Kidney Damage in Murine Lupus

小鼠狼疮的肾脏损伤

基本信息

批准号：
7111700
负责人：
Ram Raj Singh
金额：
$ 32.06万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-09-30 至 2008-05-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Lupus nephritis is believed to result from glomerular deposition of immune complexes, triggering local kidney inflammation, followed by worsening glomerulosclerosis and end stage renal disease. The mechanisms responsible for this chronic kidney disease progression are poorly understood. Several reports and our preliminary data suggest a link between decreases in T cell production of transforming growth factor beta (TGFbeta) with autoantibody production, and increases in renal TGFbeta expression with the development of chronic kidney lesions. The central hypothesis of this proposal is that TGFbeta plays dual roles in the development and progression of lupus nephritis: while decreased TGFbeta levels promote early stage lupus nephritis by enhancing T and B cell activation and autoantibody production, increased TGFbeta levels accelerate late stage kidney disease by inducing increased extracellular matrix production. The proposed studies will evaluate changes in the expression levels of TGFb, its receptors and signaling proteins in the lymphoid and renal tissues during progression of kidney disease in murine models of lupus. These studies will build on preliminary data indicating that urine TGFbeta levels rise in response to increases in TGFbeta activity in lupus kidney cells, thus serving as a diagnostic marker for chronic kidney damage. The proposed studies will also investigate the potential mechanisms of renal TGFb overexpression in lupus, and more importantly, determine the contribution of the TGFbeta system to autoantibody production and kidney damage. TGFbeta blockade in vivo using monoclonal antibodies will be investigated as a potential therapeutic approach that could inhibit or reverse the development of chronic kidney lupus disease, without worsening autoimmunity. Our broad goals in this proposal are to understand the mechanisms of kidney damage in lupus. Relevant to the current RFA, this proposal will: a) identify a diagnostic marker (e.g., urine TGFbeta levels) that will allow prediction of the progression of disease in target organs, b) make use of novel conditional, tissue-specific TGFb signaling knockout mice to investigate the mechanisms that cause matrix deposition and tissue damage, and c) explore alternative treatment strategies for preventing organ damage in lupus.

描述（由申请人提供）：狼疮肾炎被认为是由免疫复合物的肾小球沉积引起的，引发了局部肾脏炎症，随后肾小球硬化症恶化和终阶段肾脏疾病。造成这种慢性肾脏疾病进展的机制知之甚少。几份报告和我们的初步数据表明，转化生长因子β（TGFBETA）T细胞产生的减少与自身抗体的产生之间的联系，以及肾脏TGFBETA表达的增加与慢性肾脏病变的发展。 The central hypothesis of this proposal is that TGFbeta plays dual roles in the development and progression of lupus nephritis: while decreased TGFbeta levels promote early stage lupus nephritis by enhancing T and B cell activation and autoantibody production, increased TGFbeta levels accelerate late stage kidney disease by inducing increased extracellular matrix production. 拟议的研究将评估狼疮模型中肾脏疾病进展过程中淋巴机和肾脏组织中TGFB，其受体和信号蛋白的表达水平的变化。这些研究将基于初步数据，表明尿液TGFBETA水平响应狼疮肾细胞的TGFBETA活性的响应，因此是慢性肾脏损伤的诊断标记。拟议的研究还将研究狼疮中肾脏TGFB过表达的潜在机制，更重要的是，确定TGFBETA系统对自身抗体生产和肾脏损伤的贡献。使用单克隆抗体在体内进行TGFBETA封锁，将作为一种潜在的治疗方法研究，可以抑制或逆转慢性肾狼疮疾病的发展，而不会加剧自身免疫性。我们在该提案中的广泛目标是了解狼疮中肾脏损伤的机制。与当前的RFA相关，该建议将：a）确定诊断标记（例如尿液TGFBETA水平），该标志物将允许预测目标器官疾病进展，b）使用新型有条件的，组织特异性的TGFB信号敲除型敲除型造成策略损害的机构，并损害了组织的损害和C）。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Tertiary lymphoid structures as local perpetuators of organ-specific immune injury: implication for lupus nephritis.

DOI：
10.3389/fimmu.2023.1204777
发表时间：
2023
期刊：
FRONTIERS IN IMMUNOLOGY
影响因子：
7.3
作者：
Wang, Meiying;Rajkumar, Snehin;Lai, Yupeng;Liu, Xingjiao;He, Jing;Ishikawa, Tatsuya;Nallapothula, Dhiraj;Singh, Ram Raj
通讯作者：
Singh, Ram Raj

Invariant NKT cells inhibit autoreactive B cells in a contact- and CD1d-dependent manner.