The Role of Zfp296 in Controlling Autoimmunity

描述(由申请人提供)： 我们之前的研究已经证明，在狼疮易感小鼠模型NZM2410中发现的狼疮易感区间Sle5可以加速系统性自身免疫的发展。Sle5与Sle1结合，导致活化的B和T细胞早期扩张，针对更广泛的自身抗原的自身抗体水平升高，并发展为严重的狼疮性肾炎。锌指蛋白296(Zfp296)是一个位于Sle5区间的基因，其产物被预测具有转录因子的功能。我们发现在NZM2410版本的Zfp296蛋白中存在额外的磷酸化位点。虽然Zfp296的功能尚不清楚，但它在B和CD4T淋巴细胞中的表达水平较高。Zfp296在A20B细胞中的过表达抑制了抗-Ig G诱导的核因子-kappaB的激活，这是细胞存活的重要途径。这项拟议研究的目的是确定Zfp296在控制自身免疫中的作用。我们有两个具体目标。首先，我们将确定Zfp296在调节细胞激活、增殖和存活中的作用。我们将研究Zfp296过表达或敲除对抗原受体介导的细胞激活、增殖和凋亡的影响。我们还将通过过表达B6等位基因和Sle5等位基因的Zfp296来比较它们调控细胞激活、增殖和凋亡的能力的差异，以确定Sle5中的Zfp296多态性对细胞激活、增殖和存活的影响。其次，我们将确定Zfp296过表达是否可以在体内抑制自身免疫。我们将通过体内过表达Zfp296来确定Zfp296的B6等位基因对B细胞和CD4T细胞活性的影响，以及狼疮小鼠自身免疫的发展。本研究的结果将为我们了解Zfp296在免疫系统中的功能，其基因多态性在自身免疫发展中的作用，以及利用Zfp296过表达作为SLE治疗策略的可能性。 公共卫生相关性： 这项拟议的研究旨在确定候选狼疮易感基因在自身免疫发展中的作用。这项研究的结果应该有助于理解人类对应物在疾病发展中的作用，并开发一种潜在的人类狼疮治疗方法。

DESCRIPTION (provided by applicant): Our previous study has demonstrated that Sle5, a lupus susceptibility interval identified in a murine lupus- prone model, NZM2410, can accelerate the development of systemic autoimmunity. Combination of Sle5 with Sle1, a genomic interval that mediates breach of immune tolerance to nuclear antigens, leads to early expansion of activated B and T cells, elevated levels of autoantibodies targeting broader spectrum of autoantigens, and the development of severe lupus nephritis. Zinc finger protein 296 (Zfp296) is a gene located in the Sle5 interval, and its product is predicted to have function as a transcription factor. We have found that additional phosphorylation sites are present in NZM2410 version of Zfp296 protein. Although the function of Zfp296 is still unknown, it is expressed at higher level in B and CD4 T lymphocytes. Over expression of Zfp296 in A20 B cell line inhibits anti-IgG induced NF-kappaB activation, an important pathway for cell survival. The goal of the proposed study is to identify the role of Zfp296 in controlling autoimmunity. We have two specific aims. First, we will determine the role of Zfp296 in regulating cell activation, proliferation and survival. We will examine the effects of Zfp296 overexpression or knockdown on antigen receptor- mediated cell activation, proliferation, and apoptosis. We will also determine the impact of Zfp296 polymorphism as seen in Sle5 on cell activation, proliferation and survival, by overexpressing Zfp296 of B6 allele and Sle5 allele to compare the difference in their ability to regulate cell activation, proliferation, and apoptosis. Second, we will determine whether Zfp296 overexpression can suppress autoimmunity in vivo. We will use overexpression of Zfp296 in vivo to determine the impact of B6 allele of Zfp296 on activities of B and CD4 T cells, and the development of autoimmunity in lupus mice. The outcomes of this study will provide us with knowledge of Zfp296 function in immune system, the role of its polymorphism in development of autoimmunity, and the potential of using Zfp296 overexpression as a therapeutic strategy for SLE. PUBLIC HEALTH RELEVANCE: The proposed study is to identify the role of a candidate lupus susceptibility gene on the development of autoimmunity. The outcome of this study should help to understand the role of its human counterpart in disease development and to develop a potential therapeutic for human lupus.