Mechanism of IKK Signaling Network

描述（由申请人提供）：我们研究的长期目标是研究细胞内信号通路如何响应特定的细胞外刺激，从而确定预防和治疗人类疾病的潜在治疗靶点。本研究以TNFα诱导的细胞凋亡中IKK对Bad的调控为分子探针，探讨IKK信号网络的分子机制及其病理生理学意义。 使用多方面的方法，我们发现了IKK信号网络的第二个信号通路，即，IKK-Bad轴我们发现Bad是IKK的一个新靶点，也是TNFα在体外和体内诱导细胞凋亡所必需的。IKK对Bad的调节参与抑制TNFα诱导的细胞凋亡。我们假设除了激活NF-κB外，IKK还通过灭活Bad抑制TNFα诱导的细胞凋亡，即，“NF-κB激活和Bad失活”模型。 这项提议是新颖的，因为它将研究IKK-Bad轴在TNFα和其他死亡刺激诱导的凋亡中的作用，以及在坏死和自噬中的作用，以及体外和体内调节的潜在机制和病理生理功能。 这项研究将提出一个新的范式，IKK信号网络，并将提供一个更好地了解IKK信号网络的生物学功能，在细胞死亡的调节，这在许多人类疾病中起着重要作用。

DESCRIPTION (provided by applicant): The long-term goal of our research is to investigate how the intracellular signaling circuitry is wired in response to specific extracellular stimuli, thereby identifying potential therapeutic targets for prevention and treatment of human diseases. In this proposal, we will study the molecular mechanism underlying the IKK signaling network and its pathophysiological implications, using regulation of Bad by IKK in TNFα-induced apoptosis as a molecular probe. Using multifaceted approaches, we uncovered a second signaling pathway of the IKK signaling network, i.e., the IKK-Bad axis. We found that Bad is a novel target of IKK and is also required for TNFα-induced apoptosis in vitro and in vivo. Regulation of Bad by IKK is involved in inhibition of TNFα-induced apoptosis. We hypothesize that in addition to activation of NF-κB, IKK inhibits TNFα-induced apoptosis via inactivation of Bad, i.e., the "NF-κB activation and Bad inactivation" model. This proposal is novel, as it will study the role of the IKK-Bad axis in apoptosis induced by TNFα and other death stimuli, as well as in necrosis and autophagy, and the underlying mechanism and pathophysiological functions of the regulation in vitro and in vivo. This study will put forward a novel paradigm regarding the IKK signaling network and will provide a better understanding of the biological functions of the IKK signaling network in terms of regulation of cell death, which plays an important role in many human diseases.