The Role of Lpcat3 and Phospholipid Remodeling in Intestinal Homeostasis

项目摘要 肠内稳态是由隐窝中细胞增殖和细胞脱落之间的严格平衡控制的 从绒毛上。已知肠内稳态的失调会引起严重的肠道病变，包括 炎症性肠病（IBD）和胃肠癌。虽然已经取得了很大的进展 为了了解这个复杂的上皮系统如何维持体内平衡，是否以及如何脂质 在稳态和疾病状态期间，代谢可影响沿着隐窝-绒毛轴的上皮细胞 大部分尚未被探索我们实验室最近的研究已经确定了 溶血磷脂酰胆碱酰基转移酶3（Lpcat 3），一种磷脂（PL）重塑酶，在肠道中。损失 Lpcat 3在肠中选择性地减少膜中的多不饱和磷脂酰胆碱（PC），导致 降低膜流动性和曲率，并损害脂质吸收。我们接下来的研究发现， Lpcat 3和PL重塑在肠干细胞（ISC）增殖和维持肠干细胞的增殖和维持肠干细胞的增殖和维持肠干 体内平衡的原理然而，Lpcat 3影响肠道稳态的机制尚不清楚。 本研究的主要目的是了解Lpcat 3和磷脂重塑如何调节ISC 增殖和肠内稳态。目的1将检查Lpcat 3缺陷是否影响增殖， ISCs的分化，并使用离体隐窝类器官测试不同PC种类是否调节隐窝增殖 文化目的2将阐明Lpcat 3缺失促进隐窝增殖的机制。目标3将 确定PC重塑和胆固醇代谢是否可能导致肠道肿瘤发生。 候选人具有脂质代谢和癌症生物学的背景。他的长期科学目标是解开 脂质代谢和人类疾病的分子机制。为了进一步准备他的 长期的研究目标，他计划寻求培训，将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合作的环境，理想的这个项目，并为他 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， 核受体、炎症和脂质代谢。申请人还设有咨询委员会， 由Martin G Martín博士组成，他是一位有成就的胃肠道生物学家和肠道干细胞专家。 Steve Bensinger博士，国际公认的脂质代谢/质谱专家， 博士斯蒂芬·杨，肠道脂质代谢的先驱和专家。他的导师团队有一个详细的计划 以促进他的研究进展和科学事业的发展。总之，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K 01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.