Skeletal Fragility

骨骼脆弱

• 批准号: 10349486
• 负责人: Sundeep Khosla
• 金额: $ 51.41万
• 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 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10349486
• 关键词: Address; Age; Age-Related Bone Loss; Aging; Animal Model; Antibody Therapy; Apoptosis; B-Lymphocytes; Biopsy; 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 of activation protein; Modeling; Mus; Myeloid Cells; Obesity; Osteoblasts; Osteocytes; Osteogenesis; Osteoporosis; Pharmacology; Phenotype; Positioning Attribute; Program Research Project Grants; Publishing; Rattus; Role; Science; Stimulus; T-Lymphocyte; Testing; Therapeutic; Time; Transgenic Mice; Transgenic Organisms; Translations; age related; aged; base; bone; bone fracture repair; bone fragility; bone loss; bone mass; cell type; cellular pathology; cellular targeting; drug development; drug discovery; healthspan; improved; lipid biosynthesis; mouse model; multidisciplinary; neutralizing antibody; novel; osteoprogenitor cell; parathyroid hormone (1-34); 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：细胞敏感在骨骼老化中的作用 - 摘要Khosla/Farr 项目2，“细胞衰老在骨骼衰老中的作用”，检验了靶向感觉的假设 使用鼻疗法化合物的细胞可以延迟，预防或减轻与年龄相关的骨骼脆弱性。虽然我们的 已发布和其他初步数据强烈支持这一假设，更好地理解 需要针对年龄相关的骨骼功能障碍的机制来指导开发和翻译 用于骨质疏松症的鼻疗法。在这个项目中，我们解决了有关的几个关键，尚未解决的问题 细胞敏感在介导与年龄相关的骨质流失中的作用：（1） P21CIP1驱动的感应以及骨微环境中特定的感应细胞类型的感应 导致与年龄有关的骨质流失？ （2）清除感觉细胞会增强对 合成代谢刺激？ （3）感觉细胞是否调节断裂愈合？除了这些特定项目 问题，我们将从核心C（HealthSpan表型）中的常见动物模型中得出骨骼组织 测试来自核心B（药物发现与开发）的新型鼻疗法，以提高骨骼效率并扩展 使用新型转基因大鼠模型（Ink-Attac大鼠）向大鼠的小鼠发现。我们将在 我们3个特定目标的背景：目标1。定义感觉细胞引起年龄的机制。 相关的骨质流失和骨髓肥胖。使用新开发的P21-ATTAC小鼠和新型转基因 小鼠，LOX-ATTAC，能够具有细胞和临时特异性感觉细胞清除率，我们将测试 （AIM 1A）P16INK4A-与P21CIP1驱动的感应和（AIM 1B）特定细胞类型的相对贡献 中介与年龄相关的骨骼脆弱性和骨髓脂肪中的骨（髓样细胞，骨基因，骨细胞） 积累。在AIM 1C中，我们将定义SASP如何简单地抑制骨形成并刺激 骨髓成生成；然后，我们将使用中和确定负责的最重要的SASP因素 抗体和药理方法。目标2。评估感觉细胞清除对 合成代谢骨骼疗法和骨折愈合。在AIM 2A中，我们将确定是否清除感觉 细胞增强对合成代谢刺激的骨骼反应[间歇性PTH（1-34）和硬化蛋白抗体 治疗]。在AIM 2B中，我们将测试清除感觉细胞是否会损害年轻小鼠的断裂愈合 但可以增强老年小鼠的骨折愈合。目标3。确定并优化减轻干预措施 两个物种中与感应相关的骨骼脆弱性。在AIM 3A中，我们将评估替代性 使用CoreC中描述的常见小鼠模型在Core B中开发的化合物，用于骨骼效率。 AIM 3B，我们将使用所有项目共有的Ink-Attac大鼠模型来测试是否清除感觉细胞 还可以防止大鼠与年龄相关的骨质流失和骨髓肥胖，从而评估了细胞的作用 在第二种物种中介导骨骼老化的衰老，因此更接近人类的翻译。