Genetic analysis of inflammatory responses in wild-derived mice

描述（由申请人提供）：本竞争性提案更新的核心科学问题是通过遗传多样性野生小鼠的经典遗传分析发现免疫相关基因的新功能。我们已经证明并将继续证明，在免疫反应的调节方面，野生小鼠比经典实验室小鼠更像人类表型。一条研究路线继续调查IRAK2的tirapp依赖性激活，随后是p38 MAP激酶的特异性募集，p38 MAP激酶在野生来源的小鼠中过度激活，而不是实验室小鼠。我们提出了一种在野生小鼠中myd88独立募集IRAK2和TIRAP的模型，这导致p38的特异性激活。如果得到证实，该模型将挑战几个已建立的范式，如通过tlr同时激活MAP激酶和MyD88依赖的p38激活，从而拓宽了tlr介导的激活的现有模型，并提供了额外的机制见解。我们建议在野生小鼠中研究的另一种表型是它们对tnf诱导的致死率的显著抵抗，根据我们的初步数据，这是一种由四个基因座赋予的遗传特征，我们建议鉴定。鉴于我们在绘图和定位克隆方面的专业知识和记录，我们很可能会发现tnf受体途径的新成分，这些成分可以保护小鼠和人类免受tnf诱导的死亡。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耐药倾向于促进生存，我们提供了可行的科学计划来证明这一点。因此，这一建议的科学影响是很高的，因为它将确定能够定义tnf激活结果的成分。此外，拟议的基因分析将有助于识别在缺乏“强有力的有根据的猜测”的情况下难以预测的基因。最重要的是，鉴于每年有数十万患者遭受感染性休克，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）之外，我们还提供了一项研究计划，旨在揭示我们在上一个周期中发现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. ) )