Mechanisms of Glucose Dependence in Proliferating Cells

尽管人们对某些疾病的新陈代谢脆弱性有了更好的了解，但进展较小 在了解特定途径，如葡萄糖代谢，是否会有效和 作为一种治疗方法而被容忍。这个项目的长期目标是了解组织特异性的独特特征 以验证针对特定疾病的可行靶点。这项提议的总体目标是 描述一种原型代谢疗法--葡萄糖转运抑制对新陈代谢的影响 正常和过度增殖的表皮组织。中心假设是遗传和化学上的 抑制葡萄糖转运会防止病理性增生，而不会影响细胞的正常功能 皮肤。这一假说是基于一项新的发现，即Glut1缺陷皮肤经历转录和Met-1。 代谢重新编程，以允许正常的皮肤功能和动态平衡，但无法在重新增殖 对生理应激源作出回应。对构成差异的原则的透彻理解符合- 正常组织和增殖组织的代谢需求将证实抑制葡萄糖转运是一种治疗方法 针对并促进针对组织特定新陈代谢的其他新疗法的开发。这 该提案将通过三个目标来实现：1)确定葡萄糖转运的遗传抑制如何挽救 急性咪喹莫特诱导的银屑病样增生症。Glut1缺陷皮肤将通过组织学进行分析， 基因表达和代谢组学分析。遗传抑制对葡萄糖转运和诱导的影响 将通过建立体内13C同位素标记来评估代谢流上的增生。2)确定 局部应用小分子葡萄糖转运抑制剂是否可以改善hy-1的标志物？ (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类型中得到优化 培养，然后将测试这些抑制剂对器官型细胞慢性增生的影响能力。 在UVB辐射的无毛小鼠中。3)评估路径是否已经受到损失的影响 Glut1在小鼠中的表达也受到来自患者病理生理过度表达的影响 Glut1.这些目标的完成将促进葡萄糖转运抑制的发展。 治疗各种增生性皮肤病，包括牛皮癣，也将显著改善我们的 了解体内正常和疾病过程中的新陈代谢是如何调节的。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将合作评估 靶向特定代谢途径对多种疾病模型的影响。

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.