Skeletal Fragility

骨骼脆弱

• 批准号: 10561631
• 负责人: Sundeep Khosla
• 金额: $ 52.62万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10561631
• 关键词: Address; Age; Age-Related Bone Loss; Aging; Animal Model; Antibody Therapy; Apoptosis; B-Lymphocytes; Biopsy; Bone Formation Inhibition; Bone Marrow; Bone Resorption; CDKN2A gene; Caspase; Cell Aging; Cells; Cytometry; Data; Development; Disease; Fatty acid glycerol esters; Foundations; Functional disorder; Genetic; Goals; Histology; Human; Impairment; Ink; Intervention; LOX gene; Link; Marrow; Mediating; Mediator; Modeling; Mus; Myeloid Cells; Obesity; Osteoblasts; Osteocytes; Osteogenesis; Osteoporosis; Pathology; Phenotype; Positioning Attribute; Program Research Project Grants; Publishing; Rat Transgene; Rattus; Role; Science; Stimulus; T-Lymphocyte; Testing; Therapeutic; Transgenic Mice; Translations; age related; aged; bone; bone fracture repair; bone fragility; bone loss; bone mass; cell type; cellular targeting; drug development; drug discovery; healthspan; improved; lipid biosynthesis; mouse model; multidisciplinary; neutralizing antibody; novel; osteoprogenitor cell; parathyroid hormone (1-34); pharmacologic; prevent; promoter; response; senescence; skeletal; skeletal tissue; transgenic suicide gene; translation to humans; young woman

PROJECT 2: The Role of Cellular Senescence in Skeletal Aging – SUMMARY Khosla/Farr Project 2, “The Role of Cellular Senescence in Skeletal Aging,” tests the hypothesis that targeting senescent cells using senotherapeutic compounds can delay, prevent, or alleviate age-related bone fragility. Although our published and additional preliminary data strongly support this hypothesis, a better understanding of the mechanisms responsible for age-related skeletal dysfunction is needed to guide development and translation of senotherapeutics for osteoporosis. In this Project, we address several key, unresolved questions regarding the role of cellular senescence in mediating age-related bone loss: (1) What are the mechanisms of p16Ink4a- vs p21Cip1-driven senescence as well as that of specific senescent cell types in the bone microenvironment in causing age-related bone loss?; (2) Does clearance of senescent cells enhance the skeletal response to an anabolic stimulus?; and (3) Do senescent cells modulate fracture healing? In addition to these Project-specific questions, we will derive skeletal tissues from the common animal models in Core C (Healthspan Phenotyping) to test novel senotherapeutics from Core B (Drug Discovery & Development) for skeletal efficacy and to extend findings in mice to rats using a novel transgenic rat model (INK-ATTAC rat). We will address these questions in the context of our 3 Specific Aims: Aim 1. Define the mechanisms by which senescent cells cause age- related bone loss and marrow adiposity. Using a newly developed p21-ATTAC mouse and novel transgenic mouse, LOX-ATTAC, capable of cellular- and temporal-specific senescent cell clearance, we will test the relative contributions of (Aim 1a) p16Ink4a- vs p21Cip1-driven senescence and (Aim 1b) specific cell types in bone (myeloid cells, osteoprogenitors, osteocytes) in mediating age-related skeletal fragility and marrow fat accumulation. In Aim 1c, we will define how the SASP simultaneously inhibits bone formation and stimulates marrow adipogenesis; then, we will identify the most important SASP factors responsible using neutralizing antibodies and pharmacological approaches. Aim 2. Evaluate the impact of senescent cell clearance on anabolic skeletal therapies and fracture healing. In Aim 2a, we will determine whether clearance of senescent cells enhances the skeletal response to anabolic stimuli [intermittent PTH (1-34) and sclerostin antibody therapy]. In Aim 2b, we will test whether clearance of senescent cells impairs fracture healing in young mice but enhances fracture healing in aged mice. Aim 3. Identify and optimize interventions that alleviate senescence-related skeletal fragility in two species. In Aim 3a, we will evaluate the senotherapeutic compounds developed in Core B for skeletal efficacy using the common mouse models described in Core C. In Aim 3b, we will use the INK-ATTAC rat model common to all Projects to test whether clearing senescent cells also prevents age-related bone loss and marrow adiposity in rats, thereby evaluating the role of cellular senescence in mediating skeletal aging in a second species, therefore moving closer to human translation.

项目2：细胞衰老在骨骼衰老中的作用-总结Khosla/Farr 项目2，“细胞衰老在骨骼衰老中的作用”，测试了针对衰老的假设， 细胞使用senescent化合物可以延迟、预防或减轻与年龄相关的骨脆性。虽然我们的 已发表的和额外的初步数据强烈支持这一假设，更好地了解 需要负责与年龄相关的骨骼功能障碍的机制来指导发育和翻译 骨质疏松症的感觉疗法。在这个项目中，我们解决了几个关键的，未解决的问题， 细胞衰老在介导年龄相关性骨丢失中的作用：（1）p16 Ink 4a-vs p21 Cip 1驱动的衰老以及骨微环境中特定衰老细胞类型的衰老， 导致年龄相关的骨质流失？(2)清除衰老细胞是否能增强骨骼对 合成代谢刺激物？（3）衰老细胞是否调节骨折愈合？除此之外，具体项目 问题，我们将从核心C（Healthspan表型分析）中的常见动物模型中获得骨骼组织 测试核心B（药物发现与开发）中的新型senotherapeutics的骨骼功效，并扩展 使用新的转基因大鼠模型（INK-ATTAC大鼠）在小鼠到大鼠中的发现。我们将解决这些问题， 我们的三个具体目标的背景：目标1。明确衰老细胞导致衰老的机制- 相关的骨质流失和骨髓肥胖。使用新开发的p21-ATTAC小鼠和新的转基因小鼠， 小鼠，LOX-ATTAC，能够细胞和时间特异性衰老细胞清除，我们将测试 p16 Ink 4a- vs p21 Cip 1-驱动的衰老和（Aim 1b）特定细胞类型在 骨（骨髓细胞、骨祖细胞、骨细胞）介导年龄相关的骨骼脆性和骨髓脂肪 积累在目标1c中，我们将定义SASP如何同时抑制骨形成和刺激骨形成。 骨髓脂肪生成;然后，我们将确定最重要的SASP因子负责使用中和 抗体和药理学方法。目标2.评估衰老细胞清除对 合成代谢骨骼疗法和骨折愈合。在目标2a中，我们将确定是否清除衰老的 细胞增强骨骼对合成代谢刺激的反应[间歇性PTH（1-34）和硬化素抗体 治疗]。在目标2b中，我们将测试衰老细胞的清除是否会损害年轻小鼠的骨折愈合 但能促进老年小鼠的骨折愈合。目标3.确定和优化干预措施， 衰老相关的骨骼脆弱性在两个物种。在目标3a中，我们将评估 核心B中开发的化合物，使用核心C中描述的常见小鼠模型进行骨骼疗效研究。在 目的3b，我们将使用所有项目通用的INK-ATTAC大鼠模型来测试是否清除衰老细胞 还可以预防大鼠中与年龄相关的骨质流失和骨髓肥胖，从而评估细胞因子的作用。 衰老在第二个物种中介导骨骼衰老，因此更接近人类翻译。