Novel Strategies for Understanding and Treating Fibrous Dysplasia

理解和治疗纤维发育不良的新策略

• 批准号: 10658595
• 负责人: EDWARD C HSIAO
• 金额: $ 69.96万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10658595
• 关键词: Acceleration; Address; Affect; Artificial Intelligence; Automobile Driving; Binding; Biological Assay; Biological Markers; Biology; Bone Diseases; Bone Growth; Bone callus; Calvaria; Cells; Clinical; Complex; Cre driver; Cyclic AMP; DNA Sequence Alteration; Data; Disease; Dysplasia; Foundations; Fracture; Functional disorder; Future; G Protein-Coupled Receptor Signaling; G-Protein-Coupled Receptors; GNAS gene; GTP-Binding Protein alpha Subunits, Gs; Gene Expression Profile; Genes; Genetic; Health; Hematopoietic stem cells; Homeostasis; Human; Hybrids; Hyperactivity; Individual; Institution; Isoproterenol; Kinetics; Knowledge; Lead; Lesion; Ligands; McCune-Albright Syndrome; Mediating; Medical; Modeling; Molecular; Molecular Probes; Mus; Musculoskeletal Diseases; Mutation; Natural regeneration; Osteitis Fibrosa Disseminata; Osteoblasts; Osteocytes; Osteogenesis; Osteoporosis; PTH gene; Pathology; Pathway interactions; Patients; Phenotype; Physiology; Production; Property; Proteins; Public Health; Recombinants; Role; Sampling; Signal Pathway; Signal Transduction; Signaling Molecule; Testing; Therapeutic; Variant; WNT Signaling Pathway; WNT4 gene; WNT9A gene; Wnt proteins; Work; analytical method; bone; bone cell; bone fracture repair; bone loss; bone repair; bone turnover; cell type; computational intelligence; digital; effective therapy; experience; genetic approach; guanine nucleotide binding protein; improved; in vivo evaluation; induced pluripotent stem cell; mouse model; novel; novel strategies; novel therapeutic intervention; novel therapeutics; osteogenic; overexpression; parathyroid hormone-related protein; pharmacologic; prevent; rare condition; receptor; repaired; single-cell RNA sequencing; skeletal; skeletal stem cell; stem cell function; stem cell model; therapeutic target; tool; transcriptome; transcriptomics; treatment strategy

PROJECT SUMMARY Current treatments for many musculoskeletal disorders are often suboptimal. Understanding the signals controlling skeletal homeostasis and repair is of high relevance, since this knowledge is critical for developing effective therapies for common conditions such as osteoporosis and fractures. In this proposal, we study fibrous dysplasia (FD) as a way to understand the regulators of human bone formation, and test if these pathways could then be used to enhance bone repair. FD accounts for 2.5% of all bone lesions and can occur as part of McCune-Albright Syndrome (MAS). FD is caused by genetic mutations in the GNAS locus, leading to a constitutively active Gs-GPCR protein, hence increasing cAMP levels and causing aberrant cellular signaling. Medical treatments for this disfiguring disorder are sorely lacking. This proposal uses new tools, including mouse models, human induced pluripotent stem cells (iPSCs), skeletal stem/progenitor cells, and advanced genetic strategies, to address the critical knowledge gaps and to find novel therapies for these medically significant conditions. We propose three specific aims: Aim 1: Identify novel compounds that directly target Gsα-regulated cAMP and Wnt production. We previously showed that stopping excess Gs-GPCR pathway activity in mice could dramatically reverse FD-like bone lesions. Using a new artificial intelligence computational approach, we found 71 candidate compounds predicted to selectively bind the GsαR201H protein. Preliminary studies demonstrate that some of these show the desired inhibition of GsαR201H-induced basal cAMP production. This Aim takes our top candidates and further characterizes their ability to block cAMP and Wnt activity, as potential molecular tools for manipulating GNAS. We also test if the lead compounds can reverse existing FD lesions in mouse calvarial cultures. Aim 2: Test if Wnt inhibition can prevent FD bone lesions in mice. How the GNAS mutations in FD cause dramatic bone formation is still poorly defined. We recently found that three proteins, Wnt4, Wnt5a, and Wnt9a, are upregulated in both mouse and human FD bone lesions. This Aim tests if blocking these proteins can reverse FD bone lesions in mice, and examines how each Wnt protein impacts FD lesion pathology. Aim 3: Determine the pathways that are dysregulated in human FD bone lesions and assess the roles of WNT signaling in human skeletal stem/progenitor cells during fracture repair. This aim uses advanced genetics on human FD bone samples to identify the malfunctioning cell types that cause FD. We also test how overactivating WNT4, WNT5a, or WNT9a in human skeletal stem/progenitor cells affect bone formation in a fracture healing model. These results will identify new targets for treating FD and for promoting fracture healing. This application address key knowledge gaps about which Wnt signaling molecules drive FD and how they impact human osteogenesis. The proposal comes from an established, strong, collaborative, multi-institutional team with extensive experience in GPCRs, FD, bone biology, and bone analytical methods. 1

项目总结