Dissecting the function of Bcl-3 in NF-kB signaling in B cells.

对于健康人，免疫系统可以识别、攻击和摧毁体内任何位置的潜在有害传染病病原体，同时避免对健康细胞和组织发动类似的攻击。然而，异常或不适当的免疫反应可导致慢性或压倒性感染，或导致一系列自身免疫性或慢性炎症性疾病的发展，如克罗恩病、类风湿性关节炎和动脉粥样硬化。事实上，现在很明显，炎症和免疫系统对人类几乎所有的疾病都有贡献，包括癌症和神经退化。此外，免疫系统细胞中DNA突变的积累会导致淋巴瘤和白血病的发展。因此，对免疫系统和免疫细胞的透彻了解具有基本的生物学重要性，并有可能改善我们对广泛的人类疾病的理解和治疗。免疫系统驱动的生物和病理过程受到免疫细胞检测和对环境做出反应的深刻影响。在免疫细胞表面接收到的“分子信号”被传递到细胞核，在那里它们被整合和解释，导致该细胞“表达”的基因图谱发生变化。这反过来会导致整个细胞的分子组成发生根本变化，最终决定其生物学或病理功能。可以说，以这种方式调节免疫细胞反应的最重要的分子是一系列细胞内蛋白，统称为核因子kappaB(NF-kB)。这些蛋白质对于改变免疫细胞中的基因表达是至关重要的，以响应来自邻近细胞或入侵病原微生物的各种分子信号。因此，它们对免疫细胞的发育、维持和功能至关重要，对有益和有害的免疫反应都有贡献。我们对了解这些复杂的细胞内过程是如何协调和调节的，以期开发操纵免疫细胞功能以控制疾病的新疗法感兴趣。目前的应用旨在确定Bcl-3的功能，这是一种存在于免疫细胞核中的蛋白质，已知会影响核因子-kB的功能。BCL-3广泛存在于多种不同类型的细胞中，但在B细胞生物学中扮演着尤为重要的角色。这些是重要的免疫细胞，因为它们具有产生抗体的能力，而抗体对所有有益和有害的免疫反应都有贡献。BCL-3控制B细胞的生存、增殖和免疫功能，而过多的BCL-3会导致B细胞性淋巴瘤和白血病的发展。然而，目前还远不清楚Bcl-3是如何做这些事情的。我们提出的这项工作利用并整合了最先进的技术，在分子、细胞和整个动物水平上检查了Bcl-3的重要性。我们的研究结果将为该蛋白的正常和升高如何调节B细胞生物学提供新的和前所未有的见解，这些发现将具有广泛的生理和病理意义。此外，重要的是，它们将提供一个坚实的基础，在此基础上，我们可以进一步探索阻断或模拟Bcl-3功能的治疗潜力。

In healthy people, the immune system can recognise, attack and destroy potentially harmful infectious agents wherever they are in the body, while avoiding mounting similar attacks against healthy cells and tissues. However, aberrant or inappropriate immune responses can lead to chronic or overwhelming infection, or contribute to the development of a host of autoimmune or chronic inflammatory diseases, such as Crohn's disease, rheumatoid arthritis, and atherosclerosis. In fact, it is now clear that inflammation and the immune system contribute to virtually all diseases in humans, including cancer and neurodegeneration. Moreover, the accumulation of DNA mutations in cells of the immune system leads to the development of lymphomas and leukaemias. Thus, a thorough knowledge of the immune system and immune cells is of fundamental biological importance, and has the potential to improve our understanding and treatment of a broad spectrum of human diseases. The biological and pathological processes driven by the immune system are profoundly influenced by how immune cells detect and respond to their environment. 'Molecular signals' received at the surface of immune cells are conveyed to the cell's nucleus where they are integrated and interpreted, leading to alterations in the profile of genes 'expressed' by that cell. This in turn leads to fundamental changes in the molecular constituents of the entire cell, which ultimately determines its biological or pathological function. Arguably the most important molecules regulating immune cell responses in this way are a family of intracellular proteins collectively known as Nuclear Factor kappaB (NF-kB). These proteins are critical for changing gene expression in immune cells in response to a wide variety of molecular signals emanating from either neighbouring cells or from invading pathogenic microorganisms. As a result, they are of fundamental importance in the development, maintenance and function of the immune cells, and contribute to both beneficial and detrimental immune responses. We are broadly interested in understanding how these complex intracellular processes are orchestrated and regulated, with a view to developing new therapies that manipulate immune cell function to control disease. The current application aims to determine the function of Bcl-3, a protein present in the nucleus of immune cells that is known to influence NF-kB function. Bcl-3 is found in many different types of cells, but it plays particularly prominent roles in the biology of B cells. These are important immune cells because they have the capacity to make antibodies, and antibodies contribute to all beneficial and detrimental immune responses. Bcl-3 controls the survival, proliferation and immune function of B cells, while too much Bcl-3 can lead to the development of B cell-derived lymphomas and leukaemias. However, it is far from clear how Bcl-3 does these things. The work we are proposing exploits and integrates state-of-the-art technologies to examine the importance of Bcl-3 at the molecular, cellular and whole animal level. The results of our study will provide novel and unprecedented insights into how normal and elevated levels of this protein regulate B cell biology, and these findings will have broad physiological and pathological implications. In addition, and importantly, they will provide a firm foundation upon which we can further explore the therapeutic potential of blocking or mimicking Bcl-3 function.