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.

项目概要/摘要胰腺导管腺癌 (PDAC) 是癌症相关死亡的第三大原因，并且很快就会成为癌症相关死亡的第三大原因。大量流行病学研究表明，肥胖将在未来几年内成为第二位。鉴于全球肥胖率的上升，更好地了解 PDAC 的发生和死亡风险。为了研究肥胖如何驱动 PDAC，有必要了解肥胖促进 PDAC 进展的机制。我们的实验室最近将完善的肥胖遗传模型与致癌的 Kras 驱动的胰腺相结合癌症模型显示，与非肥胖对照相比，肿瘤负荷增加，生存率降低。肥胖小鼠胰腺中神经肽激素胆囊收缩素（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。结果揭示了肥胖驱动的 PDAC 的新机制，该机制是通过内分泌之间的局部激素信号传导来实现的。因此，我的总体目标是阐明细胞和分子。胰岛适应肥胖并进而促进 PDAC 进展的机制在目标 I 中，我将通过内分泌-外分泌激素信号传导进行体内和体内谱系追踪研究。通过计算机模拟来识别产生错误表达激素（例如 CCK）的 b 细胞的细胞源。 In Aim II, I。将确定 b 细胞识别所需转录因子的丢失是否会导致激素表达异常使用基因敲低实验在小鼠胰岛素瘤（产生胰岛素）细胞和原代人类 B 细胞中进行研究最后，在目标 III 中，我将进行体内功能获得和功能丧失。使用腺相关病毒的胰岛特异性基因操作来评估促肿瘤发生的实验这些研究将共同探讨 CCK 之外在 B 细胞中过度表达的激素在肥胖症中的潜力。揭示新的内分泌适应，可用于阻止肥胖驱动的胰腺外分泌此外，通过在这个项目中获得新的技术技能，广泛的指导。（来自她的赞助商、共同赞助商和合作者），在杰出的科学环境中的互动，参加高级课程和讲习班，出席会议和会议并进行演讲研讨会，全面的培训计划将显着扩大申请人的技能，为成为一名成功的独立研究科学家。