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 成骨不全症 (OI) 是一组遗传和表型异质的结缔组织 导致骨量低、骨畸形和骨折的疾病。成骨不全症的患病率估计 每 15,000 名新生儿中就有 1 人。胶原蛋白合成、胶原蛋白翻译后等多个过程的中断 修饰、信号传导缺陷和细胞内运输会导致成骨不全症。药物治疗的主要重点是 通过药物和手术治疗来增加骨量并降低骨折风险。的中流砥柱 该人群的治疗方法是双磷酸盐，它通过抑制骨转换来减少骨质流失。 然而，这些药物只能延缓骨质流失，而不能完全预防。我们已经证明了调制 Wnt/Frizzled2信号通路可以增加野生型小鼠的骨量。我在这个项目中的目标是 测试 Wnt/Frizzled2 信号通路是否可用于治疗显性和 隐性形式 OI，减少 Wnt1sw/sw 小鼠模型中的小脑功能障碍，并研究调节机制 Wnt/Frizzled2 信号通路中的成分可增加骨量。我们的初步研究表明这种调节 增加 OI 显性模型 (Col1a2tm1.1Mcbr) 和隐性模型 (Crtap-/-) 的骨量。在其他初步 研究中，我发现调节 Wnt/Frizzled2 通路会增加 mTORC1 的下游激活 信号通路。中心假设是 Wnt/Frizzled2 信号通路的调节 通过激活 mTORC1 信号通路的下游靶标来增加骨量。我们计划 通过以下方式检验我们的假设： 表征两种 OI 小鼠模型在用 调节的 Wnt/Frizzled2 信号分子，评估骨骼外表型的变化 Wnt1sw/sw 小鼠模型并研究 Wnt/Frizzled2 信号在体内和体内 mTORC1 通路中的作用 体外分别对骨量和细胞增殖和功能产生影响。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的方式 mTORC1 信号通路的改变会改变骨形成。