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/文摘

项目成果

Hyaline cartilage differentiation of fibroblasts in regeneration and regenerative medicine.

• DOI: 10.1242/dev.200249
• 发表时间: 2022-01-15
• 期刊: Development (Cambridge, England)
• 作者: Yu L;Lin YL;Yan M;Li T;Wu EY;Zimmel K;Qureshi O;Falck A;Sherman KM;Huggins SS;Hurtado DO;Suva LJ;Gaddy D;Cai J;Brunauer R;Dawson LA;Muneoka K
• 通讯作者: Muneoka K

Mouse Digit Tip Regeneration Is Mechanical Load Dependent.

• DOI: 10.1002/jbmr.4470
• 发表时间: 2022-03
• 期刊: Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research

Structural pharmacology of PTH and PTHrP.

PTH 和 PTHrP 的结构药理学。

• DOI: 10.1016/bs.vh.2022.03.001
• 发表时间: 2022
• 期刊: Vitamins and hormones
• 作者: Suva,LarryJ;Friedman,PeterA
• 通讯作者: Friedman,PeterA

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。

• DOI: 10.1007/s00223-022-01014-7
• 发表时间: 2022
• 期刊: Calcified tissue international
• 影响因子: 4.2
• 作者: Wagner,BrandonM;Robinson,JeridW;Prickett,TimothyCR;Espiner,EricA;Khosla,Sundeep;Gaddy,Dana;Suva,LarryJ;Potter,LincolnR
• 通讯作者: Potter,LincolnR

Digit specific denervation does not inhibit mouse digit tip regeneration.

• DOI: 10.1016/j.ydbio.2022.03.007
• 发表时间: 2022-06
• 期刊: DEVELOPMENTAL BIOLOGY
• 影响因子: 2.7
• 作者: Dolan, Connor P.;Imholt, Felisha;Yan, Mingquan;Yang, Tae-Jung;Gregory, Joshua;Qureshi, Osama;Zimmel, Katherine;Sherman, Kirby M.;Smith, Hannah M.;Falck, Alyssa;Leininger, Eric;Yu, Ling;Brunauer, Regina;Suva, Larry J.;Gaddy, Dana;Dawson, Lindsay A.;Muneoka, Ken
• 通讯作者: Muneoka, Ken