High Throughput Screening to Identify Small Molecule Rank Agonists

高通量筛选以鉴定小分子激动剂

• 批准号: 8945183
• 负责人: David Griggs
• 金额: $ 33.54万
• 依托单位: SAINT LOUIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8945183
• 关键词: Affect; Affinity; Age; Agonist; Albers-Schonberg disease; Animals; Antigen-Presenting Cells; Autoimmune Process; Binding; Biological; Biological Assay; Bone Diseases; Bone Marrow Cells; Bone Resorption; Bone Surface; Bone remodeling; CD8B1 gene; Cell Line; Cell Surface Receptors; Cells; Chemicals; Collection; Dependence; Disease; Dose; Elderly; Fluorescence; Forearm; Forearm Fracture; Foundations; Fracture; Hip Fractures; Hip region structure; Homeostasis; Hormones; Hydroxyapatites; Immune response; In Vitro; Inflammation; International; Investigation; Lead; Ligands; Molecular; Mus; Osteoclasts; Osteogenesis; Osteolytic; Osteoporosis; Pathway interactions; Patients; Periodontitis; Pharmaceutical Preparations; Play; Postmenopausal Osteoporosis; Property; Proteins; Publishing; Regulatory Pathway; Regulatory T-Lymphocyte; Reporting; Research; Rheumatoid Arthritis; Role; Signal Transduction; Specificity; Structure-Activity Relationship; T-Lymphocyte; Testing; Vertebral column; Woman; analog; base; bisphosphonate; bone; bone erosion; bone loss; drug development; enzyme activity; experience; high throughput screening; humanized monoclonal antibodies; humerus; in vivo; inhibitor/antagonist; interest; mRNA Expression; macrophage; men; mortality; mouse model; novel; novel therapeutic intervention; prevent; public health relevance; receptor; receptor activator of NF-kappa B; response; scaffold; screening; small molecule; small molecule libraries; tartrate-resistant acid phosphatase; tool

 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.

 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着至关重要的作用。我们最近发现，除了骨吸收外，破骨细胞还充当抗原呈递细胞，可以在 CD8 T 细胞中诱导 FoxP3。这些新型调节性 T 细胞（称为 TcREG）可防止 TEFF 激活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）处理来激活破骨细胞可以最大程度地诱导功能性 TcREG。这些 TcREG 极大地改善了骨质疏松症，并且确实导致骨形成增加。在这里，我们建议对模拟 RANKL 效应的类药物化合物进行高通量筛选。鉴定此类化合物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，它们可能被开发成药物来治疗某些类型的石骨症，在这些疾病中，患者不能产生功能性 RANKL。最后，因为我们的研究表明，RANKL 对 RANK 的低水平刺激会增加骨骼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用于治疗骨质疏松症的新型药物。