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Modeling oxidative stress and DNA damage using GI organotypic culture systems

使用胃肠道器官培养系统模拟氧化应激和 DNA 损伤

基本信息

批准号：
8697174
负责人：
JOHN P. LYNCH
金额：
$ 8万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-24 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8697174
关键词：
Acids Acute Acute Graft Versus Host Disease Adoption Adoptive Transfer Allogeneic Bone Marrow Transplantation American Anabolism BMP4 Barrett Esophagus Bone Marrow Transplantation Cell Culture System Cell Culture Techniques Cell Lineage Cell Proliferation Cells Chronic Clinical Colon Colon Carcinoma Cox Models Cyst DNA Damage DNA Methylation Detection Development Differentiation and Growth Dinoprostone Disease Disease Progression Disease model Dysplasia Effector Cell Eicosanoids Enterocytes Environment Enzymes Epigenetic Process Epithelial Epithelial Cells Epithelium Esophageal Esophagitis Esophagus Event Experimental Models Fibroblasts Fostering Gastroesophageal reflux disease Gastrointestinal tract structure Gene Expression Gene Expression Profile Gene Mutation Graft Rejection Growth Health Personnel Healthcare Healthcare Systems Human Immune In Vitro Inflammation Inflammatory Inflammatory Response Intestines Malignant Neoplasms Mediating Metaplasia Metaplastic Modeling Morphology Mucins Mus Mutation NADPH Oxidase Neoplasms Oncogenes Oxidative Stress Pain Pathogenesis Patient Care Patients Pattern Phenotype Prevention Prevention strategy Process Production Prostaglandin-Endoperoxide Synthase Prostaglandins Reflux Small Intestines Stem cells System T-Lymphocyte Testing Tissue Engineering Tissue Model Transplantation Ulcerative Colitis Work base cytokine disability graft vs host disease human disease human tissue improved in vivo innovation intestinal epithelium keratinocyte novel novel therapeutics oxidative DNA damage prevent response success tissue culture tissue/cell culture

项目摘要

DESCRIPTION (provided by applicant): Acute and chronic inflammatory environments of the gastrointestinal tract like gastroesophageal reflux disease (GERD), intestinal graft vs. host disease (GVHD), acute rejection after small intestine transplantation, and IBD conditions like Ulcerative colitis (UC), are fairly common human diseases. Disease models based on human cell and tissue culture systems that recapitulate in vivo growth and differentiation patterns would enhance our understanding of disease progression and improve prevention and detection strategies. This is an important objective of this proposal. In these disorders, epithelial cel oxidative stress is a key pathogenic factor for disease progression. This oxidative stress is partly from endogenous enzymes (Cyclooxygenases and NADPH oxidases) that induce DNA damage and mutations, and alter DNA methylation patterns, which together contributes to the development of metaplasia and cancer. We have begun to explore this using organotypic culture systems to model Cox-2 in BE pathogenesis. When we ectopically express Cox-2 in normal human esophageal keratinocytes, we observe the development of intestinal mucin-filled cysts. We propose to extend this success in physiologically relevant directions. Our main objective will be to test the hypothesis that the organotypic culture systems can be modified to model acute and chronic oxidative stress in esophageal and intestinal epithelium that physiologically resembles in vivo events in GERD, BE, GVHD, small bowel transplant rejection, and UC. We propose to test this by pursuing the following Specific Aims: 1) Adapt the esophageal organotypic culture system to better model GERD esophagitis and progression of stem cells to metaplasia and dysplasia. 2) Develop organotypic and 3D multi-cellular culture systems to model inflammatory microenvironments of GVHD, small bowel transplant rejection, and IBD including UC. GERD/BE, IBD/neoplasia, and GVHD are important, relatively common conditions that place a significant burden on the US healthcare system. We propose to develop novel multi-cellular in vitro human tissue engineered models that are representative of the pathogenesis for these conditions. These models will be of enormous value, allowing us to test hypotheses and advance our understanding of these disorders rapidly, and would have a translational impact since pharmacologic inhibition of Cox-2 is well established. This work will greatly improve our ability to study, prevent, and treat Barrett's esophagus, IBD, and GVHD. It will also foster the development of novel therapeutic and preventive strategies that will improve patient care for these important clinical conditions.

描述(申请人提供)：胃食道反流病(GERD)、移植物抗宿主病(GVHD)、小肠移植后急性排斥反应和溃疡性结肠炎(UC)等急性和慢性胃肠道炎症环境是相当常见的人类疾病。基于总结体内生长和分化模式的人类细胞和组织培养系统的疾病模型将加强我们对疾病进展的了解，改进预防和检测策略。这是这项提议的一个重要目标。在这些疾病中，上皮细胞氧化应激是疾病进展的关键致病因素。这种氧化应激是部分来自内源性酶(环氧合酶和NADPH氧化酶)，它们诱导DNA损伤和突变，并改变DNA甲基化模式，共同促进化生和癌症的发展。我们已经开始利用器官培养系统在BE发病机制中模拟COX-2来探索这一点。当我们在正常的人食道角质形成细胞中异位表达COX-2时，我们观察到了肠粘蛋白充满的囊变的发展。我们建议将这一成功扩展到与生理相关的方向。我们的主要目标是检验这样一个假设，即器官型培养系统可以被修改来模拟食道和肠道上皮的急性和慢性氧化应激，在生理上类似于GERD、BE、GVHD、小肠移植排斥反应和UC的活体事件。我们建议通过追求以下特定目标来测试这一点：1)调整食道器官型培养系统，以更好地模拟GERD食管炎和干细胞向化生和异型增生的进展。2)建立器官型和3D多细胞培养系统，模拟GVHD、小肠移植排斥反应和IBD包括UC的炎性微环境。GERD/BE、IBD/肿瘤和GVHD是重要的、相对常见的疾病，给美国医疗体系带来了重大负担。我们建议开发新的多细胞体外人类组织工程模型，以代表这些疾病的发病机制。这些模型将具有巨大的价值，使我们能够测试假说并快速提高我们对这些疾病的理解，并将产生翻译影响，因为药物对COX-2的抑制已经确立。这项工作将极大地提高我们研究、预防和治疗巴雷特食道、IBD和GVHD的能力。它还将促进新的治疗和预防战略的发展，这些战略将改善患者对这些重要临床疾病的护理。