Biology of decay accelerating factor

说明(申请人提供)：补体是先天免疫系统的一部分，在宿主防御中发挥重要作用。最近的证据表明，补体在T细胞免疫中也可能起到佐剂作用。虽然激活的补体在宿主防御中很重要，但它是一把双刃剑，如果调控不当，可能会导致严重的炎症组织损伤。为了保护宿主免受补体攻击，已经进化出几种膜锚定和液相补体调节蛋白。衰变加速因子(DAF)和H因子(FH)是两种典型的补体调节因子，一种存在于细胞表面(DAF)，另一种存在于血浆(FH)。DAF和FH的功能障碍以及其他补体调节功能障碍与几种人类炎症性疾病有关。这些疾病的发病机制，补体调节因子的相对活性和组织特异性，以及DAF和补体效应器调节T细胞免疫的机制是有待解决的突出问题。在目前的方案中，我们将使用几种基因敲除和转基因小鼠模型来解决这些问题，并检验以下两个假设：组织对补体攻击的敏感性由膜和液相补体调节因子的联合活性决定；DAF和补体通过一种独立于DAF对T细胞的内在作用的机制来调节T细胞免疫。我们提出以下三个具体目标：1)研究DAF、CRY和FH在体内宿主细胞保护中的相对作用；2)确定DAF在调节T细胞免疫中的作用部位和作用机制；3)确定C5aR和C3aR信号在T细胞免疫中的作用、部位和作用机制。这些研究将为补体及其调节因子在先天性和获得性免疫以及炎症中的作用机制提供新的见解，并将有助于理解和治疗与补体调节失调相关的人类自身免疫性和炎症性疾病。 公共卫生相关性：该项目研究补体系统在组织损伤和宿主免疫反应中的作用。我们将使用基因去除和转基因小鼠来创建动物模型，其中补体被异常激活，以模仿几种人类炎症性疾病。我们还将进行实验，以了解补体如何帮助宿主发展强大的T细胞免疫反应，以对抗感染。这些研究将增加我们对人类炎症性疾病发病机制的理解，并可能最终导致针对自身免疫和炎症性疾病的新治疗药物的开发。

DESCRIPTION (provided by applicant): Complement is part of the innate immune system that plays an important role in host defense. Recent evidence suggests that complement may also play an adjuvant role in T cell immunity. While important in host defense, activated complement is a double-edged sword that, if not properly regulated, can cause severe inflammatory tissue injury. To protect the host from complement attack, several membrane-anchored and fluid-phase complement regulatory proteins have evolved. Decay-accelerating factor (DAF) and factor H (fH) are two prototypical complement regulators, one residing on the cell surface (DAF) and the other existing in the plasma (fH). Dysfunction of DAF and fH, as well as other complement regulators, are associated with several human inflammatory disorders. The pathogenesis of these diseases, the relative activity and tissue specificity of complement regulators, and the mechanism by which DAF and complement effectors regulate T cell immunity are outstanding questions that remain to be addressed. In the present proposal, we will use several knockout and transgenic mouse models to address these questions and to test the following two hypotheses: that tissue sensitivity to complement attack is determined by combined activities of membrane and fluid phase complement regulators; and that DAF and complement regulate T cell immunity through a mechanism that is independent of an intrinsic role of DAF on T cells. We propose the following three specific aims: 1): To characterize the relative roles of DAF, Crry and fH in vivo in host cell protection; 2): To determine the site and mechanism of action of DAF in regulating T cell immunity; 3) To determine the role, site and mechanism of action of C5aR and C3aR signaling in T cell immunity. These studies will provide novel insights into the mechanism of action of complement and its regulators in innate and adaptive immunity and inflammation, and will facilitate the understanding and treatment of human autoimmune and inflammatory disorders associated with complement dysregulation. PUBLIC HEALTH RELEVANCE: This project studies the role of the complement system in tissue injury and host immune response. We will use gene ablated and transgenic mice to create animal models wherein complement is abnormally activated to mimic several human inflammatory diseases. We will also perform experiments to understand how complement might help the host develop a robust T cell immune response for fighting infection. These studies will increase our understanding of the pathogenesis of human inflammatory diseases and may ultimately lead to the development of new therapeutic drugs for autoimmune and inflammatory conditions.