IKK Signals in Lymphocyte Physiology and Pathology

描述(由申请人提供)：通过核因子-kB途径的信号对T和B淋巴细胞的成熟、维持和功能至关重要。它还参与这些细胞执行的自身免疫反应，并有助于某些类型的B细胞淋巴瘤的生存。在这一途径中的关键组成部分是IKB-Kase(IKK)，它在自身激活的基础上通过促炎和抗原受体介导的信号传递给细胞来激活NF-kB信号。IKK信号既可以是由IKK1、IKK2和NEMO蛋白组成的IKK信号，也可以单独通过IKK1的激活来进行。本方案的基本假设是，这两条通路的联合或单独激活对于T细胞和B细胞的成熟、存活和发挥其各种功能是必不可少的，也是促进某些B细胞恶性肿瘤的关键。因此，我们将探索这两种途径的失活或强制激活是如何影响发育不同阶段的T和/或B细胞的成熟、功能活动和恶性转化的。救援实验将确定负责细胞维持的IKK信号的下游靶点，并确定在缺乏抗原和BAFF受体等受体的情况下，IKK信号是否足以使细胞存活，而BAFF受体是正常生理中维持B细胞所必需的。我们还将确定细胞自主IKK信号在T和B细胞介导的自身反应中的作用。为此，将利用我们过去建立的条件基因打靶技术，使用特定细胞类型的IKK的激活和失活。

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.