The Role of Zfp296 in Controlling Autoimmunity

Zfp296 在控制自身免疫中的作用

• 批准号: 7895639
• 负责人: KUI LIU
• 金额: $ 8.22万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-15 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7895639
• 关键词: Alleles; Antigen Receptors; Antinuclear Antibodies; Apoptosis; Autoantibodies; Autoantigens; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Automobile Driving; B-Lymphocytes; Benign; CD4 Positive T Lymphocytes; Candidate Disease Gene; Cell Line; Cell Proliferation; Cell Survival; Cells; Congenic Strain; Development; Disease; Exhibits; Genes; Genetic Polymorphism; Genomics; Goals; Human; Immune Tolerance; Immune system; In Vitro; Kidney Diseases; Knowledge; Lupus; Lupus Nephritis; Mediating; Modeling; Molecular; Mus; NF-kappa B; NFKB Signaling Pathway; Nuclear Antigens; Organ; Outcome Study; Pathogenesis; Pathway interactions; Phenotype; Phosphorylation Site; Play; Predisposition; Process; Production; Proteins; Role; SLEB1 gene; SLEB2 gene; SLEB3 gene; SLEB5 gene; Signal Pathway; Single Nucleotide Polymorphism; Susceptibility Gene; Systemic Lupus Erythematosus; T-Cell Development; T-Lymphocyte; Testing; Therapeutic; Variant; anti-IgG; base; cell growth; congenic; in vivo; mouse model; novel; overexpression; public health relevance; transcription factor; zinc finger protein 296

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.

描述（由申请人提供）： 我们先前的研究已经证明，Sle 5，在小鼠狼疮易感模型NZM 2410中鉴定的狼疮易感性间隔，可以加速系统性自身免疫的发展。Sle 5与Sle 1（介导对核抗原的免疫耐受破坏的基因组间隔）的组合导致活化的B和T细胞的早期扩增、靶向更广谱的自身抗原的自身抗体水平升高以及严重狼疮肾炎的发展。锌指蛋白296（Zfp 296）是位于Sle 5区间的基因，其产物被预测具有转录因子的功能。我们已经发现，在Zfp 296蛋白的NZM 2410版本中存在额外的磷酸化位点。虽然Zfp 296的功能尚不清楚，但它在B和CD 4 T淋巴细胞中以较高水平表达。Zfp 296在A20 B细胞系中的过表达抑制抗IgG诱导的NF-κ B活化，这是细胞存活的重要途径。这项研究的目的是确定Zfp 296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Zfp 296在调节细胞活化、增殖和存活中的作用。我们将研究Zfp 296过表达或敲低对抗原受体介导的细胞活化、增殖和凋亡的影响。我们还将通过过表达B6等位基因和Sle 5等位基因的Zfp 296来比较它们调节细胞活化、增殖和凋亡的能力的差异，来确定在Sle 5中所见的Zfp 296多态性对细胞活化、增殖和存活的影响。其次，我们将确定Zfp 296过表达是否可以抑制体内自身免疫。我们将利用Zfp 296在体内的过表达来确定Zfp 296的B6等位基因对B和CD 4 T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提供Zfp 296在免疫系统中的功能，其多态性在自身免疫发展中的作用，以及使用Zfp 296过表达作为SLE治疗策略的潜力的知识。 公共卫生相关性： 这项研究的目的是确定一个候选的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了解其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。