Mechanistic investigation into Frizzled-2 signaling for treatment of Osteogenesis Imperfecta

Frizzled-2 信号传导治疗成骨不全症的机制研究

• 批准号: 10680236
• 负责人: Mary IfeOluwa Adeyeye
• 金额: $ 4.77万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10680236
• 关键词: Aftercare; Age Months; Anabolism; Antibodies; Binding; Biomechanics; Birth; Bone Diseases; Bone Matrix; Bone structure; COL1A1 gene; COL1A2 gene; Cell Nucleus; Cell Proliferation; Cell physiology; Cerebellar Diseases; Circulation; Clinical; Clinical Research; Collagen; Collagen Type I; Complex; Connective Tissue Diseases; Defect; Deformity; Disease; Dose; FDA approved; FRAP1 gene; Family; Female; Fracture; Future; Gene Proteins; Genes; Genetic Transcription; Homeostasis; Human; In Vitro; Incidence; International; Investigation; Japanese; Lead; Mediating; Medical; Meta-Analysis; Minerals; Modeling; Molecular; Molecular Analysis; Monomeric GTP-Binding Proteins; Mus; Operative Surgical Procedures; Osteoblasts; Osteocytes; Osteogenesis; Osteogenesis Imperfecta; Osteoporosis; Pathogenicity; Pathological fracture; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Phosphorylation; Physicians; Physiologic calcification; Play; Population; Post-Translational Protein Processing; Pre-Clinical Model; Prevalence; Process; Procollagen; Recurrence; Role; Scientist; Serum; Signal Pathway; Signal Transduction; Signaling Molecule; Sirolimus; Stromal Cells; System; Testing; Therapeutic; Therapeutic Uses; Training; Translational Research; Variant; WNT Signaling Pathway; WNT1 gene; Wild Type Mouse; Wnt proteins; Work; Zoledronate; beta catenin; biomechanical test; bisphosphonate; bone; bone fragility; bone loss; bone mass; bone turnover; career; crosslink; design; doctoral student; dominant genetic mutation; early onset; fracture risk; gain of function; improved; in vivo; inhibitor; insight; loss of function; male; mouse model; neurodevelopment; novel; osteoblast differentiation; overexpression; prevent; rare mendelian disorder; receptor; rho; skeletal; therapeutic candidate; therapeutically effective; tibia; trafficking; transcriptomics; treatment group

Abstract Osteogenesis imperfecta (OI) is a group of genetically and phenotypically heterogeneous connective tissue disorders that results in low bone mass, bone deformity, and bone fractures. OI has an estimated prevalence of 1 in 15,000 births. Disruptions in multiple processes such as collagen synthesis, collagen posttranslational modification, signaling defects and intracellular trafficking lead to OI. The primary focus of medical therapy has been to increase bone mass and reduce fracture risk through medical and surgical treatment. The mainstay of treatment in this population is bisphosphonates, which reduces bone loss by suppressing bone turnover. However, these drugs can only delay bone loss without fully preventing it. We've shown that modulation of the Wnt/Frizzled2 signaling pathway can in increase bone mass in wild type mice. My objective in this project is to test whether the Wnt/Frizzled2 signaling pathway can be used to treat both skeletal features of a dominant and recessive form OI, reduce cerebellar dysfunction in the Wnt1sw/sw mouse model and investigate how modulation in the Wnt/Frizzled2 signaling pathway increases bone mass. Our preliminary studies indicate this modulate increases bone mass in a dominant (Col1a2tm1.1Mcbr) and recessive model of OI (Crtap-/-). In other preliminary studies, I found that modulating the Wnt/Frizzled2 pathway increases downstream activation of the mTORC1 signaling pathway. The central hypothesis is that modulation of the Wnt/Frizzled2 signaling pathway increases bone mass through activation of downstream targets of the mTORC1 signaling pathway. We plan to test our hypothesis in the following ways: characterize the skeletal in two OI mouse models after treatment with a modulated Wnt/Frizzled2 signaling molecule, assess the changes in the extraskeletal phenotype in the Wnt1sw/sw mouse model and investigate the role of Wnt/Frizzled2 signaling in mTORC1 pathway in vivo and in vitro on bone mass and cellular proliferation and function, respectively. By assessing these aims, we will elucidate the role of Wnt/Frizzled2 signaling in bone formation and gain insight on how downstream activation of the mTORC1 signaling pathway alters bone formation.

抽象的 成骨不完美（OI）是一组遗传和表型异质结缔组织 导致低骨质，骨畸形和骨折的疾病。 OI估计患病率 15,000个分娩中有1个。胶原蛋白合成，胶原蛋白翻译后的多种过程中的破坏 修饰，信号缺陷和细胞内运输导致OI。医疗疗法的主要重点 通过医疗和手术治疗来增加骨骼质量并降低骨折风险。主要的中流tay 该人群的治疗是双膦酸盐，可通过抑制骨骼更新来减少骨质流失。 但是，这些药物只能延迟骨质流失而不会完全阻止骨质流失。我们已经表明了对 Wnt/Frizzled2信号通路可以增加野生型小鼠的骨骼质量。我在这个项目中的目标是 测试WNT/Frizzled2信号通路是否可以用于治疗主要和优势的骨骼特征 隐性形式OI，减少WNT1SW/SW鼠标模型中的小脑功能障碍，并研究如何调节 在Wnt/Frizzled2中，信号通路会增加骨骼质量。我们的初步研究表明此调节 在OI（CRTAP - / - ）的主要（COL1A2TM1.1MCBR）和隐性模型中增加骨骼质量。在其他初步中 研究，我发现调节Wnt/Frizzled2途径会增加MTORC1的下游激活 信号通路。中心假设是Wnt/Frizzled2信号通路的调制 通过激活MTORC1信号通路的下游靶标增加骨骼质量。我们计划 通过以下方式检验我们的假设：在处理两种OI小鼠模型中的骨骼 调制的Wnt/Frizzled2信号分子，评估骨架外表型的变化 WNT1SW/SW鼠标模型，并研究Wnt/Frizzled2信号在体内和在MTORC1途径中的作用 骨骼质量和细胞增殖和功能分别体外。通过评估这些目标，我们将 阐明Wnt/Frizzled2信号在骨形成中的作用，并深入了解下游激活 MTORC1信号通路的变化改变了骨形成。