Contribution of chromosome versus gonadal sex to bone mass and strength

染色体与性腺性别对骨量和强度的贡献

• 批准号: 10711910
• 负责人: Lilian Irene Plotkin
• 金额: $ 39.63万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-15 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10711910
• 关键词: Abbreviations; Address; Affect; Age Months; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Animals; Arginine; Bone Density; Brain; Cell Count; Cell physiology; Chromosomes; DNA Sequence Alteration; Dementia; Diagnosis; Dissociation; Elderly; Exhibits; Exploratory/Developmental Grant for Diagnostic Cancer Imaging; Female; Femur; Four Core Genotypes; Fracture; Frequencies; Funding; Gender; General Population; Generations; Genotype; Goals; Gonadal Steroid Hormones; Gonadal structure; Health; High Prevalence; Hip region structure; Histidine; Individual; Knowledge; Link; Longevity; Measures; Mental disorders; Microglia; Modeling; Molecular; Mus; Mutation; Myeloid Cells; Neurologic; Obesity; Osteoclasts; Osteoporosis; Ovary; Pattern; Phenotype; Physiological; Predisposition; Reporting; Risk; Risk Factors; Role; Sex Chromosomes; Sex Differences; Skeleton; Structure; TREM2 gene; Testing; Testis; Transgenes; Transgenic Organisms; Variant; Wild Type Mouse; Woman; X Chromosome; Y Chromosome; biomechanical test; bone; bone cell; bone fragility; bone health; bone loss; bone mass; bone strength; circulating biomarkers; dementia risk; genetic manipulation; genotypic sex; high risk; improved; male; men; mortality; nervous system disorder; prevent; sex; sexual dimorphism; skeletal; sry Genes; stem

SUMMARY Alzheimer's disease (AD) is a growing health concern and is the most common type of dementia worldwide, affecting women with higher frequency. Evidence indicates that mental illness and neurological and nervous system disorders can increase the risk of developing osteoporosis leading to high prevalence of bone frac- tures. Fractures, in particular of the hip, have been associated with increased mortality, especially in the elder- ly. Conversely, osteoporosis is associated with higher risk of dementia diagnosis. Yet, a direct link between dementia and osteoporosis, frequently occurring with aging, has never been conclusively demonstrated. Inter- estingly, some genetic mutations are risk factors for both AD and osteoporosis. For example, mutations of the Triggering Receptor Expressed on Myeloid Cells 2 (TREM2), a molecule expressed in microglia in brain and in osteoclasts in bone correlate with AD and dementia, and with bone fragility. Recent studies showed that mice expressing the TREM2 R47H variant (TREM2R47H/+ mice) exhibit loss of TREM2 function and neuritic dystro- phy. However, the mechanisms responsible for the TREM2 mutation effects on bone mass and strength are completely unclear. We have shown that females TREM2R47H/+ mice exhibit low bone mass accrual compared to wild type littermates, whereas no changes were observed in males. In addition, female, but not male, TREM2R47H/+ mice exhibit low total and femur BMD at 5.5, but not at 4 months of age, compared to wild type littermates. Yet, the mechanism by which aging has a stronger effect in female TREM2R47H/+ compared wild type mice is not known. Our long-term goal is to understand the basis for bone sexual dimorphism. The ob- jective of this supplement is to extend the original studies funded by the R21 award to a model of increased risk of developing AD, with the aim to start uncovering the mechanisms for the increase susceptibility to devel- oping AD in females. We propose to test the hypothesis that the differential skeletal consequences of ex- pression of the TREM2 R47H variant result from a combination of gonadal and chromosome sex- dependent mechanisms. To address this hypothesis, we aim to determine the contribution of gonadal versus chromosome sex to bone mass and strength in 5.5-month-old wild type and TREM2R47H/+ mice. Two Sub Aims are proposed. In Sub Aim a, we will examine the skeletal consequences of the TREM2 variant in male and female mice and the role of chromosomal and gonadal sex at the structural, cellular, and molecu- lar levels in wild type and TREM2R47H/+ XXM, XYM, XXF and XYF mice. In Sub Aim b, we will identify the cellular mechanism that underly the sexual dimorphism in wild type and TREM2R47H/+ mice, by determining whether osteoclasts from TREM2R47H/+ XXM, XYM, XXF and XYF mice are intrinsically different or respond to sex steroids differently, and whether the pattern of osteoclastokines differs in a sex-dependent manner. These studies will advance our knowledge of the mechanisms controlling bone cell function in a sex-dependent manner in the context of increased risk to develop AD.

总结 阿尔茨海默病（AD）是一个日益严重的健康问题，是世界上最常见的痴呆症类型， 影响女性的频率更高。有证据表明，精神疾病、神经系统疾病和 系统紊乱会增加患骨质疏松症的风险，导致骨折的高发率， 图。骨折，特别是髋部骨折，与死亡率增加有关，尤其是在老年人中- ly.相反，骨质疏松症与痴呆症诊断的高风险相关。然而， 老年痴呆症和骨质疏松症经常伴随着衰老而发生，但从未得到最终证实。间- 值得注意的是，一些基因突变是AD和骨质疏松症的危险因素。例如， 髓样细胞表达触发受体2（TREM 2），一种在脑中小胶质细胞中表达的分子， 骨中的破骨细胞与AD和痴呆以及骨脆性相关。最近的研究表明， 表达TREM 2 R47 H变体的小鼠（TREM 2 R47 H/+小鼠）表现出TREM 2功能丧失和神经炎性发育不良。 物理学然而，TREM 2突变对骨量和强度影响的机制是 完全不清楚我们已经表明，雌性TREM 2 R47 H/+小鼠表现出较低的骨量增加， 与野生型同窝仔相比，而在雄性中未观察到变化。此外，女性，而不是男性， 与野生型相比，TREM 2 R47 H/+小鼠在5.5月龄时表现出低的总BMD和股骨BMD，但在4月龄时则没有 同窝出生的然而，衰老对雌性TREM 2 R47 H/+的影响比野生型更强的机制是， 小鼠的类型未知。我们的长期目标是了解骨骼性别二型性的基础。这是... 本补充的目的是将R21奖资助的原始研究扩展到增加的模型， 发展AD的风险，目的是开始揭示发展AD的易感性增加的机制， 女性AD我们建议测试的假设，即差异骨骼的后果，前- TREM 2 R47 H变体的表达是性腺和染色体性别的组合导致的。 依赖机制。为了解决这一假设，我们的目标是确定性腺的贡献， 与染色体性别相比，5.5月龄野生型和TREM 2 R47 H/+小鼠的骨量和强度。 提出了两个分目标。在子目标a中，我们将研究TREM 2变体的骨骼后果， 以及染色体和性腺性别在结构、细胞和分子水平上的作用。 在野生型和TREM 2 R47 H/+ XXM、XYM、XXF和XYF小鼠中具有更高水平。在子目标B中，我们将识别 野生型和TREM 2 R47 H/+小鼠中两性异形的机制，通过确定是否 来自TREM 2 R47 H/+ XXM、XYM、XXF和XYF小鼠的破骨细胞本质上不同或对性类固醇有反应 不同，以及破骨细胞因子的模式是否以性别依赖的方式不同。这些研究将 推进我们的知识机制控制骨细胞功能的性别依赖性的方式， 在AD发生风险增加的背景下。