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）：关于分子机制的知识存在危险差距，肠道微生物群会影响GI癌的启动和进展过程中上皮细胞周期和干细胞动力学。这一差距代表了科学进步的障碍，因为在解决问题之前，对肠道微生物群和宿主之间营养不良导致的疾病的解释将继续无法理解。我们的长期目标是确定介导微生物群对人类健康影响的细胞信号通路，细菌群落结构和微生物产物。该提案的目的是确定对微生物群的扰动如何影响肠道干细胞（ISC）周转率，并通过扩展肿瘤的启动或进展 - 最终，对微生物群的故意操纵如何提供治疗策略。基于我们的初步数据，我们的中心假设是，高度宿主适应的微生物群（尤其是乳酸杆菌）的特定成员共同发展以通过诱导ROS的产生来促进肠细胞增殖，然后调节细胞的细胞。 肠上皮的信号传导。鉴于微生物群的一部分具有有效的促增殖潜力，我们进一步假设微生物的改变，绝对或相对数量将对上皮生长动力学产生影响，尤其是在肠道损伤的情况下，可能在肠道肿瘤的启动和进展中起作用。该假设的基本原理是一个良好的观念，即通过宿主NADPH氧化酶在不同的亚细胞域中的作用来实现生理生理的ROS，在多个信号网络中充当了关键的第二使者。此外，我们发表的和初步的数据确定了由细菌诱导的ROS产生调节的良好表征的致癌细胞信号传导途径。此外，众所周知，由于它们能够可逆地氧化低PKA半胱氨酸（“硫开关”），因此在不同的亚细胞领域中低水平ROS的生理产生充当了多个信号网络中的关键第二使者。 特定的传感器靶蛋白。基于我们的研究小组生成的这些引人入胜的初步数据，将在三个特定目标中测试中心假设。 1）表征介导微生物群诱导的干细胞增殖的信号传导途径，2）确定受操纵的微生物群在模型上皮早期肿瘤中的影响，3）识别诱导氧化还原细胞信号传导的共生细菌和细菌群落。我们的方法将采用前体肠模型，基因敲除小鼠，一种新型的氧化还原I-Cat蛋白质组学技术，以及一种高度创新的遗传学果蝇模型，其生物学可以比哺乳动物模型更大。这些调查的结果将对公共卫生产生重要的积极影响，因为对特发性肠道癌症有直接影响。调查也与 NIDDK/NIH通过解决这些条件的预防干预措施。