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.

摘要 成骨结缔组织（Osteogenesis lastata，OI）是一组遗传和表型异质性结缔组织 导致低骨量、骨畸形和骨折的疾病。OI的估计患病率 每15,000个新生儿中就有一个。多个过程的中断，如胶原蛋白合成、胶原蛋白翻译后 修饰、信号传导缺陷和细胞内运输导致OI。医学治疗的主要重点是 通过内科和外科治疗来增加骨量和降低骨折风险。的中流砥柱 在这一人群中的治疗是双膦酸盐，其通过抑制骨转换来减少骨丢失。 然而，这些药物只能延缓骨质流失，而不能完全预防。 Wnt/Frizzled 2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/Frizzled 2信号通路是否可用于治疗显性和隐性遗传的骨骼特征， 隐性形式OI，减少Wnt 1 sw/sw小鼠模型中的小脑功能障碍，并研究如何调节 在Wnt/Frizzled 2信号通路中增加骨量。我们的初步研究表明， 在OI的显性（Col1a2tm1.1Mcbr）和隐性模型（Crtap-/-）中增加骨量。在其他初步 研究中，我发现调节Wnt/Frizzled 2通路会增加mTORC 1下游的激活， 信号通路核心假设是Wnt/Frizzled 2信号通路的调节 通过激活mTORC 1信号通路的下游靶点增加骨量。我们计划 通过以下方式测试我们的假设：在用以下方法处理后，在两种OI小鼠模型中表征骨骼 一种受调节的Wnt/Frizzled 2信号分子，评估了 Wnt 1 sw/sw小鼠模型，并研究Wnt/Frizzled 2信号在体内和体内mTORC 1通路中的作用。 体外骨质量和细胞增殖和功能。通过评估这些目标，我们 阐明Wnt/Frizzled 2信号传导在骨形成中的作用，并深入了解下游激活 mTORC 1信号通路改变骨形成。