Molecular Biology of Lymphocyte and Neuronal Growth

自1986年我们发现核因子-kappaB转录因子以来，它已经成为炎症和免疫反应的关键激活物，在癌症、心脏病和自身免疫性疾病中具有重要的病理作用。因此，了解核因子-kappaB的调控及其转录功能的细节具有重要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-kappaB的理解。首先，我们将进一步研究不同形式的核因子-kappaB DNA结合位点的作用，kappaB位点。我们最近观察到，随着进化时间的推移，特定的kappaB位点是高度保守的，这意味着每个kappaB位点都包含其每个核苷酸中的信息，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。我们提出了不同的方法来理解由各种kappaB编码的信息 网站。我们的第二个目标是使用建模工具结合实验测试来更好地了解控制核因子-kappaB激活和抑制的途径。第三种方法是集中研究一种名为A20的蛋白质，该蛋白质已知在限制核因子-kappaB的激活中发挥作用。关闭核因子-kappaB和激活核因子-kappaB一样重要，因为它具有巨大的病理潜能，而A20是这方面的重要蛋白质。我们有一个线索，A20可能参与抑制对核因子-kappaB激活至关重要的关键蛋白修饰，我们将从多个方向跟踪这一点。第四种方法是研究一种迄今被忽视的核因子-kappaB的激活剂，即B94蛋白。到目前为止，我们在这里只取得了很小的进展，但我们概述了使用基因组和蛋白质组工具进行攻击的各种方法。

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.