Common Inflammation Pathways between Aging and Hypertension That Weaken Bone

衰老和高血压之间削弱骨骼的常见炎症途径

• 批准号: 10618349
• 负责人: David G Harrison
• 金额: $ 51.41万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-15 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10618349
• 关键词: Adult; Affect; Age; Age-Related Bone Loss; Aging; American Heart Association; Animals; Antibodies; Biological Assay; Biology; Blood Pressure; Blood Pressure Monitors; Bone Marrow; Bone Resorption; Bone remodeling; Cell Culture Techniques; Cell Differentiation process; Cells; Cessation of life; Clinical Pharmacology; Coculture Techniques; Collaborations; Communication; Data; Dendritic Cells; Denervation; Deterioration; Diagnosis; Disease; Disease model; Early Diagnosis; Early treatment; Economic Burden; Endothelial Cells; Endothelium; Enterobacteria phage P1 Cre recombinase; Estrogens; Exposure to; Fracture; Genes; Goals; Health; Hematopoietic; Hip Fractures; Human; Hypertension; IL17 gene; Immune; Individual; Inflammation; Inflammatory; Interleukins; Longevity; Macrophage; Macrophage Colony-Stimulating Factor; Measurement; Mechanical Stimulation; Mechanics; Mediating; Mediator; Menopause; Methodology; Modeling; Molecular; Mus; Mutant Strains Mice; Myeloid Cell Activation; Myeloid Cells; Myelopoiesis; Osteoblasts; Osteoclasts; Osteoporosis; Osteoporosis prevention; Pathway interactions; Patients; Persons; Phenotype; Play; Positioning Attribute; Pre-Clinical Model; Prevention strategy; Production; Qualifying; Quality of life; Recombinant Proteins; Research; Resistance; Role; Signal Transduction; Societies; Source; Stimulus; Stretching; Structure; Sympathetic Nervous System; Systemic hypertension; T cell transcription factor 1; T-Cell Activation; Techniques; Technology; Testing; Vascular Endothelium; Vascular remodeling; Withdrawal; Work; age related; aged; antagonist; arteriole; blood pressure elevation; blood pressure reduction; bone; bone loss; bone mass; bone quality; bone strength; cytokine; designer receptors exclusively activated by designer drugs; experimental study; fracture risk; fragility fracture; hypertensive; immune activation; improved; inducible Cre; long bone; mature animal; mechanical force; monocyte; mouse model; multidisciplinary; neutralizing antibody; new therapeutic target; novel; novel therapeutic intervention; postnatal; premature; prevent; receptor; release factor; response; skills; success; tool; translatable strategy; translational goal; treatment strategy; vasoconstriction; venule

Project Summary / Abstract Osteoporosis is under diagnosed and under treated. It is essential that we develop novel tools for early detection and treatment strategies to reduce the number of fragility fractures that accompany aging. Systemic hypertension is another disease of aging that commonly co-exists with osteoporosis and likely predisposes individuals to the disease. In this multidisciplinary project, we will investigate a common molecular basis between hypertension and osteoporosis that weakens bone during aging. Our preliminary data indicate that experimental hypertension involving mice is associated with a striking loss in bone strength, which is mediated in part by the production of colony stimulating factor 1 (CSF1) in the bone marrow. The first goal of the project will be to test the hypothesis that enhanced endothelial cell deformation and elevated blood pressure promote the age-related decline in bone strength. We will employ cell culture experiments in which endothelial cells are dynamically stretched below human monocytes with and without exogenous recombinant proteins to determine if factors released by the activated endothelium promote osteoclast differentiation. In addition, we will lower blood pressure of aged mice and determine if this improves bone strength by reducing inflammatory cytokines that favor bone resorption. The second goal will be to test the hypothesis that enhanced sympathetic tone in aging and hypertension promotes immune activation and bone loss. We are experts at modulating sympathetic tone using a technique called Designer Receptor Exclusively Activated by Designer Drugs and by local denervation techniques. Thus, we will increase sympathetic tone to determine if this mimics the age-related decline in bone strength and decrease sympathetic tone to determine if this prevents hypertension and aging-induced loss in bone strength. The third goal will be to delete the endothelial CSF1 gene in adult mice to firmly establish the endothelium as a mediator of osteoporosis. Finally, our prior work has established a critical role of the cytokine interleukin (IL) 17A in hypertension, and others have shown that it plays a critical role in bone loss due estrogen withdrawal (menopause). We will therefore generate mutant mice that will allow deletion of IL17 receptor A in adult mice and determine if this prevents hypertension-related bone loss. As a translational goal, we will treat aged or hypertensive mice with a control antibody and vehicle, a neutralizing anti-CSF1 antibody, or an IL-17RA antagonist and determine if these strategies improve bone strength. In all aims we will 1) monitor blood pressure and bone mass, 2) assess immune cell profiles in the bone marrow, and 3) comprehensively characterize bone strength including toughness and other bone quality measurements. By understanding how hypertension affects bone marrow in the context of aging and by working as a collaborative research team comprised of different skill sets, new therapeutic strategies can be identified to prevent the age-related increase in fracture risk.

项目总结/摘要 骨质疏松症的诊断和治疗不足。我们必须开发新的早期检测工具， 和治疗策略，以减少伴随衰老的脆性骨折的数量。系统性高血压 是另一种通常与骨质疏松症共存的衰老疾病， 疾病在这个多学科的项目中，我们将研究高血压之间的共同分子基础， 以及在衰老过程中削弱骨骼的骨质疏松症。我们的初步数据表明实验性高血压 涉及小鼠与骨强度的显著损失有关，这部分是由 骨髓中的集落刺激因子1（CSF 1）。该项目的第一个目标将是测试假设 增强的内皮细胞变形和升高的血压促进了与年龄相关的骨衰退， 实力我们将采用细胞培养实验，其中内皮细胞在下面动态拉伸， 用和不用外源性重组蛋白的人单核细胞，以确定是否由 活化内皮细胞促进破骨细胞分化。此外，我们将降低老年小鼠的血压 并确定这是否通过减少有利于骨吸收的炎性细胞因子来改善骨强度。的 第二个目标将是检验衰老和高血压中交感神经张力增强促进 免疫激活和骨质流失。我们是调节交感神经张力的专家， 设计者受体仅由设计者药物和局部去神经技术激活。因此，我们将 增加交感神经张力，以确定这是否模拟骨强度的年龄相关性下降， 交感神经紧张，以确定这是否防止高血压和老化引起的骨强度损失。第三 我们的目标将是删除成年小鼠的内皮细胞CSF 1基因，以牢固地建立内皮细胞作为介体 骨质疏松症最后，我们先前的工作已经确定了细胞因子白细胞介素（IL）17 A在 高血压，以及其他研究表明，它在由于雌激素戒断引起的骨质流失中起着关键作用 （更年期）。因此，我们将产生允许在成年小鼠中缺失IL 17受体A的突变小鼠 并确定这是否能防止高血压相关的骨质流失。作为一个转化目标，我们将治疗老年人或 用对照抗体和媒介物、中和性抗CSF 1抗体或IL-17 RA治疗高血压小鼠 拮抗剂，并确定这些策略是否改善骨强度。在所有目标中，我们将1）监测血压 和骨量，2）评估骨髓中的免疫细胞谱，和3）全面表征骨 强度，包括韧性和其他骨质量测量。通过了解高血压如何影响 骨髓在老龄化的背景下，并作为一个合作的研究团队，包括不同的技能， 因此，可以确定新的治疗策略来预防与年龄相关的骨折风险增加。