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.

项目摘要 肠内稳态受到密切平衡的控制 来自绒毛。已知肠内稳态失调会引起严重的肠道病理，包括 炎症性肠病（IBD）和胃肠癌。虽然取得了很多进展 要了解这种复杂的上皮系统如何保持体内稳态，是否以及如何脂质 代谢可能会在稳态和患病状态期间影响沿隐窝村沿隐窝村的上皮细胞 在很大程度上是出乎意料的。我们实验室的最新研究确定了 溶血磷脂酰胆碱酰基转移酶3（LPCAT3），一种磷脂（PL）重塑酶，肠道中。损失 肠中的LPCAT3选择性地降低膜中的多不饱和磷脂酰胆碱（PC），导致 膜的流动性和曲率降低，脂质抽象受损。我们以下研究发现 LPCAT3和PL重塑在肠道干细胞（ISC）增殖和维护中也起着重要作用 稳态。但是，LPCAT3影响肠内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 扩散和肠内稳态。 AIM 1将检查LPCAT3缺乏症是否影响增殖和 ISC的差异化，并测试不同的PC物种是否使用离体加密器官调节隐窝增殖 文化。 AIM 2将揭示LPCAT3损失促进隐窝增殖的机制。目标3意志 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。进一步为他做准备 长期研究目标，他计划寻求培训，以完成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的协作环境非常适合该项目，并使他 实现这些目标。他的导师彼得·顿托兹（Peter Tontonoz）博士是一位在该领域具有专业知识的备受推崇的科学家 核接收器，感染和脂质代谢。申请人还设有一个咨询委员会 由Martin GMartín博士组成，他是一位经验丰富的胃肠道生物学家，肠干细胞专家 生物学，史蒂夫·本辛格（Steve Bensinger）博士，国际公认的脂质代谢/质谱法专家， 斯蒂芬·杨（Stephen Young）博士，肠道脂质代谢的先驱兼专家。他的导师团队有一个详细的计划 促进他的研究进步和科学职业发展。总而言之，他的教育和研究 与强大而支持的心理团队一起经验使他成为这项研究的理想候选人 项目和K01奖。