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.
摘要
正常的衰老过程、放射治疗(RT)的副作用以及以下症状都可能导致肺功能低下
自身免疫性疾病导致各种负面后遗症,包括龋齿、口臭和
消化功能减退。干燥综合征(SS)是一种影响唾液腺的自身免疫性外分泌疾病,
0.4%的美国人的泪腺和其他外分泌器官,大多数患者是40岁以上的女性(9:1
女性与男性的比例)。SS的主要缺陷是外分泌腺功能分泌上皮的丧失。
导致功能丧失的机制是复杂的和多因素的,但包括免疫依赖和
延伸到正常衰老和RT的免疫非依赖性病理。细胞衰老是一种重要的肿瘤-
阻止细胞增殖并对伤口愈合有积极影响的抑制机制,但当激活时
慢性,会加剧组织损伤和功能丧失。最近的研究表明,衰老的细胞在
SS患者的唾液腺,因为RT,在正常衰老期间。细胞衰老对唾液的影响
SS和其他情况下的功能减退尚不完全清楚。随着年龄增长而积累的衰老细胞采用
衰老相关分泌表型(SASP),其特征是分泌细胞因子、生长因子和
破坏组织动态平衡并导致与年龄相关的病理变化的蛋白酶。SASP与组织有因果关系
通过旁分泌作用对邻近细胞的退化,以及对衰老细胞的遗传消融可以保护器官功能
通过限制SASP。类似地,系统地去除衰老细胞的抗衰老药物可以增加整体健康和寿命。
在老鼠身上。最小化SASP可限制炎症反应的幅度和持续时间,限制
外分泌功能,延缓与疾病相关的器官衰退。我们已经确定了几个控制SASP和SASP的microRNA
炎性细胞因子基因表达可作为限制衰老细胞活性的靶点。这些研究详细介绍了
这里将检验这样的假设:衰老促进SS样疾病中未消退的炎症驱动唾液腺
功能减退。我们将通过选择性地调节以有机类物质为基础的和
唾液腺功能低下的小鼠模型。我们建议处理以下具体目标:1.界定
衰老和Sjögren综合征相关miRNAs在SASP调控中的作用。目标2.确定是否
消融衰老细胞或靶向促进SASP的miRNAs可以减少未消退的炎症和
体内纤维化。3.明确衰老细胞SASP在SS疾病发展中的作用。这项研究将进一步
我们对衰老、炎症和唾液腺功能减退之间的联系的理解。比较研究
基因和RNA介导的衰老细胞消减方法和SASP表型调控的反配子将
揭示基于RNA的潜在治疗策略,用于SS患者和其他患者的唾液腺功能恢复
老化或受损的器官。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
MELINDA LARSEN其他文献
MELINDA LARSEN的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ 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:
相似海外基金
A Phase 1b, Multi-center Study of IV Gallium Nitrate in Patients with Cystic Fibrosis who are colonized with Nontuberculosis Mycobacterium (The ABATE Study).
一项针对非结核分枝杆菌定植的囊性纤维化患者静脉注射硝酸镓的 1b 期多中心研究(ABATE 研究)。
- 批准号:
10237132 - 财政年份:2020
- 资助金额:
$ 38.72万 - 项目类别:
NSERC CREATE for freshwater Harmful Algal Blooms (fHABs): Algal Bloom Assessment though Science, Technology and Education (ABATE).
NSERC CREATE 针对淡水有害藻华 (fHAB):通过科学、技术和教育 (ABATE) 进行藻华评估。
- 批准号:
448172-2014 - 财政年份:2019
- 资助金额:
$ 38.72万 - 项目类别:
Collaborative Research and Training Experience
NSERC CREATE for freshwater Harmful Algal Blooms (fHABs): Algal Bloom Assessment though Science, Technology and Education (ABATE).
NSERC CREATE 针对淡水有害藻华 (fHAB):通过科学、技术和教育 (ABATE) 进行藻华评估。
- 批准号:
448172-2014 - 财政年份:2018
- 资助金额:
$ 38.72万 - 项目类别:
Collaborative Research and Training Experience
SBIR Phase I: Novel Immuno-Nutrition Properties of a Single Cell Protein to Abate Soy-Induced Enteritis in Aquafeeds
SBIR 第一阶段:单细胞蛋白的新型免疫营养特性可减轻水产饲料中大豆诱发的肠炎
- 批准号:
1819652 - 财政年份:2018
- 资助金额:
$ 38.72万 - 项目类别:
Standard Grant
NSERC CREATE for freshwater Harmful Algal Blooms (fHABs): Algal Bloom Assessment though Science, Technology and Education (ABATE).
NSERC CREATE 针对淡水有害藻华 (fHAB):通过科学、技术和教育 (ABATE) 进行藻华评估。
- 批准号:
448172-2014 - 财政年份:2017
- 资助金额:
$ 38.72万 - 项目类别:
Collaborative Research and Training Experience
Modulating signaling pathways in endothelial cells to abate leukemic progression
调节内皮细胞信号通路以减缓白血病进展
- 批准号:
9893715 - 财政年份:2016
- 资助金额:
$ 38.72万 - 项目类别:
NSERC CREATE for freshwater Harmful Algal Blooms (fHABs): Algal Bloom Assessment though Science, Technology and Education (ABATE).
NSERC CREATE 针对淡水有害藻华 (fHAB):通过科学、技术和教育 (ABATE) 进行藻华评估。
- 批准号:
448172-2014 - 财政年份:2016
- 资助金额:
$ 38.72万 - 项目类别:
Collaborative Research and Training Experience
NSERC CREATE for freshwater Harmful Algal Blooms (fHABs): Algal Bloom Assessment though Science, Technology and Education (ABATE).
NSERC CREATE 针对淡水有害藻华 (fHAB):通过科学、技术和教育 (ABATE) 进行藻华评估。
- 批准号:
448172-2014 - 财政年份:2015
- 资助金额:
$ 38.72万 - 项目类别:
Collaborative Research and Training Experience
Will mild vs. moderate physical activity suffice to abate the progression of subclinical atherosclerosis in sedentary adults?
轻度与中度体力活动是否足以减缓久坐成人亚临床动脉粥样硬化的进展?
- 批准号:
306958 - 财政年份:2014
- 资助金额:
$ 38.72万 - 项目类别:
Operating Grants
NSERC CREATE for freshwater Harmful Algal Blooms (fHABs): Algal Bloom Assessment though Science, Technology and Education (ABATE).
NSERC CREATE 针对淡水有害藻华 (fHAB):通过科学、技术和教育 (ABATE) 进行藻华评估。
- 批准号:
448172-2014 - 财政年份:2014
- 资助金额:
$ 38.72万 - 项目类别:
Collaborative Research and Training Experience














{{item.name}}会员




