IKK:Biophysical basis of dynamic regulation

IKK是炎症和先天免疫反应的主要信号中枢。它是一种酶复合物， 从大量的细胞受体接收信号，调节转录的NF-κ B家族的活性 因素IKK的失调与许多慢性疾病有关，如慢性炎症性病变 （关节炎、动脉粥样硬化等）和许多不同类型的癌症。基因证据强烈支持IKK的关键 在生理学和病理学的许多功能中起着重要作用，但其作为药物靶点的潜力还没有被发现。 实现了机制和生物物理研究一直缺乏，我们既没有动力学的理解， IKK监管或结构信息。然而，很清楚的是，IKK通过紧密连接介导信号特异性。 刺激特异性的动态控制，诱导特定基因组的表达。最近的研究 报道了一个紧密耦合的激活和失活机制，只能描述为一个多状态 一种激活-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。通过调节这些活动，我们假设IKK 周期是以刺激和细胞类型特异性的方式驱动的，理解动力学关系将 揭示了合理靶向药物干预的机会， 相关的失调和刺激反应调节健康细胞。 在本研究中，我们将构建IKK循环的数学模型，探讨IKK的动态调节 活动然后，我们将集中在特定的控制机制的生物化学和生物物理学研究。我们尤其 检测IKK寡聚化、构象变化和上游激酶在IKK激活和抑制中的作用 关于IKK计算模拟将指导IKK动力学的遗传和药理学操纵。最后我们 我们将集中研究TNF和IL-1如何产生IKK的差异动态控制;差异剂量反应如何 和时间控制决定了细胞因子陷阱的功效。

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.