Elucidating mechanisms of endocrine-exocrine signaling in obesity-driven pancreatic cancer

阐明肥胖引起的胰腺癌中内分泌-外分泌信号传导机制

基本信息

批准号：
10723092
负责人：
Cathy Garcia
金额：
$ 3.26万
依托单位：
YALE UNIVERSITY
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：
2022-09-30 至 2025-09-29
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10723092
关键词：
Acinar Cell Address Adult B cell differentiation B-Lymphocytes Beta Cell Binding Cancer Biology Cancer Etiology Cells Cessation of life Cholecystokinin Clustered Regularly Interspaced Short Palindromic Repeats Computer software Data Dependovirus Development Developmental Biology Disease Duct (organ) structure Educational workshop Endocrine Endocrinology Environment Exhibits Exocrine pancreas Gene Expression Generations Genetic Genetic Models Genetic Transcription Goals High Fat Diet Hormones Human Immunofluorescence Immunologic In Vitro Insulin Intercept Islet Cell Islets of Langerhans KRAS oncogenesis Label Lead Malignant neoplasm of pancreas Mentors Mentorship Methods Modeling Molecular Mus Nerve Growth Factors Neuropeptides Non obese Obese Mice Obesity Pancreatic Ductal Adenocarcinoma Pancreatic Injury Physiological Play Preparation Prevalence Proliferation Marker Quantitative Reverse Transcriptase PCR RNA Interference Regulator Genes Research Resources Risk Risk Factors Role Scientist Signal Transduction Source Specific qualifier value Survival Rate Tamoxifen Technical Expertise Testing Training Transcription Repressor Tumor Burden United States Up-Regulation Viral Work cDNA Expression cDNA delivery career chromatin immunoprecipitation computerized tools congenic epidemiology study experimental study gain of function gene repression genetic manipulation hormonal signals in silico in vivo insulinoma islet islet amyloid polypeptide knock-down loss of function mouse model multidisciplinary novel overexpression pancreatic cancer model pancreatic ductal adenocarcinoma model pancreatic tumorigenesis prevent promoter receptor response single-cell RNA sequencing skills small hairpin RNA symposium transcription factor transcriptome sequencing transdifferentiation tumor initiation tumor progression tumorigenesis tumorigenic

项目摘要

PROJECT SUMMARY/ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related death and soon to become the second in the next few years. Numerous epidemiologic studies have shown that obesity increases the risk of developing and dying of PDAC. Given the rise in worldwide obesity rates, a better understanding of the mechanisms by which obesity promotes PDAC progression is necessary. To study how obesity drives PDAC, our lab recently combined a well-established genetic model of obesity with an oncogenic Kras-driven pancreatic cancer model and showed increased tumor burden and decreased survival compared to non-obese controls. Obese mice exhibited aberrant expression of the neuropeptide hormone cholecystokinin (CCK) in pancreatic islet beta (b) cells, the latter of which was sufficient to enhance Kras-driven pancreatic tumorigenesis. These results uncovered a novel mechanism of obesity-driven PDAC by local hormonal signaling between endocrine islets and exocrine acinar cells. Therefore, my overall goal is to elucidate the cellular and molecular mechanisms by which islets adapt in response to obesity and in turn promote PDAC progression through endocrine-exocrine hormonal signaling. In Aim I, I will perform lineage tracing studies in vivo and in silico to identify the cell-of-origin that gives rise to b cells mis-expressing hormones, such as CCK. In Aim II, I will determine whether loss of transcription factors required for b cell identify lead to aberrant hormone expression in mouse insulinoma (insulin-producing) cells and primary human b cells using genetic knockdown experiments and chromatin immunoprecipitation. Lastly, in Aim III, I will perform in vivo gain-of-function and loss-of-function experiments using islet specific gene manipulation by adeno-associated viruses to evaluate the pro-tumorigenic potential of hormones beyond CCK that are overexpressed in b cells in obesity. Together, these studies will reveal novel endocrine adaptations that could be targeted to halt obesity-driven pancreatic exocrine tumorigenesis. In addition, through the acquisition of new technical skills in this project, extensive mentorship (from her sponsor, co-sponsor, and collaborators), interactions within an outstanding scientific environment, participating in advanced classes and workshops, and attendance and presentation at conferences and seminars, the comprehensive training plan will markedly broaden the applicant’s skillset in preparation to be a successful independent research scientist.

项目摘要/摘要胰腺导管腺癌（PDAC）是癌症相关死亡的第三主要原因，很快成为未来几年的第二个。许多流行病学研究表明肥胖症增加 PDAC发展和死亡的风险。考虑到全球肥胖率的上升，对肥胖促进PDAC进展的机制是必要的。为了研究肥胖如何驱动PDAC，我们的实验室最近将肥胖的遗传模型与致癌性KRAS驱动的胰腺结合在一起与非肥胖对照相比，癌症模型并显示出增加的肿瘤灼伤和生存率增加。肥胖小鼠暴露于胰腺中神经肽激素胆囊动蛋白（CCK）的异常表达胰岛β（B）细胞，后者足以增强KRAS驱动的胰腺肿瘤发生。这些结果发现了通过内分泌之间的局部激素信号传导肥胖驱动的PDAC的新型机制胰岛和外分泌腺泡细胞。因此，我的总体目标是阐明细胞和分子胰岛响应肥胖的机制，进而促进PDAC进展通过内分泌 - 分泌的马信号传导。在AIM I中，我将在体内和在体内进行谱系跟踪研究识别产生Origin的硅，该细胞会导致B细胞表达误导的激素，例如CCK。在AIM II中，我将确定B细胞识别所需的转录因子的丧失是否导致异常的Horsene表达使用遗传敲低实验和染色质免疫沉淀。最后，在AIM III中，我将进行体内功能获得和功能丧失通过腺相关病毒使用胰岛特异性基因操纵的实验来评估促肿瘤肥胖症中B细胞中过表达的CCK以外的马的潜力。这些研究将在一起揭示可用于停止肥胖驱动胰腺外分泌的新型内分泌适应肿瘤发生。此外，通过在该项目中获得新的技术技能，广泛的心态（来自她的赞助商，共同发起人和合作者），在杰出的科学环境中进行互动，参加高级课程和讲习班，以及会议的出席和演讲 SEMIARS，全面的培训计划将明显扩大申请人的技能，以准备成为成功的独立研究科学家。