Senescence and Salivary Gland Dysfunction
衰老和唾液腺功能障碍
基本信息
- 批准号:10892708
- 负责人:
- 金额:$ 38.72万
- 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:2023-09-01 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:3-DimensionalAbateAblationAddressAdoptedAffectAgeAutoimmune DiseasesAutomobile DrivingCell AgingCell Differentiation processCell ProliferationCell secretionCellsChronicComplexCytokine GeneDental cariesDepositionDevelopmentDiseaseDrug ModelingsDuct (organ) structureEpithelial CellsEpitheliumExocrine GlandsExperimental ModelsExtracellular MatrixEyeFemaleFibrosisFluids and SecretionsFunctional disorderGanciclovirGene ExpressionGeneticGlandGrowth FactorHalitosisHead and Neck CancerHealthHomeostasisHumanImmuneImmune System DiseasesIn Situ HybridizationInbred NOD MiceIncidenceInflammationInflammatoryInflammatory ResponseIronLabelLacrimal gland structureLigationLinkLongevityMediatingMethodsMicroRNAsModelingMusNormal CellOperative Surgical ProceduresOral cavityOrganOrgan PreservationOrganoidsPathologyPatientsPeptide HydrolasesPharmaceutical PreparationsPhenotypePopulationPremature aging syndromeProcessProductionQuality of lifeRNARNA SequencesRadiation therapyRegulationReportingRiskRisk FactorsSalivaSalivarySalivary GlandsSeveritiesSignal TransductionSjogren&aposs SyndromeSymptomsTestingTissuesUntranslated RNAWomanWorkXerostomiaage relatedagedautoimmune exocrinopathycell typecomorbiditycytokinedefined contributioneye drynessfunctional lossfunctional restorationin vivoinnovationloss of functionmalemouse modelnanoparticlenormal agingnovelorgan injuryparacrinepreventprogramsradiation responseresponsesenescenceside effectsingle cell sequencingstem cell populationsuicide genetherapeutic RNAtissue degenerationtissue injurytumorwound healing
项目摘要
ABSTRACT
Hyposalivation can result from the normal aging process, a side-effect of radiation therapy (RT), and a symptom of
autoimmune disease leading to a variety of negative sequelae including increased incidence of dental caries, halitosis, and
reduced digestive function. Sjögren’s Syndrome (SS) is an autoimmune exocrinopathy affecting the salivary glands,
lacrimal glands, and other exocrine organs in 0.4% of the US population, with most patients being women over 40 (9:1
female to male ratio). The primary deficit underlying SS is the loss of functional secretory epithelium in exocrine glands.
The mechanisms leading to loss of function are complex and multifactorial but include both immune-dependent and
immune-independent pathologies that extend to normal aging and RT. Cellular senescence is an important tumor-
constraining mechanism that halts cellular proliferation and has positive impacts on wound healing but, when activated
chronically, can exacerbate tissue injury and loss of function. Recent work demonstrated that senescent cells accumulate in
the salivary glands of SS patients, because of RT, and during normal aging. How cellular senescence contributes to salivary
hypofunction in SS and other conditions is incompletely understood. Senescent cells that accumulate with age adopt a
senescence-associated secretory phenotype (SASP) characterized by the secretion of cytokines, growth factors, and
proteases that disrupt tissue homeostasis and contribute to age-related pathologies. SASP is causally linked to tissue
degeneration by paracrine effects on neighboring cells, and genetic ablation of senescent cells can preserve organ function
by limiting SASP. Similarly, senolytic drugs that systemically ablate senescent cells can increase general health and lifespan
in mice. Minimization of SASP may limit the amplitude and duration of the inflammatory response, restrict the loss of
exocrine function, and delay disease-related organ decline. We have identified several microRNAs that control SASP and
inflammatory cytokine gene expression that can be used as targets to limit the activity of senescent cells. The studies detailed
here will test the hypothesis that senescence promotes non-resolving inflammation in SS-like disease to drive salivary gland
hypofunction. We will test our hypothesis by selective modulation of the senescence program in both organoid-based and
murine models of salivary gland hypofunction. We propose to address the following specific aims: 1. Define the
contribution of senescence- and Sjögren’s Syndrome-associated miRNAs in SASP regulation. Aim 2. Determine if
ablation of senescent cells or targeting of miRNAs promoting SASP can reduce non-resolving inflammation and
fibrosis in vivo. 3. Define the contribution of the senescent cell SASP to SS disease development. This study will further
our understanding of the link between senescence, inflammation, and salivary gland hypofunction. Studies comparing
genetic and RNA-mediated methods for senescent cell abatement and antagomiRs for SASP phenotype modulation will
reveal potential RNA-based therapeutic strategies for the functional restoration of salivary glands of SS patients and other
aged or injured organs.
ABSTRACT
Hyposalivation can result from the normal aging process, a side-effect of radiation therapy (RT), and a symptom of
autoimmune disease leading to a variety of negative sequelae including increased incidence of dental caries, halitosis, and
reduced digestive function. Sjögren’s Syndrome (SS) is an autoimmune exocrinopathy affecting the salivary glands,
lacrimal glands, and other exocrine organs in 0.4% of the US population, with most patients being women over 40 (9:1
female to male ratio). The primary deficit underlying SS is the loss of functional secretory epithelium in exocrine glands.
The mechanisms leading to loss of function are complex and multifactorial but include both immune-dependent and
immune-independent pathologies that extend to normal aging and RT. Cellular senescence is an important tumor-
constraining mechanism that halts cellular proliferation and has positive impacts on wound healing but, when activated
chronically, can exacerbate tissue injury and loss of function. Recent work demonstrated that senescent cells accumulate in
the salivary glands of SS patients, because of RT, and during normal aging. How cellular senescence contributes to salivary
hypofunction in SS and other conditions is incompletely understood. Senescent cells that accumulate with age adopt a
senescence-associated secretory phenotype (SASP) characterized by the secretion of cytokines, growth factors, and
proteases that disrupt tissue homeostasis and contribute to age-related pathologies. SASP is causally linked to tissue
degeneration by paracrine effects on neighboring cells, and genetic ablation of senescent cells can preserve organ function
by limiting SASP. Similarly, senolytic drugs that systemically ablate senescent cells can increase general health and lifespan
in mice. Minimization of SASP may limit the amplitude and duration of the inflammatory response, restrict the loss of
exocrine function, and delay disease-related organ decline. We have identified several microRNAs that control SASP and
inflammatory cytokine gene expression that can be used as targets to limit the activity of senescent cells. The studies detailed
here will test the hypothesis that senescence promotes non-resolving inflammation in SS-like disease to drive salivary gland
hypofunction. We will test our hypothesis by selective modulation of the senescence program in both organoid-based and
murine models of salivary gland hypofunction. We propose to address the following specific aims: 1. Define the
contribution of senescence- and Sjögren’s Syndrome-associated miRNAs in SASP regulation. Aim 2. Determine if
ablation of senescent cells or targeting of miRNAs promoting SASP can reduce non-resolving inflammation and
fibrosis in vivo. 3. Define the contribution of the senescent cell SASP to SS disease development. This study will further
our understanding of the link between senescence, inflammation, and salivary gland hypofunction. Studies comparing
genetic and RNA-mediated methods for senescent cell abatement and antagomiRs for SASP phenotype modulation will
reveal potential RNA-based therapeutic strategies for the functional restoration of salivary glands of SS patients and other
aged or injured organs.
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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{{ truncateString('MELINDA LARSEN', 18)}}的其他基金
Cellular plasticity in salivary gland regeneration.
唾液腺再生中的细胞可塑性。
- 批准号:
10554429 - 财政年份:2021
- 资助金额:
$ 38.72万 - 项目类别:
Cellular plasticity in salivary gland regeneration.
唾液腺再生中的细胞可塑性。
- 批准号:
10356931 - 财政年份:2021
- 资助金额:
$ 38.72万 - 项目类别:
Nanofiber Scaffolds for Salivary Gland Regeneration
用于唾液腺再生的纳米纤维支架
- 批准号:
9884748 - 财政年份:2019
- 资助金额:
$ 38.72万 - 项目类别:
Nanofiber Scaffolds for Salivary Gland Regeneration
用于唾液腺再生的纳米纤维支架
- 批准号:
10377504 - 财政年份:2019
- 资助金额:
$ 38.72万 - 项目类别:
Nanofiber Scaffolds for Salivary Gland Regeneration
用于唾液腺再生的纳米纤维支架
- 批准号:
10626731 - 财政年份:2019
- 资助金额:
$ 38.72万 - 项目类别:
Extracellular Scaffold Elasticity and Binding Sites in Acinar Differentiation
腺泡分化中的细胞外支架弹性和结合位点
- 批准号:
8385517 - 财政年份:2011
- 资助金额:
$ 38.72万 - 项目类别:
Extracellular Scaffold Elasticity and Binding Sites in Acinar Differentiation
腺泡分化中的细胞外支架弹性和结合位点
- 批准号:
8257739 - 财政年份:2011
- 资助金额:
$ 38.72万 - 项目类别:
Engineering Functioning Salivary Glands Using Micropatterned Scaffolds
使用微图案支架工程功能唾液腺
- 批准号:
8035611 - 财政年份:2010
- 资助金额:
$ 38.72万 - 项目类别:
A high-resolution in situ proteomics atlas of salivary gland development
唾液腺发育的高分辨率原位蛋白质组学图谱
- 批准号:
7933969 - 财政年份:2009
- 资助金额:
$ 38.72万 - 项目类别:
A high-resolution in situ proteomics atlas of salivary gland development
唾液腺发育的高分辨率原位蛋白质组学图谱
- 批准号:
7824319 - 财政年份:2009
- 资助金额:
$ 38.72万 - 项目类别:
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