Genetic analysis of inflammatory responses in wild-derived mice

描述(由申请人提供)：这项竞争性提案更新的一个中心科学问题是，通过在遗传多样性的野生来源小鼠中进行经典遗传分析，找到免疫相关基因的新功能。我们已经证明并将继续证明，就免疫反应的调节而言，野生来源的小鼠比经典的实验室小鼠更接近人类的表型。一条研究路线继续研究依赖于TIRAP的IRAK2的激活，随后是p38 MAP激酶的特定招募，它在野生来源的小鼠中高度激活，但在实验室小鼠中不是。我们已经提出了一种MyD88依赖的IRAK2和TIRAP在野生源小鼠中的募集模型，它导致了p38的特异性激活。如果得到证实，这个模型将挑战几个成熟的范例，例如通过TLRs同时激活MAP激酶和依赖MyD88激活p38，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洞察力。我们计划在野生小鼠身上研究的另一个表型是它们对肿瘤坏死因子诱导的致死性的显著抵抗力，根据我们的初步数据，这是一种由四个基因座决定的遗传特征，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记录，我们很可能会发现肿瘤坏死因子受体途径的新成分，它可以保护小鼠和可能的人类免受肿瘤坏死因子诱导的死亡。为了解释这一特征，我们提出了我们的中心假设，即与导致坏死的细胞毒信号相比，MSM小鼠的肿瘤坏死因子耐药倾向于支持生存，我们提供了可行的科学计划来证明这一点。因此，这一提议的科学影响很大，因为它将确定能够定义肿瘤坏死因子激活结果的成分。此外，拟议的基因分析将有助于识别在没有“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，鉴于每年有数十万感染性休克患者，这些基因的识别将与人类健康高度相关。除了克隆抗肿瘤坏死因子的基因，这显然是这项提议的优先事项，我们还提供了一项研究计划，旨在揭示我们在前一个周期中确定的两个基因在体内的功能。))

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. ) )