Identification of Functional Targets for Asbestos Induced Autoantibodies

描述(申请人提供)：全身性自身免疫性疾病(SAID)是一种复杂、慢性、难以治疗、对患者具有破坏性的疾病。吸入石棉已被证明增加了系统性红斑狼疮等系统性红斑狼疮的风险，并诱导产生各种自身抗体。当免疫系统开始出错并损害我们自己的组织时，就会发生自身免疫，其中一些损害是由自身抗体介导的。虽然全国各地的几个实验室正在探索组织特异性自身抗体在各种疾病的发病机制中的作用，但该项目在探索由有毒环境和职业暴露诱导的一组特定自身抗体方面是独一无二的：石棉。因此，这项研究在石棉引起的肺部疾病的毒理学和特定的自身免疫机制之间架起了一座桥梁。这个项目使用小鼠模型进行，试图a)发现石棉诱导的自身抗体攻击的特定目标蛋白，b)识别 介导细胞损伤或激活的细胞信号通路(S)，以及c)证明这种损伤可以发生在活的动物身上。然后，这些发现通过阻断这些导致损害和疾病的途径，与治疗或预防方法的发展直接相关。 公共卫生相关性：这项研究在小鼠身上进行，与出于翻译目的的人类研究平行，这意味着从这项研究中获得的知识将直接与我们理解针对间皮细胞或成纤维细胞的自身抗体如何对肺组织造成损害，并加剧石棉引起的肺部疾病的进展有关。我们理解这一过程的能力将指导未来对持续进行性纤维化的治疗和预防方法，这种纤维化最终会导致石棉暴露后的死亡。

DESCRIPTION (provided by applicant): Systemic autoimmune diseases (SAID) are complex, chronic, hard to treat, and devastating to patients. Inhalation of asbestos has been shown to increase the risk of SAID such as systemic lupus, and to induce production of a variety of autoantibodies. Autoimmunity occurs when the immune system starts making mistakes and damages our own tissues, and some of this damage is mediated by autoantibodies. While several laboratories across the country are exploring tissue-specific autoantibodies in the pathogenesis of a variety of diseases, this project is unique in exploring a specific set of autoantibodies that are induced by a toxic environmental and occupational exposure: asbestos. This study therefore bridges a gap between toxicology and a specific autoimmune mechanism for asbestos induced lung disease. Performed using a mouse model, this project seeks to a) discover the specific target proteins that the asbestos- induced autoantibodies attack, b) identify the cell signaling pathway(s) that mediate the cellular damage or activation, and c) demonstrate that this damage can happen in a live animal. These discoveries are then directly relevant to development of therapeutic or preventive approaches, by blocking these pathways that lead to damage and disease. PUBLIC HEALTH RELEVANCE: This study, performed in mice, parallels a human study for translational purposes, meaning that what is learned from this study will have direct relevance to our understanding of how autoantibodies to mesothelial cells or fibroblasts can cause damage to lung tissues, and exacerbate the progression of asbestos-induced lung disease. Our ability to understand this process will guide therapeutic and preventive approaches in the future for the relentlessly progressive fibrosis that ultimately leads to death following asbestos exposure.