Genetic analysis of inflammatory responses in wild-derived mice

描述（由申请人提供）：该竞争提案更新的一个中心科学问题是通过遗传多样性野生小鼠中的经典遗传分析发现免疫相关基因的新功能。我们已经表明并将继续表明，在免疫反应的调节方面，野生型小鼠比经典实验室小鼠更像人类表型。一条调查线继续研究IRAK 2的TIRAP依赖性活化，随后特异性募集p38 MAP激酶，其在野生型小鼠中而不是实验室小鼠中过度活化。我们已经提出了一个模型，MyD88独立的招聘IRAK2和TIRAP在野生型小鼠，这导致了p38的特异性激活。如果得到证实，该模型将挑战几种公认的范式，例如通过TLR同时激活MAP激酶和MyD 88依赖性激活p38，从而拓宽TLR介导的激活的现有模型并提供额外的机制见解。我们建议在野生小鼠中研究的另一种表型是它们对TNF诱导的致死性的显着抗性，根据我们的初步数据，这是一种由四个基因座赋予的遗传性状，我们建议对其进行鉴定。鉴于我们在定位和定位克隆方面的专业知识和跟踪记录，我们很可能会发现TNF受体途径的新组分，这些组分可以保护小鼠和可能的人类免受TNF诱导的致死性。为了解释这一特性，我们提出了我们的中心假设，即与导致坏死的细胞毒性信号相比，MSM小鼠的TNF抗性偏向于促生存，我们提供了可行的科学计划来证明这一点。因此，该提议的科学影响是高的，因为它将识别能够定义TNF激活结果的组分。此外，拟议的遗传分析将有助于识别基因，否则将难以预测在没有“强有力的教育猜测”。最重要的是，鉴于每年有数十万患者患有败血性休克，这些基因的鉴定将与人类健康高度相关。除了克隆TNF抗性，这显然是本提案的优先事项，我们提供了一个研究计划，旨在揭示我们在前一个周期中确定的两个基因的体内功能。) )

DESCRIPTION (provided by applicant): A central scientific question of this competing proposal's renewal is finding novel functions of immunologically relevant genes by means of classical genetic analysis in genetically diverse wild-derived mice. We have shown and continue to show that, with respect to regulation of immune responses, wild-derived mice resemble human phenotype better than classical laboratory mice. One line of inquiry continues investigation of TIRAP-dependent activation of IRAK2 followed by specific recruitment of the p38 MAP kinase, which is hyperactivated in wild- derived but not laboratory mice. We have proposed a model of MyD88-independent recruitment of IRAK2 and TIRAP in wild-derived mice, which leads to a specific activation of p38. If confirmed, this model will challenge several well-established paradigms such as simultaneous activation of MAP kinases via TLRs and MyD88- dependent activation of p38 thus broadening existing models of TLR-mediated activation and providing additional mechanistic insight. Another phenotype that we propose to investigate in wild-derived mice is their remarkable resistance to TNF-induced lethality, which is, according to our preliminary data, a genetic trait that is conferred by four loci, which we propose to identify. Given our expertise and track record in mapping and positional cloning, it is likely that we will find novel components of TNF-receptor pathway, which protect mice and presumably humans from TNF-induced lethality. To explain the trait, we generated our central hypothesis in that TNF-resistance in MSM mice is biased towards pro-survival as compared to cytotoxic signaling that leads to necrosis, and we provide feasible scientific plan to prove that. Thus, the scientific impact of this proposal is high because it will identify component, which are capable of defining the outcome of TNF-activation. In addition, the proposed genetic analysis will help identifying genes that otherwise would be difficult to predict in the absence of " strong educated guess". Most importantly, the identification of these genes will be of high relevance to human health given several hundred thousand of patients suffering each year from septic shock. In addition to cloning of the TNF-resistance, which is clearly a priority of this proposal, we provide a research plan aimed at revealing in vivo functions of two genes that we identified in the previous cycle. ) )