Role of CD48:CD244 Pathway in Systemic Lupus Erythematosus

CD48:CD244 通路在系统性红斑狼疮中的作用

• 批准号: 8213694
• 负责人: DANIEL RABIN BROWN
• 金额: $ 8.46万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-08 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8213694
• 关键词: Activities of Daily Living; Advisory Committees; Anti-DNA Antibodies; Antigen Receptors; Area; Autoantibodies; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Award; B-Lymphocytes; Backcrossings; Basic Science; Breeding; C57BL/6 Mouse; CD4 Positive T Lymphocytes; CD58 gene; Cell Lineage; Cell surface; Cells; Childhood; Chromosomes, Human, Pair 1; Clinical; Collaborations; Complex; Data; Development; Disease; Effector Cell; Equilibrium; Exhibits; Family; Family member; Functional disorder; Gene Rearrangement; Genes; Genetic; Glomerulonephritis; Goals; Homologous Gene; Human; I-antigen; Immune; Immune Tolerance; Immune response; Immune system; Immunity; Immunoglobulins; Immunology; K-Series Research Career Programs; Kidney Diseases; Ligands; Link; Lupus; Lymphoid; Mediating; Mentors; Modeling; Molecular Biology; Mouse Strains; Mus; Pathogenesis; Pathway interactions; Patients; Peripheral; Phenotype; Physicians; Play; Predisposition; Process; Production; Proliferative Glomerulonephritis; Receptor Gene; Regulatory T-Lymphocyte; Research Personnel; Rheumatology; Role; SLAM family receptor; Scientist; Signal Transduction; Syndrome; Systemic Lupus Erythematosus; T-Cell Development; T-Lymphocyte; Testing; Therapeutic; Transgenic Mice; Translating; Variant; base; cytokine; design; embryonic stem cell; immune activation; insight; lupus-like; member; mouse model; pathogen; receptor; research study; response; skills

DESCRIPTION (provided by applicant): Project Summary The main goal of this K08 Award is to investigate the roles of the SLAM family members CD48 and CD244 in murine and human Systemic Lupus Erythematosus (SLE). The K08 Award will be mentored by Dr. Arlene Sharpe, an expert in the field of T cell costimulation and tolerance. Our preliminary data implicate CD244 and CD48 in regulating tolerance and autoimmunity. C57BL/6 CD244 deficient (-/-) mice and C57BL6 x 129 CD48-/- mice both develop features of lupus. The proposed studies will test the hypothesis that CD48:CD244 interactions regulate the balance between immune activation and tolerance. Our specific aims are: 1. Study the role of CD244 in mediating T cell and B cell tolerance. CD244-/- mice spontaneously develop autoantibodies. When CD244-/- mice were bred to the Y-linked autoimmune accelerator locus (Yaa), the resulting strain developed proliferative glomerulonephritis, in marked contrast to Yaa mice that do not develop renal disease. CD244-/- mice also exhibit alterations in regulatory T cells. Aim1A will elucidate the role of CD244 in regulatory T cell development and function. Aim1B will dissect the role of CD244 in B cell tolerance using BCR transgenic mice. 2. Characterize the adaptive immune response in CD48-deficient mice and assess how CD48 contributes to autoimmunity in a murine model of SLE. Although C57BL6 x 129 CD48-/- mice spontaneously develop activated T and B cells, anti- DNA antibodies and glomerulonephritis, the interpretation of this phenotype is complicated by possible epistatic interactions between 129 interval on mouse chromosome 1, which encompasses the CD48 gene, and C57BL/6 genes which could have mediated the loss of tolerance. Here, I will use our recently generated CD48-deficient C57BL/6 mice to investigate the roles of CD48 in regulating T and B cell responses, and determine whether B6.CD48-/- mice develop SLE-like disease. 3. Test the hypothesis that dysregulation of SLAM family member's plays a role in human SLE. I will study the expression level of SLAM family members CD48, CD58, and CD244 in patient with SLE. Attempts will be made to correlate expression levels with cytokine production. These studies will be performed in collaboration with Dr. George Tsokos, a clinical mentor and member of my K08 scientific advisory committee. In this proposal, I plan to acquire new skills in the areas of human immunology, mouse models of autoimmunity and molecular biology. My long term goal is to combine my background in basic science and pediatric rheumatology to be an academic physician-scientist and independent investigator, studying mechanisms of immune dysregulation in autoimmunity and translating these findings to new therapies.

描述（由申请人提供）：项目概述本K 08奖的主要目标是研究SLAM家族成员CD 48和CD 244在小鼠和人类系统性红斑狼疮（SLE）中的作用。K 08奖将由T细胞共刺激和耐受性领域的专家Arlene Sharpe博士指导。我们的初步数据暗示CD 244和CD 48在调节耐受性和自身免疫性。C57 BL/6 CD 244缺陷（-/-）小鼠和C57 BL 6 x 129 CD 48-/-小鼠均出现狼疮特征。拟议的研究将检验CD 48：CD 244相互作用调节免疫激活和耐受之间平衡的假设。我们的具体目标是：1.研究CD 244在T细胞和B细胞免疫耐受中的作用。CD 244-/-小鼠自发产生自身抗体。当CD 244-/-小鼠与Y-连锁自身免疫加速基因座（Yaa）交配时，产生的品系发生增殖性肾小球肾炎，与不发生肾脏疾病的Yaa小鼠形成鲜明对比。CD 244-/-小鼠也表现出调节性T细胞的改变。Aim 1A将阐明CD 244在调节性T细胞发育和功能中的作用。Aim 1 B将使用BCR转基因小鼠剖析CD 244在B细胞耐受中的作用。2.描述CD 48缺陷小鼠中的适应性免疫应答，并评估CD 48如何在SLE小鼠模型中促进自身免疫。尽管C57 BL 6 x 129 CD 48-/-小鼠自发地产生活化的T和B细胞、抗DNA抗体和肾小球肾炎，但由于小鼠1号染色体上的129间隔（包括CD 48基因）和可能介导耐受性丧失的C57 BL/6基因之间可能的上位相互作用，该表型的解释变得复杂。在这里，我将使用我们最近产生的CD 48缺陷的C57 BL/6小鼠来研究CD 48在调节T和B细胞应答中的作用，并确定B6. CD 48-/-小鼠是否发生SLE样疾病。3.验证SLAM家族成员的失调在人类SLE中起作用的假设。本研究将探讨SLAM家族成员CD 48、CD 58、CD 244在SLE患者中的表达水平。将尝试将表达水平与细胞因子产生相关联。这些研究将与乔治Tsokos博士合作进行，他是临床导师，也是我的K 08科学顾问委员会成员。在这个建议中，我计划获得在人类免疫学，小鼠自身免疫模型和分子生物学领域的新技能。我的长期目标是将我在基础科学和儿科风湿病学方面的背景联合收割机结合起来，成为一名学术医生-科学家和独立研究者，研究自身免疫中免疫失调的机制，并将这些发现转化为新的治疗方法。