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.

项目概要/摘要 骨质疏松症的诊断和治疗不足。我们必须开发用于早期检测的新颖工具 以及减少伴随衰老的脆性骨折数量的治疗策略。全身性高血压 是另一种通常与骨质疏松症共存的衰老疾病，并且可能使个体易患骨质疏松症 疾病。在这个多学科项目中，我们将研究高血压之间的共同分子基础 以及在衰老过程中骨质疏松症会削弱骨骼。我们的初步数据表明，实验性高血压 小鼠的骨强度显着下降与骨强度的显着下降有关，这部分是通过产生 骨髓中的集落刺激因子 1 (CSF1)。该项目的首要目标是检验假设 内皮细胞变形增强和血压升高会促进与年龄相关的骨质衰退 力量。我们将采用细胞培养实验，其中内皮细胞在下方动态拉伸 含有或不含外源重组蛋白的人单核细胞，以确定是否由 活化的内皮促进破骨细胞分化。此外，我们还会降低老年小鼠的血压 并确定这是否可以通过减少有利于骨吸收的炎症细胞因子来提高骨强度。这 第二个目标是检验这样的假设：衰老和高血压中交感神经张力的增强会促进 免疫激活和骨质流失。我们是使用一种称为“调节交感神经张力”的技术来调节交感神经张力的专家。 设计受体仅由设计药物和局部去神经技术激活。这样，我们将 增加交感神经张力以确定这是否模仿了与年龄相关的骨强度下降和减少 交感神经张力以确定这是否可以预防高血压和衰老引起的骨强度损失。第三个 目标是删除成年小鼠的内皮 CSF1 基因，以牢固地建立内皮作为介质 骨质疏松症。最后，我们之前的工作已经确定了细胞因子白细胞介素 (IL) 17A 在 高血压等研究表明，它在雌激素撤退导致的骨质流失中起着至关重要的作用 （绝经）。因此，我们将产生突变小鼠，从而在成年小鼠中删除 IL17 受体 A 并确定这是否可以预防与高血压相关的骨质流失。作为转化目标，我们将治疗老年人或 使用对照抗体和媒介物、中和性抗 CSF1 抗体或 IL-17RA 的高血压小鼠 拮抗剂并确定这些策略是否可以提高骨强度。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特征，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 衰老背景下的骨髓以及作为由不同技能组成的协作研究团队的工作 集，可以确定新的治疗策略，以防止与年龄相关的骨折风险增加。