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核心科学问题是通过经典遗传分析在遗传多样性的野生小鼠中寻找免疫相关基因的新功能。我们已经并将继续证明，就免疫反应的调节而言，野生小鼠比经典实验室小鼠更类似于人类表型。其中一项研究继续研究 IRAK2 的 TIRAP 依赖性激活，然后特异性招募 p38 MAP 激酶，该激酶在野生小鼠而非实验室小鼠中过度激活。我们提出了一种在野生小鼠中独立于 MyD88 募集 IRAK2 和 TIRAP 的模型，这导致 p38 的特异性激活。如果得到证实，该模型将挑战几个成熟的范例，例如通过 TLR 同时激活 MAP 激酶和 MyD88 依赖性 p38 激活，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个表型是它们对 TNF 诱导的致死性的显着抵抗力，根据我们的初步数据，这是由四个基因座赋予的遗传特征，我们建议对其进行鉴定。鉴于我们在作图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 受体途径的新成分，从而保护小鼠和可能的人类免受 TNF 诱导的致死。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性信号传导相比，MSM 小鼠的 TNF 抗性偏向于促进生存，并且我们提供了可行的科学计划来证明这一点。因此，该提案的科学影响很大，因为它将识别能够定义 TNF 激活结果的成分。此外，所提出的遗传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，考虑到每年有数十万名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（这显然是该提案的优先事项）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. ) )