Control of Epithelial Proliferation by the Microbiota

微生物群对上皮增殖的控制

• 批准号: 8757431
• 负责人: RHEINALLT MELFYN JONES
• 金额: $ 32.37万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-08 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8757431
• 关键词: Address; Animals; Back; Bacteria; Biology; Cell Cycle Regulation; Cell Proliferation; Chemicals; Colon; Communities; Cysteine; Data; Drosophila genus; Dysplasia; Employee Strikes; Epidermal Growth Factor Receptor; Epithelial; Epithelial Cells; Epithelium; Event; Generations; Genetic; Gnotobiotic; Goals; Growth; Health; High-Throughput Nucleotide Sequencing; Human; Injury; Intervention; Intestinal Cancer; Intestinal Neoplasms; Intestines; Investigation; Knockout Mice; Knowledge; Lactobacillus; Lead; Lesion; Malignant Neoplasms; Manuscripts; Mechanics; Mediating; Mediator of activation protein; Methods; Microbe; Mission; Modeling; Modification; Molecular; Molecular Profiling; Mus; NADPH Oxidase; National Institute of Diabetes and Digestive and Kidney Diseases; Neoplasms; Oncogenic; Outcome; Oxidation-Reduction; Pathway interactions; Phylogenetic Analysis; Physiological; Physiology; Play; Process; Proteins; Proteomics; Public Health; Publishing; Reactive Oxygen Species; Recombinant DNA; Regulator Genes; Relative (related person); Research; Role; Second Messenger Systems; Signal Pathway; Signal Transduction; Stem cells; Structure; Sulfur; System; Techniques; Testing; Therapeutic; Tissues; United States National Institutes of Health; WNT Signaling Pathway; base; commensal microbes; fly; gastrointestinal epithelium; gut microbiota; injured; innovation; member; microbial; microbial community; novel; public health relevance; research study; response to injury; second messenger; sensor; tumor initiation; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): There is a critical gap in our knowledge regarding the molecular mechanisms by which the intestinal microbiota influence epithelial cell cycle regulation and stem cell dynamics during the initiation and progression of GI cancers. This gap represents a barrier to scientific progress because, until it is addressed, an explanation for conditions resulting from dysbiosis between the gut microbiota and the host will continue to be beyond our understanding. Our long-term goal is to identify the cellular signaling pathways, the bacterial community structure, and the microbial products that mediate the influences of the microbiota on human health. The objective of this proposal is to identify how perturbations to the microbiota influence intestinal stem cell (ISC) turnover, and by extension tumor initiation or progression -and ultimately, how deliberate manipulation of the microbiota may offer a therapeutic strategy. Based on our preliminary data, our central hypothesis is that specific members of the highly host adapted microbiota (particularly lactobacilli) have co-evolved to facilitate intestinal cell proliferation by inducing the generation of ROS which then regulate cell signaling in the gut epithelium. Given that a subset of the microbiota possess potent pro-proliferative potential, we further hypothesize that altered, absolute or relative numbers of the microbes will have consequent effects on epithelia growth dynamics, and particularly in cases of intestinal injury, may play a role in intestinal tumor initiation and progression. The rationale fo this hypothesis is the well-established notion that physiological generation of low levels of ROS by the action of host NADPH oxidases in distinct subcellular domains act as critical second messengers in multiple signaling networks. In addition, our published and preliminary data identify well- characterized oncogenic cell signaling pathways that are modulated by bacterial-induced ROS generation. Furthermore, it is well-established that physiological generation of low levels of ROS in distinct subcellular domains act as critical second messengers in multiple signaling networks due to their ability to reversibly oxidize low pKa cysteines ("sulfur switches") of specific sensor target proteins. Based on these compelling preliminary data generated by our research group, the central hypothesis will be tested in three specific aims; 1) Characterize the signaling pathways that mediate microbiota-induced stem cell proliferation, 2) Identify the influence of manipulated microbiota in model epithelial early neoplasia, and 3) Identify symbiotic bacteria and bacterial communities that induce redox dependent cell signaling. Our approach will employ, ex-vivo enteroid model, knockout mice, a novel redox I-CAT proteomic technique, and a highly innovative genetically tractable Drosophila model whose biology can be manipulated to a far greater extent than mammalian models. The outcomes of these investigations will have an important positive impact on public health because of direct implications to idiopathic intestinal cancers. The investigation is also relevant to the mission of NIDDK/NIH by addressing preventative interventions for these conditions.

描述（由申请人提供）：关于肠道微生物群在胃肠道癌症发生和进展过程中影响上皮细胞周期调节和干细胞动态的分子机制，我们的知识存在严重差距。这一差距是科学进步的障碍，因为在解决这个问题之前，对肠道微生物群与宿主之间生态失调造成的状况的解释将继续超出我们的理解。我们的长期目标是确定细胞信号通路、细菌群落结构以及介导微生物群对人类健康影响的微生物产物。该提案的目的是确定微生物群的扰动如何影响肠道干细胞 (ISC) 的周转，进而影响肿瘤的发生或进展，最终确定对微生物群的有意操纵如何提供治疗策略。根据我们的初步数据，我们的中心假设是高度适应宿主的微生物群（特别是乳酸杆菌）的特定成员共同进化，通过诱导ROS的产生来促进肠道细胞增殖，然后调节细胞 肠道上皮细胞中的信号传导。鉴于微生物群的一个子集具有强大的促增殖潜力，我们进一步假设微生物的绝对或相对数量的改变将对上皮生长动力学产生后续影响，特别是在肠道损伤的情况下，可能在肠道肿瘤的发生和进展中发挥作用。这一假设的基本原理是一个公认的观点，即不同亚细胞域中宿主 NADPH 氧化酶的作用生理产生低水平的 ROS，在多个信号网络中充当关键的第二信使。此外，我们发表的初步数据确定了受细菌诱导的 ROS 生成调节的、特征明确的致癌细胞信号传导途径。此外，众所周知，不同亚细胞域中低水平 ROS 的生理生成可作为多个信号网络中关键的第二信使，因为它们能够可逆地氧化低 pKa 半胱氨酸（“硫开关”） 特定传感器目标蛋白。根据我们的研究小组生成的这些令人信服的初步数据，中心假设将在三个具体目标上进行测试； 1) 表征介导微生物群诱导的干细胞增殖的信号通路，2) 确定操纵微生物群对上皮早期肿瘤模型的影响，3) 确定诱导氧化还原依赖性细胞信号传导的共生细菌和细菌群落。我们的方法将采用离体肠类模型、基因敲除小鼠、一种新型氧化还原 I-CAT 蛋白质组技术和一种高度创新的遗传易处理的果蝇模型，该模型的生物学特性可以比哺乳动物模型更大程度地被操纵。由于对特发性肠癌有直接影响，这些调查的结果将对公众健康产生重要的积极影响。该调查也与使命有关 NIDDK/NIH 通过针对这些情况采取预防性干预措施。