Ceramides as novel drivers of metabolic dysfunction and colorectal cancer

神经酰胺作为代谢功能障碍和结直肠癌的新驱动因素

• 批准号: 10505169
• 负责人: Mary Christine Playdon
• 金额: $ 91.39万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-02 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10505169
• 关键词: Address; Adipose tissue; Affect; Anabolism; Animal Experiments; Automobile Driving; Azoxymethane; Binding; Biological; Blood Banks; Body Composition; Body Weight; Body Weight Changes; Body Weight decreased; Cancer and Nutrition; Cells; Ceramides; Clinical; Colorectal; Colorectal Cancer; Colorectal Neoplasms; Complex; Data; Deposition; Development; Diabetes Mellitus; Diet; Dietary Intervention; Dietary Practices; Dyslipidemias; Enzymes; Epidemiology; Ethnic Origin; European; Evaluation; Experimental Models; Fatty Acids; Fatty acid glycerol esters; Genes; Genetic; Goals; Health; Heart Diseases; Heart failure; Hepatic; Human; Hyperinsulinism; Incidence; Individual; Inflammation; Insulin Resistance; Intervention; Intestines; Investigation; Knock-out; Lesion; Link; Lipids; Liver; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of ovary; Malignant neoplasm of prostate; Measures; Mediator of activation protein; Medical; Metabolic; Metabolic dysfunction; Metabolism; Modeling; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nutritional; Obesity; Operative Surgical Procedures; Organ; Organoids; Overweight; Palmitoyl Coenzyme A; Participant; Pathogenicity; Pathway interactions; Patients; Pharmacology; Phenotype; Physical condensation; Pre-Clinical Model; Public Health; Publishing; Race; Resources; Risk; Rodent; Role; Serine; Serum; Signal Transduction; Site; Testing; Time; Time-restricted feeding; Tissues; Utah; Variant; Waist-Hip Ratio; adenoma; age difference; age group; bariatric surgery; base; cancer biomarkers; cancer prevention; cancer risk; cohort; colorectal cancer prevention; colorectal cancer risk; data repository; desaturase; design; dietary; dihydroceramide desaturase; drug candidate; efficacy study; fly; genetic epidemiology; genetic variant; inhibitor; interdisciplinary collaboration; lipid metabolism; mouse model; novel; novel therapeutics; nutrition; obesity biomarkers; pandemic disease; pi bond; pre-clinical; preclinical study; prevent; prospective; protein metabolism; response; sex; stem cell proliferation; stem cells; therapeutic candidate; translational approach; tumor; tumor metabolism; waist circumference

SUMMARY In response to the burgeoning worldwide obesity pandemic, the rate of obesity-associated colorectal cancer (CRC) remains an enormous public health burden. The metabolic determinants of CRC are complex and remain under debate. Ceramides are pathogenic lipids that signal a state of nutrition excess and accumulate in organs that are not suited for fat storage, driving insulin resistance and dyslipidemia. Our preliminary data also demonstrate that ceramides are critical intermediates linking nutritional inputs like fatty acids to intestinal stem cell proliferation. Our long-term goal is to understand the role of ceramide metabolism in the development of CRC and to identify pharmacologic and dietary strategies to intervene upon ceramide metabolism for cancer prevention. Our central hypothesis is that ceramide metabolism is a key component of metabolic dysregulation underlying CRC. We propose a transdisciplinary collaboration, utilizing epidemiologic and clinical cohorts and animal experiments, to conduct synergistic analyses and interventions to address our hypothesis. In Aim 1a, using a rigorous discovery-replication design, we will characterize a ceramide-based CRC risk score in serum from participants in the European Prospective Investigation into Cancer and Nutrition (EPIC) (n=1260cases/1260 controls), and the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer cohort (n=1234 cases/1234 controls), and identify a dietary pattern strongly linked to ceramides. In Aim 1b, we will determine the effects of medical and surgical weight loss and changes in body composition on the ceramide CRC risk score in our ongoing Utah Bariatric Surgery Cohort. In Aim 1c, we will measure the association of genetically predicted levels of circulating ceramides with risk of CRC using data from 57,873 CRC cases and 67,087 controls in the Genetics and Epidemiology of CRC Consortium (GECCO), and test for gene by dietary pattern interaction. In Aim 2, we will determine whether systemic or tissue-specific reduction of ceramides affects CRC development. We will impede ceramide synthesis by inhibiting dihydroceramide desaturase-1 (DES1) action genetically (Aim 2a) and pharmacologically (Aim 2b), and via a serine or time restricted dietary pattern (Aim 2c), to test for effects on gut, liver and adipose depots and colorectal tumor incidence in an azoxymethane mouse model of CRC. The study leverages a new class of DES1 inhibitors that lower tissue ceramides and ameliorate the pathogenic consequences of obesity. The proposed study fills a major gap in evidence for understanding how ceramides contribute to the metabolic dysregulation underlying CRC. We propose a fully translational approach integrating epidemiologic associations between ceramides and colorectal malignancies and preclinical studies testing the utility of ceramide-lowering interventions on cancer endpoints. Findings will have important implications for understanding the biologic mechanisms underpinning obesity-associated metabolic dysregulation in CRC and for identifying new targets for CRC prevention.

总结 为了应对全球范围内迅速增长的肥胖流行病，肥胖相关的结直肠癌的发病率 (CRC)仍然是一个巨大的公共卫生负担。CRC的代谢决定因素是复杂的， 仍在讨论中。神经酰胺是一种致病性脂质，它发出营养过剩的信号，并在体内积累。 这些器官不适合脂肪储存，导致胰岛素抵抗和血脂异常。我们的初步数据还 表明神经酰胺是将营养输入如脂肪酸连接到肠干的关键中间体， 细胞增殖我们的长期目标是了解神经酰胺代谢在神经发育中的作用， CRC，并确定干预神经酰胺代谢治疗癌症的药理学和饮食策略 预防我们的中心假设是，神经酰胺代谢是代谢的关键组成部分， CRC潜在的失调。我们建议进行跨学科合作，利用流行病学和临床 队列和动物实验，进行协同分析和干预，以解决我们的假设。 在目标1a中，使用严格的发现-重复设计，我们将描述基于神经酰胺的CRC风险 欧洲癌症与营养前瞻性研究（EPIC）参与者的血清评分 （n= 1260例病例/1260例对照）和前列腺癌、肺癌、结直肠癌和卵巢癌（PLCO）队列（n=1234 例/1234对照），并确定与神经酰胺密切相关的饮食模式。在目标1b中，我们将确定 内科和外科减肥以及身体成分变化对神经酰胺CRC风险的影响 在我们正在进行的犹他州减肥手术队列中的评分。在目标1c中，我们将测量基因 使用来自57，873例CRC病例和67，087例CRC病例的数据预测循环神经酰胺水平与CRC风险 CRC遗传学和流行病学联盟（GECCO）中的对照，并通过饮食模式检测基因 互动在目标2中，我们将确定神经酰胺的全身性或组织特异性减少是否会影响CRC 发展我们将通过抑制二氢神经酰胺去饱和酶-1（DES 1）的作用来阻止神经酰胺的合成 遗传（Aim 2a）和非遗传（Aim 2b），以及通过丝氨酸或时间限制饮食模式（Aim 2c），以测试在氧化偶氮甲烷中对肠道、肝脏和脂肪贮库以及结肠直肠肿瘤发生率的影响。 CRC小鼠模型。这项研究利用了一类新的DES 1抑制剂，可以降低组织神经酰胺， 减轻肥胖的致病后果。这项拟议的研究填补了证据方面的一个重大空白， 了解神经酰胺如何促进CRC基础代谢失调。我们提出一个全面的 神经酰胺类药物与结直肠恶性肿瘤流行病学关联的转化方法 以及临床前研究，测试降低神经酰胺干预对癌症终点的效用。发现将 对于理解肥胖相关的生物学机制具有重要意义。 CRC代谢失调和确定CRC预防的新靶点。