The Role of Lpcat3 and Phospholipid Remodeling in Intestinal Homeostasis

Lpcat3 和磷脂重塑在肠道稳态中的作用

• 批准号: 9816514
• 负责人: Bo Wang
• 金额: $ 16.5万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 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 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9816514
• 关键词: Acyltransferase; Advisory Committees; Affect; ApcMin/+ mice; Area; Biology; Cancer Biology; Celiac Disease; Cell Proliferation; Cell physiology; Cells; Cholesterol; Cholesterol Homeostasis; Complement; Complex; Data; Development; Disease; Endocrine; Enzymes; Epithelial; Epithelial Cells; Equilibrium; Gastrointestinal Diseases; Gene Expression Profiling; Goals; Growth; Homeostasis; Impairment; Inflammation; Inflammatory Bowel Diseases; International; Intervention; Intestinal Neoplasms; Intestines; Knockout Mice; Lecithin; Link; Lipids; Lysophosphatidylcholines; Lysophospholipids; Maintenance; Malignant neoplasm of gastrointestinal tract; Mass Spectrum Analysis; Mediating; Membrane; Membrane Fluidity; Mentored Research Scientist Development Award; Mentors; Modeling; Molecular; Nuclear Receptors; Organoids; PI3K/AKT; Pathology; Pathway interactions; Phospholipids; Play; Polyunsaturated Fatty Acids; Proliferating; Regulation; Research; Research Project Grants; Role; Scientist; Site; Stem cells; System; Technical Expertise; Testing; Training; Transgenic Mice; Up-Regulation; Villus; Work; absorption; base; career development; cholesterol biosynthesis; collaborative environment; crypt cell; experience; gastrointestinal; human disease; insight; interest; intestinal crypt; intestinal epithelium; intestinal homeostasis; lipid metabolism; migration; novel therapeutics; nutrient absorption; polyunsaturated phosphatidylcholine; response; self-renewal; skills; stem cell biology; tumor; tumorigenesis

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.

项目概要 肠道稳态由隐窝细胞增殖和细胞脱落之间的严格平衡控制 已知肠道稳态失调会导致严重的肠道病变，包括 尽管在炎症性肠病（IBD）和胃肠道癌症方面已经取得了很大进展。 了解这种复杂的上皮系统如何维持体内平衡，脂质是否以及如何维持 在稳态和患病状态下，新陈代谢可能会影响沿隐窝绒毛轴的上皮细胞 我们实验室最近的研究已经确定了其关键功能。 溶血磷脂酰胆碱酰基转移酶 3 (Lpcat3)，一种磷脂 (PL) 重塑酶，在肠道中丢失。 肠道中的 Lpcat3 选择性地减少细胞膜中的多不饱和磷脂酰胆碱 (PC)，从而导致 我们的后续研究发现，膜的流动性和曲率降低，脂质吸收受损。 Lpcat3 和 PL 重塑在肠干细胞 (ISC) 增殖和维持中也发挥着重要作用 然而，Lpcat3 影响肠道稳态的机制尚不清楚。 该提案的主要目的是了解 Lpcat3 和磷脂重塑如何调节 ISC 增殖和肠道稳态​​ 目标 1 将检查 Lpcat3 缺乏是否影响增殖和肠道稳态​​。 ISC 的分化，并使用离体隐窝类器官测试不同 PC 物种是否调节隐窝增殖 目标 2 将揭示 Lpcat3 缺失促进隐窝增殖的机制。 确定 PC 重塑和胆固醇代谢是否可能导致肠道肿瘤发生。 该候选人具有脂质代谢和癌症生物学背景，他的长期科学目标是解开谜团。 脂质代谢和人类疾病的分子机制，为他的研究做好进一步的准备。 为了实现长期研究目标，他计划寻求培训来补充他现有的技术技能，并进一步 加州大学洛杉矶分校拥有一个高度协作的环境，非常适合这个项目，也适合他发展他的专业技能。 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。 申请人还设有一个咨询委员会，负责核受体、炎症和脂质代谢的研究。 由 Martin G Martín 博士组成，他是一位出色的胃肠生物学家和肠道干细胞专家 国际公认的脂质代谢/质谱专家 Steve Bensinger 博士，以及 肠道脂质代谢领域的先驱和专家Stephen Young博士的导师团队有一个详细的计划。 促进他的研究进步和科学事业发展总之，他的教育和研究。 丰富的经验以及强大且支持性的指导团队使他成为这项研究的理想人选 项目和K01奖。