Serotonin and Skeletal Health
血清素和骨骼健康
基本信息
- 批准号:10674962
- 负责人:
- 金额:$ 72.2万
- 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:2022-08-01 至 2027-07-31
- 项目状态:未结题
- 来源:
- 关键词:AcuteAdrenergic beta-AntagonistsAdultAffectAffinityAgingAmericanAnimalsAntidepressive AgentsAreaBasic ScienceBiological AssayBiopsyBody CompositionBody measure procedureBone DensityBone ResorptionBrainCategoriesChronicClinical ResearchCommunitiesDataDeteriorationDrug usageElderlyFluoxetineFractureGene ExpressionGoalsHealthHeightHip region structureHumanMeasurementMediatingMental DepressionMeta-AnalysisMolecularMusMuscleMuscle functionMusculoskeletalMusculoskeletal DevelopmentMusculoskeletal SystemNorepinephrineNot Hispanic or LatinoObservational StudyOsteoblastsOsteogenesisParticipantPeripheralPharmaceutical PreparationsPhysical FunctionPhysical PerformancePhysical activityPorosityPostmenopauseProliferatingPsychotherapyPublishingRadialResolutionResourcesRiskRoentgen RaysRoleSafetySelective Serotonin Reuptake InhibitorSerotoninSiteSkeletal DevelopmentStructureSympathetic Nervous SystemTimeTissuesTrabecular Bone ScoreTractionTranslatingVertebral columnWashingtonWomanWorkX-Ray Computed Tomographyantidepressant effectbonebone healthbone lossbone massbone metabolismbone turnovercohortcomorbidityfallsfracture riskhigh riskhuman datahuman old age (65+)indexinginhibitorinsightinterdisciplinary approachmouse modelmulti-ethnicmultimodalitymuscle formnovelosteoblast differentiationosteoblast proliferationosteoporosis with pathological fracturepopulation basedpost strokepreventprimary outcomereuptakescreeningserotonin transporterskeletaltreatment strategy
项目摘要
Serotonin is a key regulator of bone metabolism in animals. Murine models show that central (brain) serotonin
positively regulates bone mass by inhibiting the deleterious effects of the sympathetic nervous system on
osteoblasts. In mice, selective serotonin reuptake inhibitors (SSRIs) have time-dependent effects. Acutely,
SSRIs directly inhibit osteoclastic bone resorption, but with chronic use the central effect of SSRIs predominate
causing bone loss by increasing sympathetic nervous system (SNS) tone, which counteracts the early effects
on resorption and reduces bone formation. In contrast, the role of endogenous serotonin in regulating human
skeletal health is not well delineated. Recent work, however, indicates that (SSRIs) increase the risk of fracture
by two times, but the mechanisms by which SSRIs do so in humans have not been clearly defined. Most
human studies have focused on assessing areal bone mineral density and have not considered the important
time-dependent effects of SSRIs, which has led to conflicting data. The effects of SSRIs on muscle function,
which may also contribute to fracture risk, have only started to be explored. We have begun to make progress
in this area using a multimodal approach with dual x-ray absorptiometry (DXA), high-resolution peripheral
quantitative computed tomography (HRpQCT), body composition and measurement of physical function. Our
data indicate this is a useful approach. Our recent work shows antidepressant use is associated with reduced
physical performance as well as cortical deterioration, the latter of which can be detected with DXA and HR-
pQCT. Supporting a role for serotonin in particular, participants taking antidepressants with moderate or high
affinity for the serotonin transporter (such as SSRIs and serotonin norepinephrine reuptake inhibitors) had
cortical deficits that were not present in those using other categories of antidepressants. Utilizing, DXA
HRpQCT, transiliac bone biopsy as well as novel assays assessing osteoblast proliferation, differentiation and
gene expression, the goal of this proposal is to determine if the tissue, cellular and molecular mechanisms by
which SSRIs act on the musculoskeletal system in humans is analogous to those demonstrated in murine
models. The overarching hypothesis of this proposal is that chronic use of SSRIs and antidepressants with
high/moderate serotonin transporter affinity decrease bone formation by increasing sympathetic tone, which
leads to bone loss and fracture. Effects on muscle mass and function will also be investigated. This work will
help elucidate the role of serotonin as a regulator of human musculoskeletal health and guide the development
of musculoskeletal screening and treatment strategies in those taking SSRIs and other antidepressants.
Because long-term SSRI use is common, detrimental effects on skeletal health are important to elucidate and
mitigate. Moreover, doing so may provide insight into targetable human musculoskeletal regulators.
血清素是动物骨代谢的关键调节因子。小鼠模型显示,中枢(大脑)血清素
通过抑制交感神经系统的有害作用,
成骨细胞在小鼠中,选择性5-羟色胺再摄取抑制剂(SSRIs)具有时间依赖性作用。很明显,
SSRIs直接抑制骨吸收,但长期使用SSRIs的中枢作用占主导地位
通过增加交感神经系统(SNS)张力导致骨丢失,这抵消了早期效应
并减少骨形成。与此相反,内源性5-羟色胺在调节人体免疫功能中的作用,
骨骼健康没有得到很好的描述。然而,最近的研究表明,(SSRIs)增加骨折的风险
但SSRIs在人类中发挥作用的机制尚未明确。最
人类研究集中在评估骨密度,没有考虑重要的
SSRIs的时间依赖性效应,这导致了相互矛盾的数据。SSRIs对肌肉功能的影响,
这也可能导致骨折的风险,才刚刚开始探索。我们已经开始取得进展
在该领域,使用双X射线吸收测定法(DXA)、高分辨率外周血多模式方法
定量计算机断层扫描(HRpQCT)、身体成分和身体功能测量。我们
数据表明这是一种有用的方法。我们最近的研究表明,抗抑郁药的使用与减少
身体表现以及皮质退化,后者可以用DXA和HR检测到-
pQCT。特别是支持血清素的作用,参与者服用抗抑郁药,
5-羟色胺转运蛋白(如SSRIs和5-羟色胺去甲肾上腺素再摄取抑制剂)的亲和力
使用其他类别抗抑郁药的患者中不存在的皮质缺陷。利用,DXA
HRpQCT、经髂骨骨活检以及评估成骨细胞增殖、分化和增殖的新测定,
基因表达,该提案的目标是确定组织,细胞和分子机制,
SSRIs对人体肌肉骨骼系统的作用类似于在小鼠中证实的那些。
模型这项建议的首要假设是,长期使用SSRIs和抗抑郁药,
高/中等5-羟色胺转运体亲和力通过增加交感神经张力而降低骨形成,
导致骨质流失和骨折。还将研究对肌肉质量和功能的影响。这项工作将
有助于阐明血清素作为人体肌肉骨骼健康调节剂的作用,并指导
在服用SSRIs和其他抗抑郁药的人群中进行肌肉骨骼筛查和治疗策略。
由于长期使用SSRI是常见的,对骨骼健康的有害影响是重要的,
减轻。此外,这样做可能会提供深入了解有针对性的人类肌肉骨骼调节。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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MARCELLA Donovan WALKER其他文献
MARCELLA Donovan WALKER的其他文献
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{{ truncateString('MARCELLA Donovan WALKER', 18)}}的其他基金
Skeletal Microstructure - Racial Differences and Genetic Contributors
骨骼微观结构 - 种族差异和遗传因素
- 批准号:
10210189 - 财政年份:2018
- 资助金额:
$ 72.2万 - 项目类别:
Skeletal Microstructure - Racial Differences and Genetic Contributors
骨骼微观结构 - 种族差异和遗传因素
- 批准号:
10456808 - 财政年份:2018
- 资助金额:
$ 72.2万 - 项目类别:
Skeletal Microstructure - Racial Differences and Genetic Contributors
骨骼微观结构 - 种族差异和遗传因素
- 批准号:
9975705 - 财政年份:2018
- 资助金额:
$ 72.2万 - 项目类别:
Skeletal Microstructure - Racial Differences and Genetic Contributors
骨骼微观结构 - 种族差异和遗传因素
- 批准号:
9469037 - 财政年份:2018
- 资助金额:
$ 72.2万 - 项目类别:
Primary Hyperparathyroidism: Neurocognitive Features
原发性甲状旁腺功能亢进症:神经认知特征
- 批准号:
8967918 - 财政年份:2015
- 资助金额:
$ 72.2万 - 项目类别:
Aspects of Bone Quality Among Chinese American Women
华裔美国女性骨骼质量的各个方面
- 批准号:
8071102 - 财政年份:2007
- 资助金额:
$ 72.2万 - 项目类别:
Aspects of Bone Quality Among Chinese American Women
华裔美国女性骨骼质量的各个方面
- 批准号:
7843694 - 财政年份:2007
- 资助金额:
$ 72.2万 - 项目类别:
Aspects of Bone Quality Among Chinese American Women
华裔美国女性骨骼质量的各个方面
- 批准号:
7439166 - 财政年份:2007
- 资助金额:
$ 72.2万 - 项目类别:
Aspects of Bone Quality Among Chinese American Women
华裔美国女性骨骼质量的各个方面
- 批准号:
7625064 - 财政年份:2007
- 资助金额:
$ 72.2万 - 项目类别: