Effects of Palmitic Acid esters of Hydroxy Stearic Acids (PAHSAs) on intestinal mucosal biology for the treatment of Type 2 Diabetes

项目摘要/摘要： 肥胖引起的炎症有助于胰岛素抵抗和2型糖尿病(T2D)的发展。 肠道在T2D的发展中扮演着一个重要但知之甚少的角色。越来越多的证据 与肠道免疫反应受损和肠道微生物区系失调有关 胰岛素抵抗。最近，一种新的脂类被称为棕榈酸羟基硬脂酸(PAHSA)。 发现有抗炎和抗糖尿病的作用。令人信服的初步数据表明 PAHSA改善胰岛素抵抗小鼠的葡萄糖稳态，这与肠道减少有关 炎症和肠道微生物种类的有利转变。中心假说是肠道扮演着一个 在介导多环芳烃对血糖稳态有益影响中的重要作用。这样做的目的是 建议是：1)确定PAHSA是否对改善肠道屏障功能和葡萄糖代谢有影响 由肠道T细胞介导，以及2)确定肠道微生物区系在介导PAHSA中的作用 对肠道屏障功能和糖代谢的影响。诺生菌和免疫缺陷小鼠模型， 免疫和微生物细胞的过继转移，胰岛素敏感性的评估，以及复杂的 免疫学技术将被用来确定肠道免疫反应的功能贡献 以及肠道微生物区系对调节有益的PAHSA对葡萄糖代谢的影响。这一点的指导 创新研究提案由糖尿病研究领域的领军人物芭芭拉·卡恩博士领导。卡恩博士 将提供葡萄糖动态平衡方面的专业知识。黛安·马西斯博士，著名的免疫学家和T细胞专家 免疫反应中心将担任共同导师，并将提供至关重要的免疫学专业知识。多学科 李博士学术咨询委员会的专业知识和指导将提供一个无与伦比的环境 发展和培育李博士的科学和学术事业目标。这款K01将延长李博士的培训 在内分泌肠道生理学方面的经验，并在肠道免疫学和微生物学方面发展专长 代谢性疾病的背景。强大的指导团队、结构化的培训计划和创新的研究 该提案将成功地促进李博士发展独立研究的长期职业目标 糖尿病和新陈代谢方面的课程。这项研究提案将确定PAHSA的机制 改善肠道粘膜动态平衡，这将确定新的治疗策略，以治疗肥胖和T2D。

PROJECT SUMMARY/ABSTRACT: Obesity-induced inflammation contributes to the development of insulin resistance and Type 2 Diabetes (T2D). The gut plays an important yet poorly understood role in the development of T2D. Mounting evidence implicates impaired intestinal immune responses and dysbiosis of the gut microbiota in driving the onset of insulin resistance. Recently, a novel family of lipids called Palmitic Acid Hydroxy Stearic Acids (PAHSAs) was discovered that are anti-inflammatory and anti-diabetic. Compelling preliminary data demonstrates that PAHSAs improve glucose homeostasis in insulin-resistant mice and this is associated with reduced intestinal inflammation and favorable shifts to gut microbial species. The central hypothesis is that the gut plays an important role in mediating the beneficial effects of PAHSAs on glucose homeostasis. The goals of this proposal are to 1) identify whether PAHSA effects on improved gut barrier function and glucose metabolism are mediated by gut T-cells, and 2) determine the contribution of the gut microbiota in mediating PAHSA effects on gut barrier function and glucose metabolism. Gnotobiotic and immunodeficient mouse models, adoptive transfer of immune and microbial cells, assessment of insulin sensitivity, and sophisticated immunology techniques will be used to determine the functional contribution of intestinal immune responses and the gut microbiota in regulating beneficial PAHSA effects on glucose metabolism. Mentorship of this innovative research proposal is led by Dr. Barbara Kahn, a leader in the field of diabetes research. Dr. Kahn will provide expertise in glucose homeostasis. Dr. Diane Mathis, a renowned immunologist and expert in T-cell immune responses, will serve as co-mentor and will provide vital expertise in immunology. Multidisciplinary expertise and guidance from Dr. Lee’s Academic Advisory Committee will provide an unparalleled environment to develop and foster Dr. Lee’s scientific and academic career goals. This K01 will extend Dr. Lee’s training experience in endocrine gut physiology and develop her expertise in gut immunology and microbiology in the context of metabolic disease. The strong mentorship team, structured training plan, and innovative research proposal will successfully foster Dr. Lee’s long-term career goal of developing an independent research program in diabetes and metabolism. This research proposal will define the mechanisms by which PAHSAs improve gut mucosal homeostasis which will identify novel therapeutic strategies to treat obesity and T2D.