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

项目总结/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的发展中起着重要但知之甚少的作用。越来越多的证据 表明肠道免疫反应受损和肠道微生物群失调， 胰岛素抵抗最近，一种称为棕榈酸羟基硬脂酸（PAHSAs）的新型脂质家族被发现。 有抗炎和抗糖尿病的作用。令人信服的初步数据表明， PAHSAs改善胰岛素抵抗小鼠的葡萄糖稳态，这与减少肠道 炎症和肠道微生物种类的有利转变。核心假设是，肠道发挥了 在介导PAHSAs对葡萄糖稳态的有益作用中起重要作用。这个的目标 建议是1）确定PAHSA是否影响改善肠道屏障功能和葡萄糖代谢 由肠道T细胞介导，以及2）确定肠道微生物群在介导PAHSA中的贡献 对肠道屏障功能和葡萄糖代谢的影响。无菌和免疫缺陷小鼠模型， 免疫和微生物细胞的过继转移，胰岛素敏感性评估，以及复杂的 免疫学技术将用于确定肠道免疫应答的功能贡献 以及肠道微生物群在调节PAHSA对葡萄糖代谢的有益作用中的作用。导师这个 创新的研究提案是由糖尿病研究领域的领导者Barbara Kahn博士领导的。卡恩博士 将提供葡萄糖稳态方面的专业知识。Diane马西斯博士，著名的免疫学家和T细胞 免疫反应，将作为共同导师，并将提供免疫学的重要专业知识。多学科 李博士的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 发展和培养李博士的科学和学术事业目标。这K01将延长李博士的训练 在内分泌肠道生理学的经验，并发展她在肠道免疫学和微生物学的专业知识， 代谢性疾病的背景。强大的导师团队，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的长期职业目标，发展独立的研究 糖尿病和新陈代谢的研究这项研究计划将确定PAHSAs的机制， 改善肠粘膜稳态，这将确定治疗肥胖和T2D的新的治疗策略。

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.