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更好的理解，但进展较少。 在了解靶向特定途径（如葡萄糖代谢）是否有效的基础上， 作为治疗手段。该项目的长期目标是了解组织特异性的独特功能， 代谢，以验证特定疾病的可行靶标。本建议的总体目标是 描述原型代谢疗法（抑制葡萄糖转运）对代谢的影响 正常和过度增生的表皮组织。核心假设是， 抑制葡萄糖转运将防止病理性增生，而不影响正常的功能， 皮肤这一假设是基于新的发现，即Glut 1缺陷的皮肤经历转录和代谢， 代谢重编程，以允许正常的皮肤功能和体内平衡，但不能在重新增殖， 对生理压力作出反应深入了解微分方程的基本原理- 正常和增殖组织的代谢需求将证实葡萄糖转运抑制作为治疗 靶向并促进开发针对组织特异性代谢的其他新型疗法。这 该提案将通过三个目标实现：1）确定葡萄糖转运的遗传抑制如何拯救 急性咪喹莫特诱导的银屑病样增生。将通过组织学分析Glut 1缺陷皮肤， 基因表达和代谢组学分析。基因抑制对葡萄糖转运的影响及诱导 将通过已建立的体内13 C同位素标记来评估增生对代谢通量的影响。2)确定 葡萄糖转运的小分子抑制剂的局部应用是否可以a）改善Hy的标记物， B）逆转无毛小鼠中UVB诱导的慢性增生。 葡萄糖转运的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，然后将测试这些抑制剂影响器官型CUL中慢性增生的能力， 真实模型和UVB照射的无毛小鼠。3)评估是否已经受到损失影响的途径 小鼠中Glut 1的表达也受到来自发生Glut 1病理生理过度表达的患者的活检的影响。 Glut1。这些目标的实现将促进葡萄糖转运抑制的发展， 对包括银屑病在内的多种增生性皮肤病进行潜在治疗，也将显着推进我们的研究 了解体内正常和疾病过程中代谢是如何调节的。遗传学专家， 分子细胞生物学、代谢组学、病理学和临床患者登记处将合作评估 靶向特定代谢途径对多种疾病模型的影响。