Molecular Mechanisms Regulating Noncanonical NF-kB Signaling

调节非典型 NF-kB 信号传导的分子机制

• 批准号: 8455764
• 负责人: Shao-Cong Sun
• 金额: $ 31.6万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-01-01 至 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8455764
• 关键词: Ablation; Address; Antibody Formation; Antiviral Agents; Autoimmunity; B-Cell Activation; B-Lymphocytes; Biological Process; Cell Survival; Coupled; Data; Development; Disease; Embryo; Event; Family; Functional disorder; Homeostasis; Homologous Gene; Immune; Immune response; Immunoglobulin A; Immunotherapy; Inflammation; Inflammatory Response; Intestines; Kidney Diseases; Knock-out; Knockout Mice; Knowledge; Laboratories; Lead; Lymphoid; Malignant Neoplasms; Malignant lymphoid neoplasm; Mediating; Molecular; NF-kappa B; Natural Immunity; Organ; Pathway interactions; Phosphotransferases; Production; Protein Kinase; Proteins; Proteolysis; Recruitment Activity; Regulation; Research Project Grants; Role; Signal Transduction; Stimulus; Study models; Symptoms; TBK1 gene; TNF receptor-associated factor 3; TNFRSF5 gene; Ubiquitination; arm; base; cell growth; human disease; immune function; in vivo; innovation; novel; prevent; public health relevance; response; transcription factor; tumorigenesis

DESCRIPTION (provided by applicant): The NF-¿B family of transcription factors regulates diverse biological processes, including immune response, inflammation, cell growth and survival. NF-¿B activation involves two major pathways: the canonical and noncanonical pathways. Despite the extensive studies of the canonical pathway, the noncanonical pathway is still poorly understood. Recent studies, pioneered by the PI¿s group, suggest that activation of the noncanonical NF-¿B pathway involves degradation of an inhibitory protein, TRAF3, and stabilization of the NF-¿B-inducing kinase (NIK). However, how these signaling events are negatively controlled is still unknown. This knowledge is highly significant, since deregulated activation of the noncanonical NF-¿B pathway is associated with severe human diseases, including lymphoid disorders and cancer. The overall objective of this continuation application is to characterize the molecular mechanisms mediating the negative regulation of signal-induced noncanonical NF-¿B signaling. The proposed studies are based on highly innovative preliminary data from our laboratory. In particular, we have identified two novel signaling factors the deubiquitinase Otud7b and the protein kinase TBK1, with pivotal roles in the negative regulation of noncanonical NF-¿B signaling. Our data suggest that Otud7b and TBK1 may act in different signaling steps to prevent aberrant activation of noncanonical NF-¿B. Using newly generated Otud7b knockout (KO) mice and TBK1 conditional KO mice, we have obtained evidence suggesting an important role for Otud7b and TBK1 in regulating antibody responses and maintaining lymphoid homeostasis in the intestine, an organ with dynamic host-microbiota interactions. Our central hypothesis is that Otud7b and TBK1 control the magnitude of signal-induced noncanonical NF-¿B activation and, thereby, maintain normal immune homeostasis and responses. To address this hypothesis and accomplish our overall objective, we will (1) examine how the deubiquitinase Otud7b controls signal-induced TRAF3 degradation and noncanonical NF-¿B activation; (2) elucidate the mechanism by which TBK1 regulates the fate of NIK and the magnitude of noncanonical NF-¿B signaling; and (3) characterize the in vivo role of Otud7b and TBK1 in regulating noncanonical NF-¿B signaling and immune functions. The PI¿s laboratory pioneered the studies that led to the discovery of the noncanonical NF-¿B pathway as well as to the elucidation of the mechanism underlying the steady-state noncanonical NF-¿B regulation. We believe that the studies proposed in the current application will once again lead to a major advancement of the field, since they address the currently unknown mechanism that negatively controls signal-induced noncanonical NF-¿B activation. In addition to the conceptual innovation, the newly generated Otud7b KO mice and TBK1 conditional KO mice serve as highly innovative models for studying the pathophysiology of noncanonical NF-¿B signaling.

描述（申请人提供）：NF-B家族转录因子调节多种生物学过程，包括免疫应答、炎症、细胞生长和存活。NF-B的激活涉及两个主要途径：经典途径和非经典途径。尽管对经典途径进行了广泛的研究，但对非经典途径的了解仍然很少。最近的研究，由PI小组开创，表明非经典NF-κ B途径的激活涉及抑制蛋白TRAF 3的降解和NF-κ B诱导激酶（NIK）的稳定。然而，这些信号事件是如何负控制的仍然是未知的。这一认识是非常重要的，因为非经典NF-B途径的失调激活与严重的人类疾病有关，包括淋巴疾病和癌症。本继续申请的总体目标是表征介导信号诱导的非经典NF-B信号传导的负调节的分子机制。 拟议的研究是基于我们实验室高度创新的初步数据。特别是，我们已经确定了两个新的信号传导因子，去泛素化酶Otud 7 B和蛋白激酶TBK 1，在非经典NF-B信号传导的负调控中具有关键作用。我们的数据表明Otud 7 B和TBK 1可能在不同的信号步骤中起作用，以防止非经典NF-B的异常激活。使用新产生的Otud 7 b敲除（KO）小鼠和TBK 1条件性KO小鼠，我们已经获得了证据，表明Otud 7 b和TBK 1在调节抗体应答和维持肠道（一个具有动态宿主-微生物群相互作用的器官）中的淋巴稳态方面具有重要作用。我们的中心假设是Otud 7 B和TBK 1控制信号诱导的非经典NF-B激活的幅度，从而维持正常的免疫稳态和应答。为了解决这一假设并实现我们的总体目标，我们将（1）研究去泛素化酶Otud 7 b如何控制信号诱导的TRAF 3降解和非经典NF-κ B激活;（2）阐明TBK 1调节NIK命运和非经典NF-κ B信号转导的大小的机制;（3）表征Otud 7 b和TBK 1在调节非经典NF-κ B信号转导中的体内作用。B信号传导和免疫功能。 PI他的实验室开创了非经典NF-B通路的发现以及稳态非经典NF-B调节机制的阐明。我们相信，本申请中提出的研究将再次导致该领域的重大进展，因为它们解决了目前未知的负控制信号诱导的非经典NF-B激活的机制。除了概念上的创新，新产生的Otud 7 B KO小鼠和TBK 1条件性KO小鼠作为高度创新的模型，用于研究非经典NF-B信号传导的病理生理学。