BCCMA: Foundational Research to Act Upon and Resist Conditions Unfavorable to Bone (FRACTURE CURB): Role of Hypertension in Favoring Osteoporosis
BCCMA:针对和抵抗不利于骨骼的条件(骨折遏制)的基础研究:高血压在促进骨质疏松症中的作用
基本信息
- 批准号:10483572
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-10-01 至 2026-09-30
- 项目状态:未结题
- 来源:
- 关键词:AddressAdultAffectAgeAge YearsAgingAmlodipineAnabolismAngiotensin IIAnimalsBloodBlood PressureBlood VesselsBone MarrowBone RegenerationBone ResorptionBone callusCalcium Channel BlockersCartilageCatecholaminesCell CountCell LineCellsChronicChronic DiseaseClinicalClinical ManagementClinical ResearchCollaborationsCombined Modality TherapyCytoprotectionDOCADiabetes MellitusDiagnosisDiseaseDisease modelDual-Energy X-Ray AbsorptiometryEarly DiagnosisEndothelial CellsEngineeringEnsureEstrogen deficiencyEstrogensEuthanasiaFemaleFractureGene ExpressionGene ProteinsGoalsGonadal Steroid HormonesHealthHealth PersonnelHip FracturesHospitalsHypertensionImplantInflammatoryInjectionsKnock-outLeadLinkLongevityLoxP-flanked alleleMacrophage Colony-Stimulating FactorMacrophage Colony-Stimulating Factor ReceptorMarrowMechanicsMediatorMedicalMetabolismModelingMonitorMorbidity - disease rateMouse StrainsMusMusculoskeletal PainOperative Surgical ProceduresOrchiectomyOsteoblastsOsteocytesOsteogenesisOsteoporosisOsteoporosis preventionOutcomeOutcome MeasureOvariectomyPTH genePathway interactionsPatientsPopulationPositioning AttributePre-Clinical ModelPredispositionPrevalencePreventionPrevention approachProductionResearchResearch PersonnelResistanceRiskRoleServicesSignal PathwaySignal TransductionSodium ChlorideSourceTailTamoxifenTechniquesTestingTestosteroneTherapeuticTimeTissuesUnited States Department of Veterans AffairsUrineVeteransage relatedagedblood pressure reductionbonebone cellbone fracture repairbone healthbone lossbone massbone qualitybone repairbone strengthcadherin 5cytokinedentin matrix protein 1experimental studyfracture riskfragility fracturehormonal signalshypertensiveimprovedin vitro Modelin vivoinducible Creinhibitorinnovationinsightloss of functionmalemilitary veteranmortalitymouse Cre recombinasemouse modelnegative affectnormotensivenovelnovel strategiesnovel therapeutic interventionosteoclastogenesisosteoporosis with pathological fracturepre-clinicalpreventprotein expressionresearch studysexside effecttooltranslatable strategytranslational studytreatment effecttreatment grouptreatment strategyurinary
项目摘要
To ensure aging Veterans remain active and mobile with as little musculoskeletal pain as possible, new
approaches to the prevention of osteoporosis and promotion of timely bone regeneration following a fracture are
necessary. This collaborative research study brings together a group of VA investigators with diverse
perspectives, insights, models, and techniques, to synergistically attack a major clinical problem that leads to
high morbidity and mortality among Veterans, a bone fracture. The overall research strategy of each integrated
project is to use pre-clinical models of a disease that either weakens bone or delays bone repair, to investigate
novel ways to enhance the ability of parathyroid hormone (PTH) to promote bone formation, and to assess
disease and treatment effects on bone in a unified, stringent manner. Already under-diagnosed and under-
treated, osteoporosis is likely to increase the number of fragility fractures being treated at VA hospitals without
novel tools for early detection and novel treatment strategies that circumvent the rare but devastating side effects
of current therapies that inhibit bone loss. Addressing this unmet clinical need, the overall aims are to identify
therapeutic strategies to improve bone health among Veterans and to enhance the bone anabolism of PTH
signaling. The collaboration will address this overarching hypothesis: health problems disproportionately
affecting Veterans activate signaling pathways that increase bone resorption, suppress bone formation, or
impede the transition of cartilage to bone in a fracture callus such that improvements in the clinical management
of osteoporosis lie in understanding how these health problems hurt bone health. This project recognizes that
hypertension and osteoporosis often develop together as patients grow older beyond 50 years of age and that
female and male Veterans are susceptible to both chronic diseases. Based on our preliminary studies of what
happens to bone in standard pre-clinical mouse models of hypertension, we will investigate a mechanism by
which hypertension weakens bone with the ultimate goal of identifying a new therapeutic strategy in the
prevention of osteoporosis. Specifically, the first aim of the project will be to test the hypothesis that sex steroids,
namely estrogen and testosterone, influence the decline in bone mass and bone quality that occurs with the
onset of hypertension. Achieving this goal involves assessing the relative effect of estrogen deficiency (or
testosterone deficiency) and hypertension on the fracture resistance of mouse bone. Furthermore, by
investigating treatment and surgery effects on gene and protein expression in bone and bone marrow, on
markers of bone resorption and bone formation, and on the number and activity of bone cells, the project will
provide insight into how rising blood pressure and rising sympathetic tone negatively affects bone. In the second
aim, we will ascertain whether an inflammatory factor known as colony stimulating factor 1 (CSF1) is a major
mediator of bone loss in hypertension and do so with respect to the cellular source of this cytokine. Doing so
requires the induction of hypertension in 2 different mouse strains engineered to either prevent bone forming
(mature osteoblasts) and bone sensing cells (osteocytes) from producing CSF1 or preventing cells lining blood
vessels (endothelial cells) from producing CSF1. Transitioning from mechanic studies to translational studies,
we will determine whether inhibiting CSF1 signaling in combination with intermittent parathyroid hormone
treatment, an approved therapy for osteoporosis, and/or with a calcium channel blocker, an approved therapy
for hypertension, improves the fracture resistance of bone in aged, hypertensive mice. In all these aims, the
assessment of fracture resistance is comprehensive going beyond bone mass and bone volume to include the
matrix. By understanding how hypertension affects bone and by working as a collaborative research team, new
therapeutic strategies will be sought to prevent the age-related increase in fracture risk. This is needed because
osteoporotic fractures lead to many complications in Veteran population and because osteoporosis is
underdiagnosed and undertreated.
为了确保老年退伍军人保持活跃和移动尽可能少的肌肉骨骼疼痛,新的
项目成果
期刊论文数量(0)
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Jeffry Stephen Nyman其他文献
Jeffry Stephen Nyman的其他文献
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{{ truncateString('Jeffry Stephen Nyman', 18)}}的其他基金
Validation of pre-clinical models of musculoskeletal healing following trauma
创伤后肌肉骨骼愈合的临床前模型的验证
- 批准号:
10392328 - 财政年份:2021
- 资助金额:
-- - 项目类别:
Validation of pre-clinical models of musculoskeletal healing following trauma
创伤后肌肉骨骼愈合的临床前模型的验证
- 批准号:
10618789 - 财政年份:2021
- 资助金额:
-- - 项目类别:
Advancing Raman spectroscopy toward the clinical assessment of bone quality
推动拉曼光谱应用于骨质量的临床评估
- 批准号:
9752446 - 财政年份:2018
- 资助金额:
-- - 项目类别:
Effects of Sodium-dependent Glucose Co-transporter 2 Inhibition on Bone.
钠依赖性葡萄糖协同转运蛋白 2 抑制对骨的影响。
- 批准号:
9193426 - 财政年份:2016
- 资助金额:
-- - 项目类别:
Effects of Sodium-dependent Glucose Co-transporter 2 Inhibition on Bone.
钠依赖性葡萄糖协同转运蛋白 2 抑制对骨的影响。
- 批准号:
9304883 - 财政年份:2016
- 资助金额:
-- - 项目类别:
The Role of Tissue Matrix in the Fracture Resistance of Diabetic Bone
组织基质在糖尿病骨抗骨折中的作用
- 批准号:
9317431 - 财政年份:2016
- 资助金额:
-- - 项目类别:
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