Mining host-microbe interactions in the neonatal pancreas to combat diabetes

项目摘要 出生后，新生儿暴露于各种各样的环境微生物中，这些微生物迅速在婴儿体内定植 胃肠道，然后逐渐增加的多样性在第一年的儿童的生活。有趣的是， 居民微生物群多样性的减少可用于预测1型糖尿病（T1 D）的发病， 易感儿童，这表明早期生活微生物群多样性在预防糖尿病方面至关重要。并发 随着微生物群的初始定植和多样化，产生胰岛素的β细胞在出生后经历必要的 发展过程。我的研究生工作表明斑马鱼孵化后需要肠道细菌 β细胞增殖。在我的博士后研究中，我继续证明，无菌小鼠也有明显的缺陷， 在β-细胞质量和胰岛素生产能力，这可归因于在特定的过程中微生物刺激的损失， 与β细胞发育里程碑相对应的出生后生命窗口。我还发现， 在此期间富集的细菌足以恢复无菌小鼠中的β细胞发育。 因此，我假设特定的微生物诱导新生儿β细胞发育，缺乏微生物 在T1 D之前发生的多样性限制了新生儿β细胞的建立，并减少了超过 自身免疫性破坏我在宿主-微生物相互作用和胰腺发育方面的背景使我 独特的准备来解决这个问题，这里的目标将为我提供必要的培训， 推进这个项目以及我自己的职业目标。我建议利用我现有的专业知识， 通过寻求免疫学和糖尿病疾病模型的额外培训， 免疫表型参与β细胞的发展，并测试是否有微生物对β细胞的影响， 发育可以调节疾病的严重程度。这次培训将为我的知识基础增添新的内容， 将广泛适用于我的目标，即在一家顶级研究机构领导一个实验室，研究 胰腺健康和疾病中的常驻微生物群。我相信这些研究途径有可能 改变我们对胰腺疾病病因学的理解和方法，我的长期愿景是发展 治疗糖尿病和胰腺癌的新方法，将改善人类生活质量。 为了确保我奋进建立一个成功的独立实验室，我组建了一个团队， 支持教师导师谁是免疫学和糖尿病领域的领先专家。大学 犹他州在这一提议上是无与伦比的，因为它集中了一批杰出的研究人员，他们通过以下方式合作： 机构组织，如糖尿病和代谢研究中心。从研究生院开始， 成功地建立了合作，并寻求专业知识，使我的想法在这里向前发展，从他们的 植入这个提议也不例外，我计划在我自己的实验室里把它开发成一个成功的平台， 可以用于预防和治疗糖尿病。

Project Abstract After birth, newborns are exposed to a wide array of environmental microbes, which rapidly colonize the infant gastrointestinal tract and then gradually increase in diversity during the first years of the child’s life. Interestingly, reduced diversity of the resident microbiota can be used to predict Type 1 Diabetes (T1D) onset in genetically susceptible children, suggesting that early life microbiota diversity is critical in preventing diabetes. Concurrent with initial colonization and diversification of the microbiota, insulin-producing β-cells undergo essential postnatal developmental processes. My graduate work showed that zebrafish require intestinal bacteria for post-hatching proliferation of β-cells. In my postdoc I have gone on to show that germ-free mice also have significant deficits in β-cell mass and insulin production capacity which can be attributed to loss of microbial stimuli during a specific window of postnatal life corresponding with β-cell developmental milestones. I have also found that unique bacteria that are enriched during this time are sufficient to restore β-cell development in germ-free mice. Therefore, I hypothesize that specific microbes induce neonatal β-cell development and that the lack of microbial diversity that occurs prior to T1D limits the establishment of neonatal β-cells and reduces the chance to outpace autoimmune destruction. My background in host-microbe interactions and pancreatic development make me uniquely poised to address this question and the aims herein will provide me with essential training that will both advance this project as well as my own career goals. I propose to build upon my existing expertise in gnotobiology by seeking additional training in immunology and diabetes disease models to address important immune phenotypes involved in β-cell development and to test whether microbes with effects on β-cell development can modulate disease severity. This training will add new dimension to my knowledge base that will be broadly applicable to my goal of leading a lab at a top-tier research institution studying the role of the resident microbiota in pancreatic health and disease. I believe these avenues of research have the potential to alter our understanding and approach to pancreatic disease etiologies, and my long-term vision is to develop novel approaches in the fight against diabetes and pancreatic cancer that will improve the quality of human life. To ensure I succeed in my endeavor to establish a successful independent lab, I have assembled a team of supportive faculty mentors who are leading experts in the immunology and diabetes fields. The University of Utah is matchless for this proposal, as it has a concentration of exceptional researchers who collaborate through institutional organizations such as the Diabetes and Metabolism Research Center. Since graduate school I have successfully built collaborations and sought out the expertise that have carrier my ideas herein forward from their inception. This proposal is no exception, and I plan to develop it into a successful platform in my own lab that can be harnessed toward the prevention and treatment of diabetes.