Determining cell-specific mechanisms that drive aberrant bone regeneration in Down syndrome

确定驱动唐氏综合症骨再生异常的细胞特异性机制

• 批准号: 10654983
• 负责人: Lindsay A Dawson
• 金额: $ 163.35万
• 依托单位: TEXAS A&M AGRILIFE RESEARCH
• 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/10654983
• 关键词: Acute; Age; Aging; Amputation; Anabolic Agents; Antibodies; Bone Density; Bone Injury; Bone Regeneration; Bone Resorption; Cells; Chromosome 21; Complex; Craniofacial Abnormalities; Databases; Defect; Digit structure; Down Syndrome; Encapsulated; Environment; Exhibits; Female; Foundations; Gene Expression; Goals; Human; Human Chromosomes; Impairment; Inbred ICR Mice; Individual; Injury; Life Expectancy; Live Birth; Metabolic; Modeling; Molecular; Mus; Osteoblasts; Osteoclasts; Osteoporosis; Outcome; Patients; Phalanx; Phase; Phenotype; Population; Populations at Risk; Process; Proliferating; Research; Resolution; Testing; Translating; Trisomy; Vulnerable Populations; age effect; age related; aged; bone; bone cell; bone fracture repair; bone healing; bone mass; bone strength; bone turnover; cell type; early onset; healing; in vivo; male; mouse Ts65Dn; mouse model; normal aging; recruit; response; response to injury; sex; sexual dimorphism; skeletal; skeletal injury; skeletal regeneration; stem cells; therapy development; transcriptome; young adult

PROJECT SUMMARY This new R01 application entitled “Determining cell-specific mechanisms that drive aberrant bone regeneration in Down syndrome” is focused on identifying the mechanistic and cellular changes that drive age-and-sex-specific deficits in skeletal regeneration as well as rescuing bone regeneration using multiple murine models of Down syndrome (DS). All individuals with DS exhibit hallmark skeletal defects, i.e. short stature and craniofacial abnormalities, and collectively present with a sexually dimorphic and variable spectrum of low bone mineral density (BMD) that predisposes this vulnerable group to skeletal injuries. Remarkably, male DS patients display an earlier onset and greater propensity for low BMD than DS females. Recent studies using murine models of DS (Dp16 and Ts65Dn mice) to parallel both the variability and the sexually dimorphic low BMD observed in DS patients, have shown that fracture healing is severely impaired in male DS mice and female Dp16 mice, whereas Ts65Dn females heal fractures at a similar rate as wild-type controls. These findings demonstrate how low BMD in DS mice translates to an injury environment that if recapitulated in humans would have profound consequences for this at-risk group, especially as they age. To understand the complex bone healing phenotype in DS, this project utilizes a mammalian model of bone regeneration, amputation of the digit tip, the terminal phalanx (P3), as well as multiple DS murine models (Dp16 and Ts65Dn mice) that possess inherently different mechanisms of bone accrual that recapitulate the sexually dimorphic low BMD phenotype observed in DS patients. Studies in Aim 1 will establish an expansive and high resolution DS transcriptome database in the context of an acute P3 bone injury response, as well as characterize osteoclast and osteoblast recruitment and activity during bone regeneration in multiple murine models of DS. Studies in Aim 2 will decouple the sexually dimorphic DS-related impacts from the sexually dimorphic aged-related impacts on osteoclasts and osteoblasts in the setting of bone regeneration. Aim 3 will determine the capacity for bone anabolic agents (PTH and anti-sclerostin antibody) to rescue bone regeneration in DS mice. The successful completion of this project will provide the foundation for developing fine-tuned sex-and-age-specific therapies to mitigate the consequences of poor bone healing in DS individuals.

项目概要 这个新的 R01 申请题为“确定在唐氏综合症中驱动异常骨再生的细胞特异性机制” “综合症”的重点是确定导致年龄和性别特异性骨骼缺陷的机制和细胞变化 使用多种唐氏综合症（DS）小鼠模型进行再生以及挽救骨再生。 DS 患者表现出标志性的骨骼缺陷，即身材矮小和颅面畸形，并共同表现为 性别二态性和低骨矿物质密度（BMD）的变化范围使这个弱势群体容易 值得注意的是，男性 DS 患者比 DS 患者发病更早，骨密度更低。 最近的研究使用 DS 小鼠模型（Dp16 和 Ts65Dn 小鼠）来平行分析变异性和性别。 在 DS 患者中观察到的二态性低 BMD 表明，雄性 DS 小鼠的骨折愈合严重受损， 雌性 Dp16 小鼠，而 Ts65Dn 雌性小鼠骨折愈合速度与野生型对照相似。 证明人类 DS 小鼠的低 BMD 会如何转化为伤害环境，如果重述的话，会产生 对这一高危人群产生深远的影响，尤其是随着年龄的增长，了解复杂的骨愈合表型。 DS，该项目利用哺乳动物的骨再生模型，放大指尖、末节指骨（P3）， 以及多种 DS 小鼠模型（Dp16 和 Ts65Dn 小鼠），它们具有本质上不同的骨生成机制 概括了在 DS 患者中观察到的性别二态性低 BMD 表型，目标 1 中的研究将建立一个模型。 急性 P3 骨损伤反应背景下的广泛且高分辨率 DS 转录组数据库，以及 表征多种 DS 小鼠模型骨再生过程中破骨细胞和成骨细胞的募集和活性。 目标 2 的研究将把 DS 相关的性二态性影响与年龄相关的性二态性影响脱钩 目标 3 将确定骨合成代谢剂的能力。 （PTH和抗硬化蛋白抗体）拯救DS小鼠的骨再生 该项目的成功完成将是一个重要的里程碑。 为微调性别和年龄特异性疗法奠定基础，以减轻骨质疏松的后果 DS 个体的愈合。