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

羟基硬脂酸棕榈酸酯 (PAHSA) 治疗 2 型糖尿病对肠粘膜生物学的影响

• 批准号: 10219652
• 负责人: Jennifer Lee
• 金额: $ 4.05万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10219652
• 关键词: Adaptive Immune System; Address; Adipose tissue; Adoptive Transfer; Advisory Committees; Anti-Inflammatory Agents; Antidiabetic Drugs; Antiinflammatory Effect; Attenuated; Automobile Driving; Biological Assay; Biology; Cecum; Cells; Coculture Techniques; Colitis; Data; Development; Diabetes Mellitus; Endocrine; Environment; Esters; Family; Fostering; Gnotobiotic; Goals; Gut Mucosa; Health; High Fat Diet; Homeostasis; Human; Hydroxy Acids; Immune; Immune response; Immune system; Immunologist; Immunology; Impairment; Inflammation; Inflammatory; Insulin; Insulin Resistance; Interleukin-1 beta; Intestinal Mucosa; Intestines; K-Series Research Career Programs; Lipids; Lipopolysaccharides; Mediating; Mentors; Mentorship; Metabolic Diseases; Metabolism; Microbe; Microbiology; Mission; Mus; National Institute of Diabetes and Digestive and Kidney Diseases; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Palmitic Acids; Pathologic; Peripheral; Physiology; Play; Production; Property; Propionates; Public Health; Research; Research Proposals; Rodent; Role; Stearic Acids; Structure; T cell response; T cell therapy; T-Lymphocyte; Techniques; Testing; Therapeutic; Tissues; Training; Volatile Fatty Acids; Work; blood glucose regulation; career; cytokine; diabetic; dysbiosis; experience; glucose metabolism; glucose tolerance; gut microbes; gut microbiome; gut microbiota; immunodeficient mouse model; improved; inflammatory disease of the intestine; innovation; insulin sensitivity; metabolic endotoxemia; microbial; multidisciplinary; novel; novel therapeutics; programs; response

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.

项目摘要/摘要： 肥胖引起的炎症会导致胰岛素抵抗和 2 型糖尿病 (T2D) 的发展。 肠道在 T2D 的发展中发挥着重要但人们知之甚少的作用。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是导致肠道菌群失调的原因 胰岛素抵抗。最近，一种名为棕榈酸羟基硬脂酸（PAHSA）的新型脂质家族被开发出来。 发现具有抗炎和抗糖尿病作用。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。中心假设是肠道起着 在调节 PAHSA 对葡萄糖稳态的有益作用中发挥着重要作用。本次活动的目标 建议 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，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。知生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反应的功能贡献 以及肠道微生物群调节 PAHSA 对葡萄糖代谢的有益作用。本次辅导 创新研究计划由糖尿病研究领域的领军人物 Barbara Kahn 博士领导。卡恩博士 将提供葡萄糖稳态方面的专业知识。 Diane Mathis 博士，著名免疫学家、T 细胞专家 免疫反应，将作为共同导师，并将提供免疫学方面的重要专业知识。多学科 李博士学术顾问委员会的专业知识和指导将提供无与伦比的环境 发展和培养李博士的科学和学术职业目标。这台K01将扩展李博士的培训 拥有内分泌肠道生理学方面的经验，并发展了她在肠道免疫学和微生物学方面的专业知识 代谢疾病的背景。强大的导师团队、结构化的培训计划、创新的研究 该提案将成功促进李博士发展独立研究的长期职业目标 糖尿病和新陈代谢计划。该研究提案将定义 PAHSA 的机制 改善肠道粘膜稳态，这将确定治疗肥胖和 T2D 的新治疗策略。