Targeting Choline Phospholipid Metabolism in Lymphangioleiomyomatosis

靶向胆碱磷脂代谢治疗淋巴管平滑肌瘤病

• 批准号: 9009781
• 负责人: Carmen Priolo
• 金额: $ 44.38万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-15 至 2020-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9009781
• 关键词: Acyltransferase; Address; Binding Proteins; Cell Proliferation; Cell model; Cells; Cellular Metabolic Process; Choline; Choline Kinase; Clinical Trials; Coculture Techniques; Communication; Complex; Development; Diffuse; Disease; Disease Progression; Down-Regulation; Ear; Endothelial Cells; Enzymes; FRAP1 gene; Forced expiratory volume function; Goals; Growth; Health; Homeostasis; Inflammation; Lecithin; Lipids; Lung; Lymphangiogenesis; Lymphangioleiomyomatosis; Lymphangiomyoma; Lymphatic; Lymphatic Endothelial Cells; Lymphatic vessel; Lysophosphatidylcholines; Malignant Neoplasms; Metabolic; Modeling; Modification; Molecular; Monitor; Mus; Mutation; Nutrient; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Phospholipase; Phospholipase A2; Phospholipases A; Phospholipid Metabolism; Phospholipids; Plasma; Play; Pleural effusion disorder; Pneumothorax; Positron-Emission Tomography; Production; Protein Isoforms; Publishing; Pulmonary Function Test/Forced Expiratory Volume 1; Radioisotopes; Recurrence; Regulatory Element; Renal Angiomyolipoma; Respiratory physiology; Role; Signal Transduction; Sirolimus; Smooth Muscle Actin Staining Method; Source; Sterols; Stress; TSC1 gene; TSC2 gene; Testing; Therapeutic; Therapeutic Agents; Tumor Suppressor Genes; Unsaturated Fatty Acids; Woman; Work; angiogenesis; arachidonate; cell growth; cell motility; clinically significant; cost; density; design; genetic approach; imaging biomarker; in vivo; inhibitor/antagonist; kinase inhibitor; lipid metabolism; lung injury; mTOR Inhibitor; mTOR protein; microPET; mouse model; novel; preclinical trial; prevent; pulmonary function; randomized placebo controlled trial; response; small hairpin RNA; specific biomarkers; stable isotope; therapeutic target; transcription factor; treatment response; uptake

 DESCRIPTION (provided by applicant): Lymphangioleiomyomatosis (LAM) is a rare, multisystem disease of women. Pulmonary LAM consists of a diffuse proliferation of smooth muscle actin-positive cells and increased lymphatic vessel density. LAM cells harbor inactivating mutations in either the TSC1 or TSC2 tumor suppressor gene, resulting in constitutive activation of mammalian TOR (target of rapamycin) complex 1 (mTORC1). mTORC1 integrates growth factor and nutrient signaling to stimulate cell growth and metabolism. Critical unmet needs in LAM are the development and optimization of effective therapeutic strategies and the availability of sensitive and specific biomarkers of disease progression and response to therapy, which could streamline the design, duration, and cost of early phase clinical trials. Our long-term goal is to identify mTORC1-dependent or independent metabolic vulnerabilities of LAM cells that can be targeted therapeutically in LAM. In lipidomic studies, we identified enhanced choline phospholipid metabolism in cellular models of LAM compared to control cells, and elevated phosphatidylcholine (PC) and lysophosphatidylcholine (LPC) species in LAM patient plasma compared to healthy women. Our central hypothesis is that abnormal lipid metabolism contributes to the molecular pathogenesis of LAM and represents a source for therapeutic targets and metabolic imaging biomarkers of disease progression in LAM. This hypothesis will be tested in three Aims. Aim 1. To identify the molecular mechanisms underlying dysregulation of choline phospholipid synthesis in LAM. Our working hypothesis is that the de novo PC synthesis and PC remodeling pathways are aberrantly activated via mTOR-dependent and independent mechanisms in TSC2-deficient cells. Aim 2. To determine the impact of aberrant lipid metabolism on LAM cell proliferation and LAM-associated lymphangiogenesis. Our working hypothesis is that lipid and signaling modifications downstream of choline kinase or PLA2 participate in the proliferation of LAM cells and trigger lymphatic microvascular endothelial cell migration and proliferation. Aim 3. To determine the impact of therapeutic targeting of choline phospholipid metabolism in LAM in vivo. Our working hypothesis is that aberrant lipid metabolism in LAM can be targeted therapeutically and used diagnostically. We will conduct preclinical trials of inhibitors of choline phospholipid metabolism using mouse models of LAM, [11C]choline Micro-PET (positron emission tomography) to detect in vivo changes in choline uptake of TSC2-deficient cells, and a mouse-ear model of LAM cell-associated lymphangiogenesis. The proposed studies have clinical significance because they will address the potential for key enzymes of the choline phospholipid pathway as targets in LAM therapeutics, and for [11C]choline as a metabolic imaging biomarker of disease progression and/or response to treatment in LAM patients.

 描述（由申请人提供）：淋巴管平滑肌瘤病（LAM）是一种罕见的女性多系统疾病。肺 LAM 包括平滑肌肌动蛋白阳性细胞的弥漫性增殖和淋巴管密度的增加。 LAM 细胞的 TSC1 或 TSC2 肿瘤抑制基因存在失活突变，导致哺乳动物 TOR（雷帕霉素靶标）复合物 1 (mTORC1) 的组成型激活。 mTORC1 整合生长因子和营养信号传导以刺激细胞生长和新陈代谢。 LAM 中未满足的关键需求是有效治疗策略的开发和优化，以及疾病进展和治疗反应的敏感和特异性生物标志物的可用性，这可以简化早期临床试验的设计、持续时间和成本。我们的长期目标是确定 LAM 细胞依赖 mTORC1 或独立的代谢脆弱性，这些脆弱性可以作为 LAM 治疗的靶点。在脂质组学研究中，我们发现与对照细胞相比，LAM 细胞模型中的胆碱磷脂代谢增强，与健康女性相比，LAM 患者血浆中的磷脂酰胆碱 (PC) 和溶血磷脂酰胆碱 (LPC) 种类升高。我们的中心假设是，异常的脂质代谢有助于 LAM 的分子发病机制，并代表了 LAM 疾病进展的治疗靶点和代谢成像生物标志物的来源。这一假设将在三个目标中得到检验。目标 1. 确定 LAM 中胆碱磷脂合成失调的分子机制。我们的工作假设是，在 TSC2 缺陷细胞中，PC 从头合成和 PC 重塑途径是通过 mTOR 依赖性和独立机制异常激活的。目标 2. 确定异常脂质代谢对 LAM 细胞增殖和 LAM 相关淋巴管生成的影响。我们的工作假设是胆碱激酶或 PLA2 下游的脂质和信号传导修饰参与 LAM 细胞的增殖并触发淋巴微血管内皮细胞迁移和增殖。目标 3. 确定 LAM 体内胆碱磷脂代谢靶向治疗的影响。我们的工作假设是，LAM 中的异常脂质代谢可以作为治疗目标并用于诊断。我们将使用 LAM 小鼠模型、检测 TSC2 缺陷细胞体内胆碱摄取变化的 [11C]胆碱 Micro-PET（正电子发射断层扫描）以及 LAM 细胞相关淋巴管生成的小鼠耳模型，进行胆碱磷脂代谢抑制剂的临床前试验。拟议的研究具有临床意义，因为它们将探讨胆碱磷脂途径的关键酶作为 LAM 治疗靶标的潜力，以及 [11C]胆碱作为 LAM 患者疾病进展和/或治疗反应的代谢成像生物标志物的潜力。