Inhibition of Antigen Presentation in Multiple Sclerosis

超出提供的空间。该项目的长期目标是开发小分子抗原提呈抑制剂，用于治疗多发性硬化症(MS)。MHC II类分子被认为在疾病过程中发挥关键作用，将髓鞘抗原的多肽递送到CD4T细胞。全基因组研究已经证明了与MHC II类区域的连锁，并且在家族性和散发性病例中，人类白细胞抗原-DR2单倍型(DRB1*1501)与疾病易感性有关。研究人员先前已经确定了人类白细胞抗原-DR2(DRA，DRB1*1501)的晶体结构，它展示了代表特定抑制剂潜在靶点的结合部位的特征。对DM或不变链缺陷小鼠的研究表明，中枢神经系统的抗原提呈对于中枢神经系统炎症的发展是严格要求的。该项目的主要假设是，阻止髓鞘抗原呈递到CD4T细胞的关键步骤的小分子可以防止MS病变的发展。该项目将与最近成立的哈佛神经变性与修复中心(HCNR)密切合作，该中心正在开发一项针对神经疾病的药物发现计划。该中心和这一特定项目的目标是在正在进行的研究努力的基础上开发治疗方法，并在相关动物模型中测试化合物。抑制物的鉴定将集中在抗原提呈细胞中肽负载到MHC II类分子上的机制。尤其相关的是DM催化的不变链衍生的CLIP多肽的解离，因为它先于抗原肽与MHC II类分子结合。研究人员开发了一种哺乳动物表达系统，该系统提供了适量的HLA-DR2/CLIP复合体，用于分析大而多样的小分子文库。初步研究表明，荧光偏振提供了灵敏的实时读出与这些HLA-DR2/CLIP复合体结合的多肽的方法。该项目的具体目标是：开发鉴定阻断髓鞘多肽递送的小分子的分析方法(目标1)，在与细胞内肽负载相关的条件下检查大量和多样化的小分子集合(目标2)，并研究化合物抑制髓鞘抗原递送的机制(目标3)。表演网站========================================Section End===========================================

EXCEED THE SPACE PROVIDED. The long-term objective of this project is to develop small molecule inhibitors of antigen presentation for the treatment of multiple sclerosis (MS). MHC class II molecules are thought to play a critical role in the disease process by presenting peptides from myelin antigens to CD4 T cells. Genome-wide studies have demonstrated linkage to the MHC class II region, and the HLA-DR2 haplotype (DRB1*1501)is associated with disease susceptibility in both familial and sporadic cases. The investigator has previously determined the crystal structure of HLA-DR2 (DRA, DRB1*1501 ), which demonstrates features of the binding site that represent potential targets for specific inhibitors. Studies in mice deficient in DM or invariant chain have demonstrated that antigen presentation in the CNS is strictly required for the development of CNS inflammation. The major hypothesis of this project is that small molecules which block critical steps in the presentation of myelin antigens to CD4 T cells can prevent the development of MS lesions. The project will be performed in close collaboration with the recently established Harvard Center for Neurodegeneration and Repair (HCNR) that is developing a drug discovery program directed at neurological diseases. The goal of the center, and of this particular project, is to develop therapeutic approaches based on ongoing research efforts, and to test compounds in relevant animal models. The identification of inhibitors will focus on the mechanisms of peptide loading onto MHC class II molecules in antigen presenting cells. Particularly relevant is the DM catalyzed dissociation of the invariant chain derived CLIP peptide since it precedes binding of antigenic peptides to MHC class II molecules. The investigator has developed a mammalian expression system that provides suitable quantities of the HLA-DR2/CLIP complex for analysis of large and diverse libraries of small molecules. Preliminary studies demonstrate that fluorescence polarization provides a sensitive, real-time readout of peptide binding to these HLA-DR2/CLIP complexes. The specific aims of the project are: To develop assays for the identification of small molecules that block presentation of myelin peptides (Aim 1), to examine a large and diverse collection of small molecules under conditions relevant for intracellular peptide loading (Aim 2), and to study the mechanisms by which compounds inhibit presentation of myelin antigens (Aim 3). PERFORMANCE SITE ========================================Section End===========================================