T cell regulation by adult prostate stem cells
成体前列腺干细胞对 T 细胞的调节
基本信息
- 批准号:10382302
- 负责人:
- 金额:$ 18.81万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-04-02 至 2025-03-31
- 项目状态:未结题
- 来源:
- 关键词:5 Alpha-Reductase InhibitorAddressAdrenergic alpha-AntagonistsAdultAffectAgeAntigensApoptosisAutoimmuneBasal CellBehaviorBenign Prostatic HypertrophyBiological AssayBiological ProcessCD8-Positive T-LymphocytesCD8B1 geneCell physiologyCellsChronicCoupledDataDevelopmentDiseaseEpithelialEvaluationExhibitsFluorescence-Activated Cell SortingFoundationsFrequenciesFunctional disorderGenesGranzymeGrowth FactorHarvestHomeostasisHumanHyperplasiaImmuneImmune TargetingImmunologic Suppressor FactorsIn VitroIncidenceIncontinenceInflammationInflammatoryInvestigationLightMediatingMesenchymal Stem CellsModelingMusMyeloid-derived suppressor cellsNitric OxideNocturiaNoduleOperative Surgical ProceduresOvalbuminPECAM1 genePTPRC genePathologicPathway interactionsPatientsPlayPopulationPrevalenceProductionProliferatingProstateProstatic DiseasesProstatic hypertrophyQuality of lifeRegulator GenesResistanceRoleSamplingSampling StudiesStromal HyperplasiaT cell anergyT cell regulationT cell responseT-Cell ProliferationT-LymphocyteTissuesTransgenic OrganismsTumor-infiltrating immune cellsUrethraanergyautoimmune inflammationcancer initiationcell killingcytokinedifferential expressiondisabling symptomepithelial stem cellexhaustionexperimental studyimmunoregulationimprovedin vivoinflammatory milieumale healthmenmicturition urgencymouse modelnovelprogenitorprogrammed cell death ligand 1prostatitissingle cell mRNA sequencingsingle-cell RNA sequencingstemstem cell populationstem cellstargeted treatment
项目摘要
Project summary/abstract:
Adult prostate stem cells (PSC) are a rare epithelial progenitor population in the prostate. While essential for
normal homeostasis, they have also been implicated in hyperplasia and cancer initiation.1-7 Inflammation can
fuel hyperplastic diseases through its production of growth factors and cytokines;1, 8, 9 however, the impact of
inflammatory factors on PSC and how PSC interact with infiltrating immune cells is not well studied. To examine
the cross-talk between epithelial PSC and immune cells, the proposed studies will utilize the Prostate Ovalbumin
Expressing Transgenic 3 (POET3), an inducible mouse model of abacterial T cell induced inflammation that
produces epithelial and stromal hyperplasia, functioning as a model for human autoimmune prostatitis.10
Current studies in our lab have taken prostates from inflamed and non-inflamed (naïve) POET3 mice, which
were harvested, digested, and separated by fluorescence-activated cell sorting (FACS) to isolate an enriched
basal PSC population defined as lineage negative (CD45-/CD31-), stem cell antigen-1+, CD49f+ (LSC).11, 12 Single
cell mRNA sequencing comparing freshly isolated LSC from naïve (nLSC) and inflamed (iLSC) mice revealed
differential expression of multiple immune regulatory genes, suggesting a possible role in regulating T cell
response. In vitro suppression assays conducted in our lab confirmed that while neither mature luminal nor nLSC
impacted T cell proliferation, iLSC were able to suppress CD8+ T cells. This effect is independent of recognized
mechanisms, nitric oxide production, IDO1, or PD-L1.13 Notably, prostates from inflamed mice show a marked
enrichment for LSC, suggesting that these cells are protected from T cell attack. Coupled with human BPH data
indicating prominent T cell populations enriched for exhaustion and anergy genes, these findings suggest a
potential novel mechanism of T cell suppression not previously identified in LSC that is induced under
inflammatory conditions, possibly as a tissue protective mechanism.
Thus, we hypothesize that adult basal prostate stem cells are able to harness immune regulatory capabilities
to suppress T cell function and survive T cell mediated attack. Using the POET3 model of autoimmune
inflammation and human BPH samples, studies described herein will explore the T cell suppressive factors
utilized by PSC in vitro and evaluate the impact of PSC suppression in vivo.
The resulting data will provide a foundation for more thorough study of rare stem/progenitor cells in immune
regulation while shedding light on their contribution to epithelial hyperplasia during inflammation.
项目总结/摘要:
成体前列腺干细胞(PSC)是前列腺中罕见的上皮祖细胞群。虽然对于
除了正常的体内平衡外,它们还与增生和癌症的发生有关。
燃料增生性疾病通过其生产的生长因子和细胞因子;1,8,9然而,影响
关于炎症因子对PSC的影响以及PSC如何与浸润性免疫细胞相互作用的研究尚不充分。审查
上皮PSC和免疫细胞之间的串扰,拟议的研究将利用前列腺卵清蛋白
表达转基因3(POET 3),一种无菌T细胞诱导炎症的诱导型小鼠模型,
产生上皮和基质增生,作为人类自身免疫性结肠炎的模型。
我们实验室目前的研究已经从炎症和非炎症(幼稚)POET 3小鼠中取出前列腺,
收获,消化,并通过荧光激活细胞分选(FACS)分离,以分离富集的
基础PSC群体定义为谱系阴性(CD 45-/CD 31-)、干细胞抗原-1+、CD 49 f+(LSC)。11,12
细胞mRNA测序比较了从幼稚(nLSC)和发炎(iLSC)小鼠新鲜分离的LSC,
多个免疫调节基因的差异表达,表明在调节T细胞中可能起作用。
反应在我们实验室进行的体外抑制试验证实,虽然成熟的管腔和nLSC
在受影响的T细胞增殖中,iLSC能够抑制CD 8 + T细胞。这种影响独立于公认的
13值得注意的是,来自发炎小鼠的前列腺显示出显著的炎症机制,一氧化氮产生,IDO 1或PD-L1。
这表明这些细胞被保护免受T细胞攻击。结合人类BPH数据
这些发现表明,显著的T细胞群富含耗竭和无反应性基因,
潜在的新的T细胞抑制机制,以前未在LSC中发现,
炎症状况,可能作为组织保护机制。
因此,我们假设成人基底前列腺干细胞能够利用免疫调节能力,
以抑制T细胞功能并在T细胞介导的攻击中存活。使用POET 3自身免疫模型
在炎症和人BPH样品中,本文所述的研究将探索T细胞抑制因子
通过PSC在体外使用,并评估PSC抑制在体内的影响。
这些数据将为更深入地研究免疫系统中罕见的干/祖细胞提供基础。
调节,同时阐明它们在炎症期间对上皮增生的贡献。
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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Timothy L. Ratliff其他文献
Elevated Cyclic Adenosine 3′, 5′ Monophosphate Enhances Lactic Acid Production by <em>Streptococcus lactis</em>
- DOI:
10.3168/jds.s0022-0302(81)82584-2 - 发表时间:
1981-03-01 - 期刊:
- 影响因子:
- 作者:
Timothy L. Ratliff;Dwight E. Talburt - 通讯作者:
Dwight E. Talburt
1861: Involvement of Growth Factors in the Process of Post-Vasectomy Micro-Recanalization
- DOI:
10.1016/s0022-5347(18)32034-2 - 发表时间:
2007-04-01 - 期刊:
- 影响因子:
- 作者:
Brandon C. Stahl;Timothy L. Ratliff;Barry R. De Young;Moshe Wald - 通讯作者:
Moshe Wald
Comparison of viral vectors: gene transfer efficiency and tissue specificity in a bladder cancer model.
病毒载体的比较:膀胱癌模型中的基因转移效率和组织特异性。
- DOI:
- 发表时间:
2003 - 期刊:
- 影响因子:6.6
- 作者:
D. Siemens;S. Crist;J. Austin;J. Tartaglia;Timothy L. Ratliff - 通讯作者:
Timothy L. Ratliff
UROLOGICAL SURVEYUro-Science
泌尿科检查Uro-Science
- DOI:
- 发表时间:
2004 - 期刊:
- 影响因子:0
- 作者:
Timothy L. Ratliff - 通讯作者:
Timothy L. Ratliff
Suppressive Effects of Regional Lymph Node Cells and Extracts on Antibody-Dependent Cellular Cytotoxicity
- DOI:
10.1016/s0022-5347(17)57501-1 - 发表时间:
1978-03-01 - 期刊:
- 影响因子:
- 作者:
William J. Catalona;Arlene T. Feldman;Timothy L. Ratliff;Robert E. Mccool - 通讯作者:
Robert E. Mccool
Timothy L. Ratliff的其他文献
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{{ truncateString('Timothy L. Ratliff', 18)}}的其他基金
Impact of Inflammation on Adult Prostate Stem Cells
炎症对成体前列腺干细胞的影响
- 批准号:
10439754 - 财政年份:2020
- 资助金额:
$ 18.81万 - 项目类别:
Impact of Inflammation on Adult Prostate Stem Cells
炎症对成体前列腺干细胞的影响
- 批准号:
10218167 - 财政年份:2020
- 资助金额:
$ 18.81万 - 项目类别:
Impact of Inflammation on Adult Prostate Stem Cells
炎症对成体前列腺干细胞的影响
- 批准号:
10655549 - 财政年份:2020
- 资助金额:
$ 18.81万 - 项目类别:
Use of Micro-RNA Arrays to Identify MDSC Functional Pathways and Markers
使用 Micro-RNA 阵列识别 MDSC 功能途径和标记
- 批准号:
8451031 - 财政年份:2013
- 资助金额:
$ 18.81万 - 项目类别:
Use of Micro-RNA Arrays to Identify MDSC Functional Pathways and Markers
使用 Micro-RNA 阵列识别 MDSC 功能途径和标记
- 批准号:
8601921 - 财政年份:2013
- 资助金额:
$ 18.81万 - 项目类别:
Inflammation and Prostate Cancer Development and Progression
炎症与前列腺癌的发生和进展
- 批准号:
8096809 - 财政年份:2010
- 资助金额:
$ 18.81万 - 项目类别:
Inflammation and Prostate Cancer Development and Progression
炎症与前列腺癌的发生和进展
- 批准号:
8009233 - 财政年份:2010
- 资助金额:
$ 18.81万 - 项目类别:
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