IKK Signals in Lymphocyte Physiology and Pathology

淋巴细胞生理学和病理学中的 IKK 信号

• 批准号: 6830767
• 负责人: KLAUS RAJEWSKY
• 金额: $ 47.25万
• 依托单位: IMMUNE DISEASE INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-12-01 至 2008-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6830767
• 关键词: B cell lymphoma; B cell receptor; B lymphocyte; BCL2 gene /protein; T lymphocyte; apoptosis; asthma; biological signal transduction; cell proliferation; colitis; developmental immunology; enzyme activity; enzyme complex; experimental allergic encephalomyelitis; gene mutation; genetically modified animals; immune response; interleukin 2; laboratory mouse; leukocyte activation /transformation; neoplastic transformation; nuclear factor kappa beta; serine threonine protein kinase

DESCRIPTION (provided by applicant): Signaling through the NF-kB pathway is of critical importance for T and B lymphocyte maturation, maintenance and function. It is also involved in autoimmune reactions performed by these cells and contributes to the survival of certain classes of B cell lymphomas. Critical components in this pathway are the IkB-kinases (IKKs) which activate NF-kB signaling upon their own activation by pro-inflammatory and antigen receptor mediated signals delivered to the cells. IKK signaling can either involve the IKK signal some consisting of IKK1, IKK2 and the NEMO protein, or proceed through IKK1 activation alone. The underlying hypothesis of the present proposal is that the activation of these two pathways, either in combination or separately, is essential for T and B cells to mature, survive and perform their various functions, and also for the promotion of certain B cell malignancies. We will therefore explore in which way the inactivation of either pathway, or its enforced activation, affect the maturation, functional activities and malignant transformation of T and/or B cells at various stages of development. Rescue experiments will identify the downstream targets of IKK signaling which are responsible for cellular maintenance, and also establish whether IKK signaling is sufficient for cellular survival in the absence of receptors such as the antigen and BAFF receptor, known to be required for B cell maintenance in normal physiology. We will also define the role of cell-autonomous IKK signals in T and B cell mediated autoreactivity. Cell type-specific activation and inactivation of IKKs will be used for this purpose, exploiting techniques of conditional gene targeting which we have established in the past.

描述（由申请人提供）：通过NF-KB途径进行信号传导对于T和B淋巴细胞的成熟，维护和功能至关重要。它还参与了这些细胞进行的自身免疫反应，并有助于某些类别的B细胞淋巴瘤的存活。该途径中的临界成分是IKB-激酶（IKK），它们通过传递到细胞的促炎和抗原受体介导的信号来激活NF-KB信号传导。 IKK信号传导可以涉及IKK信号，其中一些由IKK1，IKK2和NEMO蛋白组成，或者仅通过IKK1激活进行。本提案的基本假设是，这两种途径的激活是组合或单独的，对于T和B细胞的成熟，生存和执行各种功能以及促进某些B细胞恶性肿瘤是必不可少的。因此，我们将以途径的灭活或强制激活的方式探索影响T和/或B细胞在开发的各个阶段的成熟，功能活性和恶性转化。救援实验将确定负责细胞维持的IKK信号传导的下游靶标，并确定在没有受体（例如抗原和BAFF受体）的情况下，IKK信号是否足以用于细胞存活，这是正常生理学中B细胞维持所必需的。我们还将定义细胞自治信号在T和B细胞介导的自动反应性中的作用。细胞类型特异性的激活和IKK的灭活将用于此目的，从而利用了我们过去已经建立的条件基因靶向技术。