High Throughput Screening to Identify Small Molecule Rank Agonists

 描述（由申请人提供）：破骨细胞是人体的主要骨吸收细胞，在绝经后骨质疏松症、类风湿性关节炎和牙周炎等疾病中的骨重塑和骨侵蚀中发挥重要作用。我们最近发现，除了吸收骨，破骨细胞也作为抗原呈递细胞，可以诱导FoxP 3在CD 8 T细胞。这些新的调节性T细胞，称为TcREG，阻止TEFF的活化并直接抑制破骨细胞活性。值得注意的是，我们已经证明，通过低剂量RANKL（NF-κ B配体的受体-激活剂）处理，破骨细胞的激活最大程度地诱导功能性TcREG。这些TcREG极大地改善骨质疏松症，并且确实导致骨形成增加。在这里，我们建议进行高通量筛选药物样化合物，模拟RANKL的效果。这些化合物的鉴定将在三个方面有所帮助：首先，它们将用于剖析小鼠模型中的途径和机制。其次，它们可能被开发成治疗某些类型的骨硬化症的药物，其中患者不能产生功能性RANKL。最后，由于我们的研究表明RANKL对RANK的低水平刺激增加了骨中抑制炎症和破骨细胞活性的调节性T细胞的数量，因此小分子RANK激动剂有可能产生一类新的骨质疏松症治疗药物。

 DESCRIPTION (provided by applicant): Osteoclasts are the body's primary bone resorbing cells that play a vital role in bone remodeling and bone erosion in conditions such as postmenopausal osteoporosis, rheumatoid arthritis and periodontitis. We have recently discovered that in addition to resorbing bone, osteoclasts also act as antigen-presenting cells that can induce FoxP3 in CD8 T-cells. These novel regulatory T-cells, called TcREG, prevent the activation of TEFF and directly suppress osteoclast activity. Significantly, we have shown that activation of osteoclasts by treatment with low-dose RANKL (receptor-activator of NF-kappa B ligand) maximally induces functional TcREG. These TcREG greatly ameliorate osteoporosis, and indeed lead to increased bone formation. Here we propose to conduct high-throughput screening for drug-like compounds that mimic RANKL's effect. Identification of such compounds will be helpful in three ways: first, they will be used to dissect pathways and mechanisms in mouse models. Second, they may be developed into drugs to treat certain types of osteopetrosis in which patients cannot produce functional RANKL. Finally, because our studies show that low-level stimulation of RANK by RANKL increase the number of regulatory T-cells in bone that suppress inflammation and osteoclast activity, small molecule RANK agonists have the potential to give rise to a new class of drugs for treatment of osteoporosis.