Understanding the skeleton in Down Syndrome

了解唐氏综合症的骨骼

• 批准号: 10209603
• 负责人: LARRY J. SUVA
• 金额: $ 160.51万
• 依托单位: TEXAS A&M AGRILIFE RESEARCH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-10 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10209603
• 关键词: Ablation; Affect; Anabolism; Antibodies; Behavioral; Bone Density; Bone Marrow; Bone Regeneration; Bone Resorption; Calcineurin; Cardiovascular system; Cells; Chromosome 21; Clinical; Complex; Craniofacial Abnormalities; Defect; Down Syndrome; Down-Regulation; FDA approved; Female; Fracture; Fracture Healing; Gene Expression; Genes; Goals; Homeostasis; Human Characteristics; Human Chromosomes; Individual; Intervention; Knockout Mice; Knowledge; Leg; Life Expectancy; Live Birth; Modeling; Morbidity - disease rate; Mus; Neurologic; Osteoblasts; Osteoclasts; Osteocytes; Osteogenesis; Osteopenia; Osteoporosis; Pathway interactions; Phalanx; Pharmacologic Substance; Phase; Phenotype; Physiology; Population; Populations at Risk; Process; Regulation; Regulator Genes; Research; Role; Skeleton; Testing; Time; Transgenic Organisms; Trauma; Trisomy; Video Microscopy; WNT Signaling Pathway; Withholding Treatment; bone; bone fracture repair; bone health; bone loss; bone mass; bone strength; bone turnover; dosage; experimental study; fracture risk; in vivo; insight; macrophage; male; mouse Ts65Dn; mouse model; normal aging; novel; novel therapeutic intervention; osteoblast differentiation; osteoclastogenesis; overexpression; pre-clinical; repaired; response; skeletal; transcriptome sequencing

SUMMARY/ABSTRACT This new R01 application entitled “Understanding bone mass in Down Syndrome” is focused on determining the cellular mechanism for the low bone turnover we have identified in people and mice with Down Syndrome (DS), and on characterizing fracture healing responses in different DS mouse models to gain insight into how to better target fracture healing in the DS population with increased propensity to fracture. This proposal will determine the contribution of Regulator of calcineurin 1 (RCAN1) that impacts both NF-κB activity in osteoclasts and Wnt signaling in osteoblasts/osteocytes to the inherently low bone mineral density (BMD) in DS. The proposed experiments will also determine the impact of cessation of the current clinical bone anabolic interventions in the setting of DS as well as define DS fracture healing. Aim 1 will elucidate the pathways through which RCAN1 controls osteoclast and osteoblast differentiation and function. Aim 2 will provide the first direct evidence of fracture healing and repair in the context of low bone accrual and DS. Aim 3 will determine the effects of discontinuation of current pharmaceutical anabolic therapies (anti-sclerostin antibody and intermittent PTH) on bone mass accrual in three preclinical mouse models of DS. The successful completion of this study will lead to a paradigm shift in our understanding of the DS bone phenotype and a new landscape of high-quality research that will provide clarification of the mechanisms that contribute to the low bone mass in DS and more importantly, provide the basis for new directions for the treatment of the fractures and profound osteopenia that affects this population.

摘要/摘要 这个名为“了解唐氏综合症患者的骨量”的新 R01 应用程序专注于确定 我们在患有唐氏综合症的人和小鼠中发现了低骨转换的细胞机制 (DS)，并描述了不同 DS 小鼠模型的骨折愈合反应，以深入了解如何 为了更好地针对骨折倾向增加的 DS 人群进行骨折愈合。 确定钙调磷酸酶调节因子 1 (RCAN1) 对 NF-κB 活性的影响 破骨细胞和成骨细胞/骨细胞中的 Wnt 信号传导导致固有的低骨矿物质密度 (BMD) DS.拟议的实验还将确定停止当前临床骨合成代谢的影响。 对 DS 的干预以及定义 DS 骨折愈合的目标 1 将阐明其途径。 RCAN1 通过其控制破骨细胞和成骨细胞的分化和功能，从而提供目标 2。 在骨生成量低和 DS 目标 3 的情况下骨折愈合和修复的第一个直接证据将。 确定停止当前药物合成代谢疗法（抗硬化素抗体 和间歇性 PTH）对三种 DS 临床前小鼠模型骨量增长的影响。 这项研究的完成将导致我们对 DS 骨表型的理解发生范式转变，并产生新的 高质量研究的前景将澄清导致低水平的机制 DS 中的骨量，更重要的是，为骨折治疗的新方向提供基础 以及影响该人群的广泛骨质减少。

项目成果

Hyaline cartilage differentiation of fibroblasts in regeneration and regenerative medicine.

再生和再生医学中成纤维细胞的透明软骨分化。

• 发表时间: 2022-01-15
• 作者: Yu, Ling;Lin, Yu;Yan, Mingquan;Li, Tao;Wu, Emily Y;Zimmel, Katherine;Qureshi, Osama;Falck, Alyssa;Sherman, Kirby M;Huggins, Shannon S;Hurtado, Daniel Osorio;Suva, Larry J;Gaddy, Dana;Cai, James;Brunauer, Regina;Dawson, Lindsay A;Muneo
• 通讯作者: Muneo

Structural pharmacology of PTH and PTHrP.

PTH 和 PTHrP 的结构药理学。

• 发表时间: 2022
• 作者: Suva, Larry J;Friedman, Peter A
• 通讯作者: Friedman, Peter A

Hmga2 deficiency is associated with allometric growth retardation, infertility, and behavioral abnormalities in mice.

Hmga2 缺乏与小鼠异速生长迟缓、不育和行为异常有关。

• 发表时间: 2022-02-04
• 作者: Lee, Mi Ok;Li, Jingyi;Davis, Brian W;Upadhyay, Srijana;Al Muhisen, Hadil M;Suva, Larry J;Clement, Tracy M;Andersson, Leif
• 通讯作者: Andersson, Leif

Mouse Digit Tip Regeneration Is Mechanical Load Dependent.

鼠标指尖再生取决于机械负载。

• 发表时间: 2022-02
• 作者: Dolan, Connor P;Imholt, Felisha;Yang, Tae;Bokhari, Rihana;Gregory, Joshua;Yan, Mingquan;Qureshi, Osama;Zimmel, Katherine;Sherman, Kirby M;Falck, Alyssa;Yu, Ling;Leininger, Eric;Brunauer, Regina;Suva, Larry J;Gaddy, Dana;Dawson, Lindsay
• 通讯作者: Dawson, Lindsay

Guanylyl Cyclase-B Dependent Bone Formation in Mice is Associated with Youth, Increased Osteoblasts, and Decreased Osteoclasts.

小鼠体内鸟苷酸环化酶 B 依赖性骨形成与青春期、成骨细胞增加和破骨细胞减少有关。

• 发表时间: 2022-11
• 影响因子: 4.2
• 作者: Wagner, Brandon M;Robinson, Jerid W;Prickett, Timothy C R;Espiner, Eric A;Khosla, Sundeep;Gaddy, Dana;Suva, Larry J;Potter, Lincoln R
• 通讯作者: Potter, Lincoln R