SLE AUTOANTIGEN TRAFFICKING AND DISPLAY DURING APOPTOSIS

描述（由申请人提供）： 该指导K 08奖的申请提交的目的是为候选人提供必要的进一步经验和培训，以作为在自身免疫和细胞凋亡领域工作的独立研究者。 系统性红斑狼疮（SLE）的特点是一个独特的谱致病性自身抗体，主要针对无处不在的核靶点，即自身抗原。为了了解SLE的病因，了解这些特异性自身抗原如何驱动自身免疫反应是很重要的。自身抗原的来源和为什么只有某些细胞核和细胞质蛋白成为自身抗原的原因仍然是未知的。由于凋亡细胞或其碎片的清除受损可导致某些模型中的SLE样疾病，并且由于SLE自身抗原集中于UV-B损伤的细胞的凋亡泡，因此凋亡细胞已被提出作为可能在自发性自身免疫性疾病中发挥重要作用的自身抗原的关键储库。根据该提议，候选人打算通过研究凋亡期间自身抗原聚集成泡和小体的生物学并研究其在B细胞和树突细胞（DC）中的免疫相关性来探索自身抗原在凋亡细胞内构成一组独特的免疫原的可能性。该提案将提供重要的见解，自身抗原的来源，并进入细胞凋亡的作用，暴露狼疮抗原的免疫活性细胞。该提案还可能有助于更好地了解狼疮易感个体的自身免疫如何发生，从而找到针对SLE中凋亡细胞及其产物的合理疗法。 博士Caricchio的长期目标是将体外系统获得的知识应用于狼疮小鼠模型并最终应用于人类狼疮，并进一步研究凋亡细胞在SLE发病机制中的作用。在Cohen博士和其他导师的指导下，Caricchio博士计划在获奖期间建立一个独立实验室并开展自己支持的项目。流变学的部门和一般的宾夕法尼亚大学的生物医学研究社区将支持他的科学成长智力和作为一个板凳研究员。

DESCRIPTION (provided by applicant): This application for the mentored K08 award is submitted with the goal of providing the candidate with the further experience and training necessary to function as an independent investigator working in the field of autoimmunity and apoptosis. Systemic lupus erythematosus (SLE) is characterized by a unique spectrum of pathogenic autoantibodies, mainly directed at ubiquitous nuclear targets, namely the autoantigens. To understand the etiology of SLE, it is important to know how these specific autoantigens are driving the autoimmune response. The source of autoantigens and the reason why only certain nuclear and cytoplasmic proteins become autoantigens are still unknown. Because impaired clearance of apoptotic cells or their debris can lead to SLE-like disease in certain models and because SLE autoantigens concentrate on apoptotic blebs of cells injured by UV-B, apoptotic cells have been proposed as a critical reservoir of autoantigens that may play an essential role in spontaneous autoimmune disease. With this proposal the candidate intends to explore the possibility that autoantigens constitute a unique set of immunogens within the apoptotic cells by studying the biology of the autoantigen clustering into blebs and bodies during apoptosis and investigating its immunological relevance in both B cells and dendritic cells (DC). The proposal will provide important insights into the source of autoantigens, and into the role of apoptosis in exposing lupus antigens to the immune competent cells. The proposal may also lead to a better understanding of how autoimmunization in a lupus prone individual takes place and therefore to a rational therapy for targeting apoptotic cells and their products in SLE. Dr. Caricchio long-term goals are to apply and to extend the knowledge obtained with in vitro systems to lupus mouse models and ultimately to human lupus and to further investigate the role of apoptotic cells in the pathogenesis of SLE. Under Dr. Cohen's and other mentors' guidance, Dr. Caricchio plans during the period of the award to establish an independent laboratory and pursue his own supported projects. The Division of Rheumatology and in general the biomedical research community of the University of Pennsylvania will support his scientific growth both intellectually and as a bench researcher.