IKK:Biophysical basis of dynamic regulation

IKK是炎症和先天免疫反应的主要信号中枢。它是一种酶复合体， 从大量细胞受体接收信号，调节核因子-kB转录家族的活性 各种因素。IKK的错误调节与许多慢性疾病有关，例如慢性炎症病理。 (关节炎、动脉粥样硬化等)和许多不同类型的癌症。基因证据有力地支持了IKK的批评 并在许多生理和病理功能中发挥中心作用，但其作为药物靶点的潜力尚未被 意识到了。机械学和生物物理学的研究一直很缺乏，我们既没有对 IKK规则也不是结构性信息。然而，有一点是明确的，那就是ikk通过紧绷来调节信号的特异性。 一种特定于刺激并诱导特定基因集合表达的动态控制。最近的研究表明 报告了一种紧密耦合的激活和失活机制，该机制只能由多状态描述 激活-失活循环，涉及几种具有不同功能的酶的功能，如泛素 连接酶、激酶、磷酸酶和折叠酶。通过对这些活动的监管，我们假设IKK 周期是以刺激和细胞类型特定的方式驱动的，了解动力学关系将 揭示合理的有针对性的药物干预的机会，区分疾病 健康细胞中相关的调节失调和刺激反应调节。 在本方案中，我们将构建IKK循环的数学模型，以探索IKK的动态调节 活动。然后，我们将重点研究特定的控制机制的生化和生物物理研究。特别是，我们 检测IKK寡聚、构象变化和上游激酶在IKK激活和抑制中的作用 当然是伊克。计算机模拟将指导IKK动力学的遗传和药理学操作。最后，我们 我们的研究将集中在肿瘤坏死因子和白介素1如何产生对IKK的差异动态控制；如何产生差异剂量反应 时间控制决定了细胞因子陷阱的有效性。

IKK is the major signaling hub for inflammatory and innate immune responses. It is an enzyme complex that receives signals from a large number of cellular receptors regulates that activity of the NF-kB family of transcription factors. Misregulation of IKK is associated with many chronic diseases, such as chronic inflammatory pathologies (arthritis, atherosclerosis, etc) and many different types of cancer. Genetic evidence strongly supports IKK's critical and central role in many functions in physiology and pathology, but its potential as a drug target has not been realized. Mechanistic and biophysical studies have been lacking, and we have neither a kinetic understanding of IKK regulation nor structural information. However, what is clear is that IKK mediates signaling specificity by tight dynamic control that is stimulus-specific and induces the expression of specific sets of genes. Recent studies have reported on a tightly coupled activation and inactivation mechanism that can only be described by a multi-state activation-inactivation cycle that involves the function of several enzymes with different functions, such as ubiquitin ligases, kinases, phosphatases, and foldases. Through regulation of these activities, we hypothesize that the IKK cycle is driven in a stimulus- and cell type-specific manner, and that understanding the kinetic relationships will reveal opportunities for rationally targeted pharmacological intervention that discriminate between disease associated misregulation and stimulus-responsive regulation in healthy cells. In this proposal, we will construct a mathematical model of the IKK cycle to explore the dynamic regulation of IKK activity. We will then focus biochemical and biophysical studies on specific control mechanisms. In particular, we test the roles of IKK oligomerization, conformational changes, and upstream kinases in IKK activation and inhibition of IKK. Computational simulations will guide genetic and pharmacological manipulation of IKK dynamics. Finally, we will focus our study on how TNF and IL-1 produce differential dynamic control of IKK; how differential dose response and temporal control determine the efficacy of cytokine traps.