Shaping the Microenvironment by DPEP1 Facilitates Adenoma Progression
通过 DPEP1 塑造微环境促进腺瘤进展
基本信息
- 批准号:10697369
- 负责人:
- 金额:$ 37.95万
- 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:2022-09-15 至 2027-08-31
- 项目状态:未结题
- 来源:
- 关键词:AttentionBehaviorBindingBiological AssayBiological MarkersBiological ProcessCell LineCellsCellular biologyCharacteristicsCoculture TechniquesColonColonic AdenomaColorectal AdenomaColorectal CancerCommunicationConfocal MicroscopyDataDipeptidasesDipeptidesElectrical ResistanceEnzyme-Linked Immunosorbent AssayEpitheliumExposure toExtracellular MatrixFlow CytometryFutureHumanImmuneImmunofluorescence ImmunologicIn VitroInvadedKnock-outKnowledgeLesionLeukocyte ElastaseMalignant NeoplasmsMalignant neoplasm of pancreasManuscriptsMediatingMonitorMusNatureNeoplasm MetastasisNeutrophil InfiltrationOrganoidsPatientsPolypsPopulationProliferatingPropertyProteinsReporterReportingRoleSamplingSelection CriteriaShapesSignal TransductionSourceSpecimenStainsSystemTechniquesTestingTissue MicroarrayTissuesTumor Suppressor ProteinsWestern Blottingadenomacancer biomarkerscancer cellcolon cancer cell lineelastase inhibitorexosomeextracellular vesicleshealthy volunteerimmunoreactivityin vivointerestmicrobiotamouse modelneutrophilpremalignantprotein biomarkersrepositorysingle-cell RNA sequencingspatial relationshipstem cellstimelinetranscriptome sequencingtumortumor microenvironmenttumor progression
项目摘要
PROJECT SUMMARY/ABSTRACT
Project 1: Shaping the Microenvironment by DPEP1 Facilitates Adenoma Progression
Project 1 aims to examine how shaping the microenvironment by DPEP1 facilitates adenoma progression. This
will be a basic project. We propose that dipeptidase-1 (DPEP1) marks those adenomas with the potential to
progress to colorectal cancer (CRC) through an active bi-directional communication with neutrophils. DPEP1
has two functions: dipeptidase activity and recently identified neutrophil-binding activity. Our hypothesis is that
DPEP1, largely through its neutrophil-binding activity, marks adenomas with a predilection for progression. We
have found that DPEP1 immunoreactivity is detected in 27% of colorectal adenomas but this increases to 72%
of CRCs, consistent with DPEP1 marking the small subset of adenomas that progress to CRC. Utilizing human
specimens, a unique Transwell co-culture system of adenoma organoids and freshly isolated neutrophils isolated
from healthy volunteers, and an informative mouse model, we will test if DPEP1-expressing adenomas more
effectively communicate with neutrophils and create a neutrophil-enriched microenvironment, increasing the
likelihood that these adenomas will progress. Exosomes have attracted a great deal of recent attention as a rich
source of cargo that may serve as cancer biomarkers. We have found that DPEP1 is released in exosomes from
CRC cell lines and that it highly enriched in a subset of exosomes that contain known CRC biomarkers, CEA
and EPCAM. Of interest, neutrophils also release small extracellular vesicles (sEVs) that contain neutrophil
elastase in a form that cannot be inhibited by elastase inhibitors, and thus it is especially potent in degrading the
extracellular matrix, a key step in cancer invasion. We will also use a unique neutrophil reporter mouse to monitor
onset and perdurance of neutrophil infiltration, along with the properties of these neutrophils, in an inducible,
stem cell-driven mouse model of colonic adenomas.
.
项目摘要/摘要
项目1:通过DPEP 1塑造微环境促进腺瘤进展
项目1旨在研究DPEP 1如何塑造微环境促进腺瘤进展。这
这将是一个基本的项目。我们认为,二肽酶-1(DPEP 1)标志着这些腺瘤的潜力,
通过与中性粒细胞的主动双向交流发展为结直肠癌(CRC)。dpep1
具有两种功能:二肽酶活性和最近鉴定的亲脂蛋白结合活性。我们的假设是
DPEP 1主要通过其亲脂蛋白结合活性,标志着腺瘤的进展倾向。我们
发现DPEP 1免疫反应性在27%的结直肠腺瘤中检测到,但这一比例增加到72%,
这与DPEP 1标记进展为CRC的腺瘤的小子集一致。利用载人
标本,腺瘤类器官和新鲜分离的中性粒细胞分离的独特的Transwell共培养系统
从健康志愿者和一个信息丰富的小鼠模型,我们将测试是否DPEP 1表达腺瘤更多
有效地与嗜中性粒细胞沟通,创造一个嗜中性粒细胞富集的微环境,
这些腺瘤进展的可能性。外来体作为一种丰富的生物学功能,
可以作为癌症生物标志物的货物来源。我们已经发现DPEP 1在外来体中从
CRC细胞系,并且其高度富集含有已知CRC生物标志物CEA的外来体亚组
关于EPCAM有趣的是,中性粒细胞还释放含有中性粒细胞的小细胞外囊泡(sEV)
弹性蛋白酶以不能被弹性蛋白酶抑制剂抑制的形式存在,因此它在降解
细胞外基质,癌症侵袭的关键步骤。我们还将使用一种独特的中性粒细胞报告小鼠来监测
中性粒细胞浸润的发生和持续,沿着这些中性粒细胞的性质,在诱导,
干细胞驱动结肠腺瘤小鼠模型。
.
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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Robert J. Coffey其他文献
Studies on uterine collagenase in tissue culture. II. Effect of steroid hormones on enzyme production.
组织培养子宫胶原酶的研究。
- DOI:
- 发表时间:
1971 - 期刊:
- 影响因子:0
- 作者:
John J. Jeffrey;Robert J. Coffey;A. Z. Eisen - 通讯作者:
A. Z. Eisen
Stereotactic drainage of Aspergillus brain abscess with long-term survival: case report and review.
曲霉菌脑脓肿的立体定向引流与长期生存:病例报告和回顾。
- DOI:
- 发表时间:
1989 - 期刊:
- 影响因子:4.8
- 作者:
Michael L. Goodman;Robert J. Coffey - 通讯作者:
Robert J. Coffey
Sa1613 - Expression of Lrig1, a Negative Regulator of Egfr, is Dynamically Altered in Different Stages of Gastric Carcinogenesis
- DOI:
10.1016/s0016-5085(18)31437-9 - 发表时间:
2018-05-01 - 期刊:
- 影响因子:
- 作者:
Hyunji Kim;Sungsook Yu;Yejin Cho;Robert J. Coffey;James R. Goldenring;Ki Taek Nam;Mijeong Yang;Keunwook Lee;Sang-Ho Jeong;Kyung-Min Lim - 通讯作者:
Kyung-Min Lim
Sa1629 - Testosterone-Dependent Differential Expression of Egfr in Male and Female Mice and Its Implications for Carcinogenesis and Treatment Response
- DOI:
10.1016/s0016-5085(18)31453-7 - 发表时间:
2018-05-01 - 期刊:
- 影响因子:
- 作者:
Won Jae Huh;Kathleen Rhoades;Robert J. Coffey - 通讯作者:
Robert J. Coffey
Tu1204 BETTER UNDERSTANDING OF MENETRIER'S DISEASE ANDJUVENILE POLYPOSIS SYNDROME BY RNA SEQUENCING
- DOI:
10.1016/s0016-5085(20)33215-7 - 发表时间:
2020-05-01 - 期刊:
- 影响因子:
- 作者:
Sargoel Rezanejad;Marisol A. Ramirez;Qi Liu;Robert J. Coffey;Won Jae Huh - 通讯作者:
Won Jae Huh
Robert J. Coffey的其他文献
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{{ truncateString('Robert J. Coffey', 18)}}的其他基金
Integrative Single-Cell Atlas of Host and Microenvironment in Colorectal Neoplastic Transformation
结直肠肿瘤转化中宿主和微环境的综合单细胞图谱
- 批准号:
10820067 - 财政年份:2023
- 资助金额:
$ 37.95万 - 项目类别:
Shaping the Microenvironment by DPEP1 Facilitates Adenoma Progression
通过 DPEP1 塑造微环境促进腺瘤进展
- 批准号:
10518847 - 财政年份:2022
- 资助金额:
$ 37.95万 - 项目类别:
Role of WNT-EGFR crosstalk by EVs and exomeres in normal colon and colon cancer
EV 和外泌体 WNT-EGFR 串扰在正常结肠和结肠癌中的作用
- 批准号:
10544807 - 财政年份:2020
- 资助金额:
$ 37.95万 - 项目类别:
Project 1: Interrogating Distinct Tumor-Initiating Cells in CRC
项目 1:研究 CRC 中不同的肿瘤起始细胞
- 批准号:
10700848 - 财政年份:2019
- 资助金额:
$ 37.95万 - 项目类别:
Distribution of Molecular Features for Colorectal Cancers in Northern Tanzania
坦桑尼亚北部结直肠癌的分子特征分布
- 批准号:
10845027 - 财政年份:2019
- 资助金额:
$ 37.95万 - 项目类别:
Vanderbilt-Ingram Cancer Center SPORE in Gastrointestinal Cancer
范德比尔特-英格拉姆癌症中心 SPORE 在胃肠道癌症中的应用
- 批准号:
9975125 - 财政年份:2019
- 资助金额:
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