Molecular Biology of Lymphocyte and Neuronal Growth

自从我们在1986年发现NF-κ B转录因子以来，它已经成为炎症和免疫应答的关键激活剂，在癌症、心脏病和自身免疫性疾病中具有重要的病理作用。由于这些原因，了解NF-κ B的控制及其转录能力的细节具有重大的医学和生物学意义。在拟议的工作中，我们将采取四种方法来加深我们对NF-κ B的理解。首先，我们将进一步研究NF-κ B的各种形式的DNA结合位点（kappaB位点）的作用。我们最近观察到，特定的kappaB位点在进化过程中高度保守，这意味着每个位点的每一个核苷酸中都包含信息，考虑到基因组中存在的各种各样的位点，这一结论非常令人惊讶。我们提出了各种方法来理解各种kappaB编码的信息 网站.我们的第二个目标是使用建模工具与实验测试相结合，以更好地了解控制NF-κ B激活和抑制的途径。第三种方法是集中研究一种蛋白质A20，已知其在限制NF-κ B活化中发挥作用。NF-κ B的关闭与其激活一样重要，因为它具有巨大的病理潜力，而A20是这方面的重要蛋白质。我们有一个线索，A20可能参与抑制一个关键的蛋白质修饰，这对NF-κ B活化很重要，我们将在许多方向上进行跟踪。第四种方法是研究迄今为止被忽视的NF-κ B激活剂B 94蛋白。到目前为止，我们只取得了最小的进展，但我们概述了使用基因组和蛋白质组学工具的各种攻击方法。

DESCRIPTION (provided by applicant) Since we discovered the NF-kappaB transcription factor in 1986, it has emerged as a key activator of inflammatory and immune responses with important pathologic roles in cancer, heart disease and autoimmune diseases. For these reasons, understanding the details of the control of NF-kappaB and of its transcriptional capabilities has great medical as well as biological significance. In the proposed work, we will take four approaches to deepening our understanding of NF-kappaB. First, we will further investigate the roles of the various forms of the DNA binding site for NF-kappaB, the kappaB site. We have recently observed that particular kappaB sites are highly conserved over evolutionary time, implying that each contains information within every one of its nucleotides, a conclusion that was very surprising given the wide variety of sites that exist in the genome. We propose various approaches to understanding what information is encoded by the various kappaB sites. Our second goal is to use modeling tools combined with experimental tests to better understand the pathways that control NF-kappaB activation and repression. The third approach is to concentrate study on one protein, A20, which is known to play a role in limiting NF-kappaB activation. The turning off of NF-kappaB is as important as its activation, because it of its enormous pathologic potential, and A20 is an important protein in this regard. We have a clue that A20 might be involved in inhibiting a key protein modification that is important for NF-kappaB activation and we will follow that up in many directions. The fourth approach is to study an activator of NF-kappaB that has thus far been neglected, the B94 protein. Here we have made only minimal progress thus far but we outline a variety of methods of attack using genomic and proteomic tools.