The Role of Lpcat3 and Phospholipid Remodeling in Intestinal Homeostasis

项目总结 肠道内的动态平衡是由隐窝内的细胞增殖和细胞脱落之间的严格平衡控制的。 从别墅里出来的。众所周知，肠道内环境平衡失调会导致严重的肠道病变，包括 炎症性肠病(IBD)和胃肠道癌症。尽管已经取得了很大的进展 了解这个复杂的上皮系统如何维持动态平衡，是否以及如何脂类 在动态平衡和疾病状态下，代谢可能影响隐窝绒毛轴上皮细胞 在很大程度上是未被开发的。我们实验室最近的研究已经确定了关键的功能 溶血磷脂酰基转移酶3(Lpcat3)是肠道中的一种磷脂重塑酶。损失 肠道中Lpcat3的选择性减少膜中的多不饱和磷脂酰胆碱(PC)，导致 膜流动性和曲率降低，脂质吸收受损。我们随后的研究发现， Lpcat3和PL重塑在肠干细胞(ISC)的增殖和维持中也起着重要作用 动态平衡。然而，Lpcat3影响肠道内环境平衡的机制尚不清楚。 这项建议的主要目的是了解Lpcat3和磷脂重塑如何调节ISC 增殖和肠道动态平衡。目标1将检查Lpcat3缺乏是否影响增殖和 ISCs的分化，并利用体外隐窝器官测试不同PC物种是否调节隐窝的增殖 文化。目标2将揭开Lpcat3缺失促进隐窝增殖的机制。目标3将 确定PC重构和胆固醇代谢是否可能有助于肠道肿瘤的发生。 这位候选人有脂代谢和癌症生物学方面的背景。他的长期科学目标是解开 脂代谢和人类疾病的分子机制。为了进一步为他的 长期研究目标，他计划寻求培训，以补充他现有的技术技能，并进一步 发展他的专业技能。加州大学洛杉矶分校有一个高度协作的环境，非常适合这个项目和他 实现这些目标。他的导师Peter Tontonoz博士是一位备受尊敬的科学家，在该领域拥有专业知识 核受体、炎症和脂类代谢。申请人还有一个咨询委员会，该委员会 由马丁·G·马丁博士组成，他是一位成就卓著的胃肠生物学家和肠道干细胞专家 生物学，国际公认的脂类代谢/质谱学专家Steve Bensinger博士，以及 斯蒂芬·杨博士，肠道脂肪代谢的先驱和专家。他的导师团队有一个详细的计划 为他的研究进步和科学事业发展提供便利。总而言之，他的教育和研究 经验加上强大和支持的指导团队使他成为这项研究的理想人选 项目和K01奖。

PROJECT SUMMARY Intestinal homeostasis is controlled by a strict balance between cell proliferation in the crypts and cell shedding from the villi. Dysregulation of intestinal homeostasis is known to cause severe intestinal pathologies, including inflammatory bowel diseases (IBD) and gastrointestinal cancer. Although much progress has been made towards understanding how this complex epithelial system maintains homeostasis, whether and how lipid metabolism may influence the epithelial cells along the crypt-villus axis during homeostatic and diseased states has been largely unexplored. Recent studies from our lab has identified critical functions of lysophosphatidylcholine acyltransferase 3 (Lpcat3), a phospholipid (PL) remodeling enzyme, in intestine. Loss of Lpcat3 in intestine selectively reduces polyunsaturated phosphatidylcholine (PC) in membranes, leading to decreased membrane fluidity and curvature, and impaired lipid absorption. Our following studies discovered that Lpcat3 and PL remodeling also play important roles in intestinal stem cell (ISC) proliferation and the maintenance of homeostasis. However, the mechanisms by which Lpcat3 affects intestinal homeostasis are not clear. The primary aim of this proposal is to understand how Lpcat3 and phospholipid remodeling regulate ISC proliferation and intestinal homeostasis. Aim 1 will examine if Lpcat3 deficiency affects proliferation and differentiation of ISCs, and test if different PC species regulate crypt proliferation using ex vivo crypt organoid culture. Aim 2 will unravel the mechanisms by which loss of Lpcat3 promotes crypt proliferation. Aim 3 will determine if PC remodeling and cholesterol metabolism may contribute to intestinal tumorigenesis. The candidate has a background in lipid metabolism and cancer biology. His long term scientific goal is to unravel the molecular mechanisms underlying lipid metabolism and human diseases. To further prepare himself for his long-term research goal, he plans to seek training that will complement his existing technical skills and further develop his professional skills. UCLA has a highly collaborative environment ideal to this project and for him to achieve these goals. His mentor, Dr. Peter Tontonoz, is a highly respected scientist with expertise in the areas of nuclear receptors, inflammation and lipid metabolism. The applicant also has an advisory committee that consists of Dr. Martin G Martín, an accomplished gastrointestinal biologist and expert in intestinal stem cell biology, Dr. Steve Bensinger, an internationally recognized expert in lipid metabolism/mass spectrometry, and Dr. Stephen Young, a pioneer and expert in lipid metabolism in intestine. His mentor team has a detailed plan to facilitate his research progress and scientific career development. In summary, his educational and research experience together with a strong and supportive mentoring team make him an ideal candidate for this research project and the K01 award.