Mechanisms of Glucose Dependence in Proliferating Cells

增殖细胞的葡萄糖依赖性机制

• 批准号: 10380590
• 负责人: Richard C Wang
• 金额: $ 35.28万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 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 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10380590
• 关键词: Acute; Affect; Anabolism; Biological; Biological Assay; Biological Markers; Biopsy; Cell Proliferation; Cells; Cellular biology; Chemicals; Chronic; Clinical; Complement; Data; Defect; Dependence; Development; Disease; Disease Marker; Disease model; Drug Metabolic Detoxication; Foundations; Gene Expression; Generations; Genetic; Genetic Transcription; Glucose; Glucose Transport Inhibition; Glucose Transporter; Goals; Growth; Health; Histology; Homeostasis; Human; Hyperplasia; Imiquimod; In Vitro; Inbred HRS Mice; Interphase Cell; Isotope Labeling; Label; Lesion; Lipids; Metabolic; Metabolic Pathway; Metabolism; Modeling; Molecular; Molecular Biology; Mus; Nucleotides; Oxidation-Reduction; Oxidative Stress; Pathologic; Pathology; Pathway interactions; Patients; Pentosephosphate Pathway; Persons; Process; Production; Proliferating; Proteins; Psoriasis; Role; Safety; Skin; Sphingolipids; Squamous cell carcinoma; Symptoms; Testing; Therapeutic; Tissues; Topical application; UV carcinogenesis; UVB induced; Ultraviolet B Radiation; aminoacid biosynthesis; base; cell type; glucose metabolism; glucose transport; glucose uptake; healthy volunteer; improved; in vivo; in vivo Model; inhibitor; innovation; insight; keratinocyte; metabolic profile; metabolomics; multidisciplinary; novel; novel strategies; novel therapeutic intervention; novel therapeutics; overexpression; patient registry; physiologic stressor; prevent; prototype; sample collection; skin disorder; skin organogenesis; small molecule inhibitor; therapeutic target; transport inhibitor

Despite an improved understanding of the metabolic vulnerabilities of some diseases, less progress has been made on understanding whether targeting specific pathways, like glucose metabolism, would be effective and tolerated as therapies. The long-term goal of this project is to understand the unique features of tissue-specific metabolism in order to validate viable targets for specific diseases. The overall objective of this proposal is to characterize the impact of a prototype metabolic therapy, the inhibition of glucose transport, on the metabolism of normal and hyperproliferative epidermal tissues. The central hypothesis is that genetically and chemically inhibiting glucose transport will prevent pathological hyperplasia, without affecting the normal function of the skin. This hypothesis is based on the novel finding that Glut1 deficient skin undergoes transcriptional and met- abolic reprogramming to allow for normal skin function and homeostasis, but is unable to proliferate in re- sponse to physiological stressors. A thorough understanding of the principles that underlie the differential met- abolic requirements of normal and proliferating tissues will validate glucose transport inhibition as a therapeutic target and facilitate the development of additional, novel therapies to target tissue-specific metabolism. This proposal will be achieved through three aims: 1) Determine how genetic inhibition of glucose transport rescues acute, imiquimod-induced psoriasiform hyperplasia. Glut1 deficient skin will be analyzed through histology, gene expression, and metabolomic assays. The impact of genetic inhibition of glucose transport and induced hyperplasia on metabolic flux will be assessed through established in vivo 13C isotopic labeling. 2) Determine whether the topical application of small-molecule inhibitors of glucose transport can a) improve markers of hy- perplasia in organotypic skin equivalents, and b) reverse chronic, UVB-induced hyperplasia in hairless mice. The topical application of small molecule inhibitors of glucose transport will first be optimized in organotypic cultures, and then those inhibitors will be tested for their ability to affect chronic hyperplasia in organotypic cul- ture models and in UVB-irradiated, hairless mice. 3) Assess whether pathways already implicated by the loss of Glut1 in mice are also affected in biopsies from patients who develop pathophysiological overexpression of Glut1. Completion of these proposed goals will facilitate the development of glucose transport inhibition as po- tential therapy for diverse hyperplastic skin diseases, including psoriasis, and also will significantly advance our understanding of how metabolism is regulated in normal and disease processes in vivo. Experts in genetics, molecular cell biology, metabolomics, pathology, and clinical patient registries will collaborate to assess the impact of targeting a specific metabolic pathway on multiple models of disease.

尽管对某些疾病的代谢脆弱性有了改善的了解，但进展较少 了解靶向特定途径（例如葡萄糖代谢）是否有效，并且 耐受为疗法。该项目的长期目标是了解组织特异性的独特特征 代谢以验证特定疾病的可行靶标。该提议的总体目的是 表征原型代谢疗法的影响，葡萄糖转运对代谢的抑制作用 正常和高增殖性表皮组织。中心假设是从遗传和化学上 抑制葡萄糖的转运将防止病理增生，而不会影响 皮肤。该假设是基于新的发现，即glut1不足的皮肤经历转录和met- 放松的重编程以允许正常的皮肤功能和稳态，但无法在重新播放 对生理压力源的响应。对差异的基础的原则的彻底理解 - 正常组织和增殖组织的余地要求将验证葡萄糖转运抑制作治疗 靶向并促进靶向组织特异性代谢的其他新型疗法的发展。这 提案将通过三个目的来实现：1）确定葡萄糖转运的遗传抑制如何救助 急性，咪喹莫丁诱导的牛皮癣形状增生。 GLUT1皮肤不足的皮肤将通过组织学分析， 基因表达和代谢组学测定。遗传抑制葡萄糖转运和诱导的影响 代谢通量的增生将通过在体内13C同位素标记中进行评估。 2）确定 小分子抑制葡萄糖转运的局部应用是否可以a）改善hy-标记 器官皮肤等效物中的呼吸症和b）反向慢性UVB诱导的无毛小鼠的增生。 葡萄糖转运小分子抑制剂的局部应用将首先在器官型中进行优化 培养物，然后将测试这些抑制剂的能力 Ture模型和UVB辐射的无毛小鼠。 3）评估损失牵涉的途径是否已经与 小鼠中的glut1的生物受到影响，来自患者的活检 glut1。这些提出的目标的完成将有助于发展葡萄糖转运的抑制作用 针对包括牛皮癣在内的多种增生皮肤疾病的特级疗法，也将显着提高我们的 了解在体内正常和疾病过程中如何调节新陈代谢的理解。遗传学专家， 分子细胞生物学，代谢组学，病理学和临床患者注册将合作评估 针对特定代谢途径对多种疾病模型的影响。