IKK Signals in Lymphocyte Physiology and Pathology

描述（由申请人提供）：通过NF-kB通路的信号传导对T和B淋巴细胞的成熟、维持和功能至关重要。它还参与由这些细胞进行的自身免疫反应，并有助于某些类型B细胞淋巴瘤的存活。该途径的关键成分是ikb激酶（IKKs）， IKKs通过传递给细胞的促炎和抗原受体介导的信号激活NF-kB信号。IKK信号可以包括IKK1、IKK2和NEMO蛋白组成的IKK信号，也可以单独通过IKK1激活进行。本提案的基本假设是，这两种途径的激活，无论是联合还是单独，对于T细胞和B细胞的成熟，存活和执行其各种功能，以及促进某些B细胞恶性肿瘤都是必不可少的。因此，我们将探索这两种途径的失活或其强制激活是如何影响T细胞和/或B细胞在不同发育阶段的成熟、功能活动和恶性转化的。救援实验将确定IKK信号的下游目标，这些目标负责细胞维持，并确定IKK信号是否足以在缺乏抗原和BAFF受体等受体的情况下维持细胞存活，这些受体已知是正常生理中B细胞维持所必需的。我们还将定义细胞自主IKK信号在T和B细胞介导的自身反应中的作用。IKKs的细胞类型特异性激活和失活将用于此目的，利用我们过去建立的条件基因靶向技术。

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.