IKK Signals in Lymphocyte Physiology and Pathology

描述（由申请方提供）：通过NF-κ B通路的信号传导对于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。该途径中的关键组分是IkB-激酶（IKK），其在自身被递送至细胞的促炎和抗原受体介导的信号激活后激活NF-kB信号传导。IKK信号传导可以涉及IKK信号，其中一些由IKK 1、IKK 2和NEMO蛋白组成，或者通过IKK 1单独活化进行。本发明的基本假设是，这两种途径的激活，无论是组合的还是单独的，对于T和B细胞成熟、存活和执行它们的各种功能是必需的，并且对于某些B细胞恶性肿瘤的促进也是必需的。因此，我们将探讨在何种方式的失活途径，或其强制激活，影响成熟，功能活动和恶性转化的T和/或B细胞在不同的发展阶段。拯救实验将鉴定负责细胞维持的IKK信号传导的下游靶标，并且还确定IKK信号传导是否足以在不存在受体如抗原和BAFF受体的情况下维持细胞存活，已知受体是正常生理学中B细胞维持所需的。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性中的作用。IKK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.