Role of p21 positive senescent cells in radiation-induced skeletal injury and repair
p21阳性衰老细胞在辐射引起的骨骼损伤和修复中的作用
基本信息
- 批准号:10711159
- 负责人:
- 金额:$ 40.35万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-08-01 至 2028-04-30
- 项目状态:未结题
- 来源:
- 关键词:AP20187AcuteAdipocytesAdverse eventAffectAgingApoptosisArchitectureBiological MarkersBiology of AgingBone MarrowBone Marrow CellsCDKN2A geneCancer SurvivorCaspaseCell AgingCellsChronicClinical ResearchCre-LoxPCrossbreedingCyclin-Dependent Kinase InhibitorCytometryDNA DamageDasatinibDataDeteriorationEarly InterventionElderlyEnvironmentEnzymesExcisionFibrosisFractureFunctional disorderGene ExpressionGene Expression ProfileGenerationsGeneticGrowthGrowth FactorHematopoieticITGAM geneIn Situ HybridizationIndependent LivingInflammatoryKnowledgeLOX geneMediatingMesenchymalMouse StrainsMusMyeloid CellsNatureOsteoblastsOsteocytesOsteogenesisOsteoporosisOxidative StressPathway interactionsPatientsPatternPhenotypePhysiologicalPlasmaPopulationProteinsQuality of lifeQuercetinRNARadiationRadiation therapyRisk ReductionRoleSeminalStromal CellsTestingTimeTransgenesTransgenic MiceVisualizationWorkagedbiomarker identificationbonebone cellbone fracture repaircell typechemokinecytokinefracture riskfunctional restorationhealinginjury and repairlong term recoverynovelpharmacologicphenotypic biomarkerpreventregenerativeresponsesenescenceskeletalskeletal injurystemstressortheoriestherapeutic target
项目摘要
Project Summary/Abstract
Skeletal deterioration and related fracture risk is exacerbated in the elderly cancer survivors receiving
radiation treatment (RTx), affecting independent living, and reducing quality of life. Cellular senescence, one of
the major pathways induced following RTx-induced DNA damage, is characterized by a pro-inflammatory
senescence associated secretory phenotype (SASP, consisting of chemokines, cytokines, growth factors, matrix
degrading enzyme, etc), and is mainly regulated by cyclin dependent kinase inhibitors (CDKi’s) p16Ink4a and
p21Cip1. Till recently, it was understood that p16Ink4a and p21Cip1 co-expressed in all senescent cells and regulated
their function interchangeably. This theory however did not match with the expression pattern of p16Ink4a and
p21Cip1 post-RTx or in aging. Using gene expression and RNA in situ hybridization studies, we have recently
shown that cells express p21 or p16Ink4a in unique populations of bone marrow cells, osteoblasts, and osteocytes
independent of the expression of either senescence marker. Only a small proportion of cells express both p16Ink4a
and p21Cip1. Furthermore, we have compelling preliminary data using mass cytometry of bone cells, which
allowed us to visualize these independent unique populations of p16Ink4a and p21Cip1 expressing cells without any
coexpression of SASP, suggesting a physiological function of these CDKis. Interestingly, in a parallel analysis
in radiated bones, we identified elevated levels of Cd11b+p21+ myeloid cell population, which was accompanied
by expression of several SASP factors, thus allowing us to characterize these p21+ cells as p21+ senescent
(p21+SEN) cells. In a recent seminal finding, using transgenic mice harboring transgenes that enable the selective
elimination of either p16Ink4a or p21Cip1 expressing cells, the elimination of p21+SEN cells in the p21-ATTAC
[apoptosis through targeted activation of caspase] mice, but not the elimination of p16+SEN cells in the p16-INK-
ATTAC mice, could mitigate most of the RTx-related adverse events in bone in young mice. Whether this
approach of clearance of p21+SEN cells will work to alleviate RTx-related bone deterioration in old mice, which
have a pre-existing high burden of senescent cells, remains to be seen. Based on our compelling preliminary
data, we will test our central hypothesis that: “Acute generation of p21+SEN cells mediate RTx-related skeletal
deterioration and BMSC dysfunction, but targeted early clearance of p21+SEN cells can alleviate RTx-related
chronic skeletal deterioration and promote fracture healing”. To test our central hypothesis, our aims are: (aim
1)To identify key mechanisms that are involved in RTx-related skeletal deterioration following early clearance of
p21+SEN cells in young and aged mice, (aim 2): To assess bone architectural changes following cell specific
clearance (using our novel Cre-LoxP mice, p21-LOX-ATTAC) of p21+Cd11b+SEN myeloid cells and (aim3): To
assess if prior clearance of senescent cells pharmacologically or by genetic clearance of p21+SEN cells will
promote fracture healing. The project will address questions related to basic biology of aging and role of p21 in
skeletal cells and lay the groundwork to support the idea that an early intervention could prove effective to counter
adverse changes from RTx, and to alleviate chronic skeletal deterioration and reduce the risk of potential
fractures.
项目总结/摘要
老年癌症幸存者的骨骼恶化和相关骨折风险加剧,
放射治疗(RTx),影响独立生活,降低生活质量。细胞衰老,
RTx诱导的DNA损伤后诱导的主要途径,其特征在于促炎性
衰老相关分泌表型(SASP),包括趋化因子、细胞因子、生长因子、基质
降解酶等),并且主要受细胞周期蛋白依赖性激酶抑制剂(CDKi)p16 Ink 4a和
p21Cip1。直到最近,人们才了解p16 Ink 4a和p21 Cip 1在所有衰老细胞中共表达,并调节衰老细胞的凋亡。
它们的功能可以互换。然而,这一理论与p16 Ink 4a的表达模式不相符,
p21 Cip 1在RTx后或老化中。利用基因表达和RNA原位杂交研究,我们最近
显示细胞在骨髓细胞、成骨细胞和骨细胞的独特群体中表达p21或p16 Ink 4a,
独立于任一衰老标志物的表达。只有一小部分细胞同时表达p16 Ink 4a
p21Cip1。此外,我们有令人信服的初步数据,使用大量的骨细胞计数,
使我们能够可视化这些独立的独特的p16 Ink 4a和p21 Cip 1表达细胞群,而没有任何
SASP的共表达,表明这些CDKis的生理功能。有趣的是,在平行分析中,
在辐射骨中,我们发现Cd 11b +p21+髓样细胞群水平升高,
通过几种SASP因子的表达,从而使我们能够将这些p21+细胞表征为p21+衰老细胞,
(p21+SEN)细胞。在最近的一项开创性发现中,使用携带转基因的转基因小鼠,
消除p16 Ink 4a或p21 Cip 1表达细胞,消除p21-ATTAC中的p21+SEN细胞
[通过靶向激活半胱天冬酶的凋亡]小鼠,但不是p16-INK-1中p16+SEN细胞的消除。
ATTAC小鼠可以减轻年轻小鼠骨骼中的大多数RTx相关不良事件。这是否
清除p21+SEN细胞的方法将有助于减轻老年小鼠RTx相关的骨退化,
是否具有预先存在的高衰老细胞负担,仍有待观察。基于我们令人信服的初步证据
数据,我们将测试我们的中心假设:“p21+SEN细胞的急性产生介导RTx相关的骨骼肌损伤。
恶化和BMSC功能障碍,但靶向早期清除p21+SEN细胞可以减轻RTx相关的
慢性骨骼退化和促进骨折愈合”。为了检验我们的中心假设,我们的目标是:(目标
1)确定在早期清除RTx后与RTx相关的骨骼恶化有关的关键机制,
年轻和老年小鼠中的p21+SEN细胞(目的2):评估细胞特异性免疫后的骨结构变化,
p21+ Cd 11b +SEN骨髓细胞的清除(使用我们的新型Cre-LoxP小鼠,p21-LOX-ATTAC)和(aim 3):
评估先前通过p21+SEN细胞的遗传清除或通过p21+SEN细胞的遗传清除是否
促进骨折愈合。该项目将解决与衰老的基础生物学和p21在衰老中的作用有关的问题。
骨骼细胞,并奠定基础,以支持这一想法,即早期干预可以证明有效地对抗
RTx的不利变化,并缓解慢性骨骼恶化和降低潜在的风险
骨折
项目成果
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