Vitamin D mediated protection in inflammatory bowel disease

 描述(由申请人提供)：人类流行病学数据和动物研究都表明，血清维生素D水平低与发展炎症性肠病(IBD)的风险增加有关。维生素D缺乏在全球范围内日益普遍，并可能通过改变免疫反应、肠道上皮屏障功能和/或肠道微生物组的组成，在遗传易感个体中促进IBD。虽然很明显，饮食在塑造微生物群方面发挥了作用，但维生素D等个别微量营养素的影响在很大程度上仍未被探索。在本申请中，我将通过使用发生IBD和结肠癌的小鼠模型来进一步阐明维生素D调节肠道环境以抑制炎症的机制。Smad3-/-小鼠存在转化生长因子β信号转导失调，这是人类炎症性肠病和结肠癌患者经常受到影响的一条途径，当感染肠道细菌H.bilis时，小鼠会患结肠炎。我们实验室以前的工作已经证明，补充饮食中的维生素D可以显著减少Smad3/-小鼠的结肠炎和随后的炎症相关结肠癌。我们假设，在疾病发展的初始阶段，高水平的饮食维生素D通过对适应性免疫细胞(可能是T淋巴细胞)和/或肠道上皮细胞的影响来抑制细菌诱导的结肠炎。我们将使用在特定细胞群中缺乏维生素D受体信号的小鼠来探索这一假说。除了免疫和上皮细胞种群的变化外，我们的初步数据表明，饮食中维生素D的增加改变了肠道微生物区系，这可能会影响我们模型中IBD的发展。因此，我们将描述补充维生素D引起的结肠微生物区系的变化，并评估导致这些变化的潜在机制。总之，这些研究将为维生素D改善IBD的机制提供实质性的见解。除了对人类健康有直接的翻译影响外，这些研究还将使我获得粘膜免疫学和微生物组分析方面的尖端培训，以及高级多学科生物信息学和统计学培训。我将通过由这些领域的专家组成的指导团队，以及包括教学指导和动手实验在内的培训计划，掌握这些研究领域的最先进知识。我的职业目标是成为一名在胃肠道疾病研究方面有经验的独立研究科学家。我建议研究饮食、肠道微生物区系和肠道疾病之间的相互作用，这是医学研究的一个重要发展领域。此外，我将通过这些研究获得的培训将为我作为一名研究科学家的长期成功奠定基础。我在兽医实验室动物研究方面的培训，再加上我将从这个研究项目中获得的专业知识，将为我继续我的生物医学研究生涯提供一个健全和灵活的基础，并将直接促进我向 研究独立性。

 DESCRIPTION (provided by applicant): Both human epidemiologic data and animal studies suggest that low serum vitamin D levels are associated with an increased risk for developing Inflammatory Bowel Disease (IBD). Vitamin D deficiency is increasingly prevalent worldwide, and may promote IBD in genetically susceptible individuals through changes in immune responses, gut epithelial barrier function, and/or the composition of the gut microbiome. While it is clear that diet plays a role in shaping the microbiome, the influence of individual micronutrients, such as vitamin D, remains largely unexplored. In this application I will further elucidate the mechanisms through which vitamin D modulates the intestinal environment to suppress inflammation by using a mouse model that develops IBD and colon cancer. Smad3-/- mice have dysregulated transforming growth factor β signaling, a pathway frequently affected in human IBD and colon cancer patients, and develop colitis when infected with a gut bacteria, H. bilis. Previous work in our laboratory has demonstrated that supplementing dietary vitamin D significantly reduces colitis and subsequent inflammation-associated colon cancer in Smad3-/- mice. We hypothesize that elevated dietary vitamin D suppresses bacterial-induced colonic inflammation through its effects on adaptive immune cells (likely T lymphocytes) and/or intestinal epithelial cells during the initial stages of disease development. We will explore this hypothesis using mice lacking vitamin D receptor signaling in specific cell populations. In addition to changes in immune and epithelial cell populations, our preliminary data suggest that increased dietary vitamin D alters the gut microbiota, which likely impacts the development of IBD in our model. We will therefore characterize the changes in colonic microbiota induced by supplemental vitamin D and will evaluate potential mechanisms inducing these changes. Together these studies will provide substantial insights into the mechanisms through which vitamin D ameliorates IBD. In addition to having direct translational impacts on human health, these studies will allow me obtain cutting edge training in mucosal immunology and microbiome analysis, as well as advanced multidisciplinary bioinformatics and statistics training. I will obtan state-of-the-art knowledge in these fields of study through a mentoring team of experts in these fields and through a training program that includes didactic instruction and hands-on experiments. My career goal is to become an independent research scientist with experience in studying gastrointestinal diseases. I propose to study the interactions between diet, gut microbiota, and intestinal disease, which is an important developing area of medical research. Moreover, the training I will obtain through these studies will lay a foundation for long-term success as a research scientist. My training in veterinary lab animal research, combined with the expertise I will gain from this research project will provide me with a sound and flexible basi to continue my research career in biomedical research and will directly facilitate my transition to research independence.