，先天免疫基因的表观遗传调控，以及先天免疫细胞适应性反应指令的机制。

DESCRIPTION (provided by applicant): The innate immune system is the first line of defense against pathogens. Innate immune cells lack the exquisite specificity of the adaptive immune system, yet in order to respond in a measured way they must be able to tailor their response to the specific pathogen. These cells have therefore evolved pattern recognition receptors including the Toll-like receptors (TLRs) that recognize conserved molecular patterns characteristic of the microbe, which are not found within the host. While much is known about the mechanisms through which TLRs mediate immune responses, a number of critical questions remain unanswered. Central to these is a complete knowledge of all the components of the TLR signaling pathways and an understanding of how the architectural arrangement of these components leads to the appropriate coordination of host defense. We have utilized the tools of systems biology to discover Sharpin, a novel component of TLR signaling, and our preliminary studies of the protein have altered our understanding of the architecture of the TLR pathway. We have demonstrated that Sharpin acts at the level of the NEMO-containing IKK complex and controls a novel branch point in the TLR2/NF-?B pathway that is necessary for the production of Th1 cytokines. In this proposal, we will: 1. Determine the mechanism by which Sharpin influences transcriptional responses of TLR- dependent genes through epigenetic modification of chromatin structure and enhanceosome formation. 2. Delineate the manner by which Sharpin transduces TLR2/MyD88 signals through the IKK complex to regulate transcriptional responses. 3. Determine the role of Sharpin in controlling innate and adaptive immune responses to bacterial pathogens in vivo. The proposed study will advance our knowledge of the TLR2/MyD88 pathway, NF-?B activation, epigenetic regulation of innate immune genes, and mechanisms underlying the instruction of adaptive responses by innate immune cells.