Investigating the role of GAPDHS in melanoma metabolism and metastasis

研究 GAPDHS 在黑色素瘤代谢和转移中的作用

• 批准号: 10643669
• 负责人: Jennifer Gibson Gill
• 金额: $ 25.98万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10643669
• 关键词: Award; Biological Markers; Biological Models; Biology; Biometry; Carbon; Catalytic Domain; Categories; Cells; Cessation of life; Citric Acid Cycle; Clinical; Data; Dedications; Dependence; Dermatology; Disease; Distant; Enzymes; Equilibrium; Excision; Glucose; Glyceraldehyde-3-Phosphate Dehydrogenases; Glycolysis; Goals; Human; Immunotherapy; Infusion procedures; Isotopes; Knowledge; Laboratories; Malignant Neoplasms; Mediating; Medical center; Melanoma Cell; Mentors; Mentorship; Metabolic; Metabolic Pathway; Metabolism; Molecular; Mutate; Neoplasm Metastasis; Nutrient; Nutrient availability; Operative Surgical Procedures; Organ; Oxidation-Reduction; Oxidative Stress; Pathway interactions; Patients; Primary Neoplasm; Process; Pyruvate Carboxylase; Regulation; Research; Research Personnel; Resources; Role; Sampling; Site; Skin Cancer; Techniques; Testing; Texas; Therapeutic; Time; Training; Universities; biobank; biomarker development; cancer cell; career; clinical practice; comparison control; experience; glucose metabolism; high risk; improved outcome; in vivo; in vivo Model; interest; knowledge base; melanoma; melanoma biomarkers; metabolomics; neoplastic cell; novel; novel strategies; patient derived xenograft model; professor; programs; targeted treatment; therapeutic target; therapy resistant; tool; transcriptome sequencing; tumor metabolism; tumor progression

Project Summary/Abstract: Melanoma is the leading cause of skin cancer deaths because it metastasizes efficiently to distant organs. Metastasis requires significant plasticity for cancer cells to survive the metabolic barriers distinct from the original primary tumor site including higher oxidative stress, limited nutrient availability, and changing microenvironments. The specific metabolic changes required for melanoma to undergo this process are poorly understood. We recently identified a novel suppressor of melanoma metastasis, the enzyme glyceraldehyde 3- phosphate dehydrogenase, spermatogenic (GAPDHS). We characterized the functional role of GAPDHS in a patient-derived xenograft (PDX) model and demonstrated its impact on glycolysis and pyruvate carboxylase activity. In this proposal, we will investigate the metabolic changes associated with GAPDHS that drive metastasis and determine whether its expression can be used to predict tumor progression in melanoma patients. Specifically, we will determine whether the enzymatic activity of GAPDHS in central glycolysis is required for suppressing metastasis (Aim 1), if its downstream suppression of pyruvate carboxylase activity influences metastasis (Aim 2), and whether GAPDHS expression serves as a biomarker of melanoma metabolism and metastasis in patients (Aim 3). As an Assistant Professor of Dermatology at the University of Texas Southwestern Medical Center, I devote 80% of my time to my research interests under the mentorship of Dr. Ralph DeBerardinis, with the remaining time dedicated to clinical practice. My goal is to transition to a career as a successful independent investigator overseeing my own laboratory and research program. To achieve this, I am seeking a K08 award to provide support for an additional period of mentored research to gain experience with cancer metabolism, biomarker development, and advanced biostatistics, which are all necessary to achieve my research goals. With the guidance of a distinguished mentorship committee, I will have access to the training, resources, and support necessary to establish a successful independent research program focused on identifying metabolic vulnerabilities in melanoma metastasis.

项目摘要/摘要： Melanoma is the leading cause of skin cancer deaths because it metastasizes efficiently to distant organs. 转移需要癌细胞具有显着的可塑性，才能在不同于癌细胞的代谢屏障中存活下来。 原始原发肿瘤部位包括较高的氧化应激、有限的营养可用性和变化 微环境。黑色素瘤经历这一过程所需的具体代谢变化很少 明白了。我们最近发现了一种新型黑色素瘤转移抑制剂，即甘油醛 3- 生精磷酸脱氢酶 (GAPDHS)。我们描述了 GAPDHS 在 患者来源的异种移植（PDX）模型并证明了其对糖酵解和丙酮酸羧化酶的影响 活动。在本提案中，我们将研究与 GAPDHS 相关的代谢变化，这些变化驱动 转移并确定其表达是否可用于预测黑色素瘤的肿瘤进展 患者。具体来说，我们将确定 GAPDHS 在中枢糖酵解中的酶活性是否是 required for suppressing metastasis (Aim 1), if its downstream suppression of pyruvate carboxylase activity influences metastasis (Aim 2), and whether GAPDHS expression serves as a biomarker of melanoma 患者的代谢和转移（目标 3）。 As an Assistant Professor of Dermatology at the University of 德克萨斯西南医学中心，在导师的指导下我将80%的时间投入到我的研究兴趣上 由 Ralph DeBerardinis 博士负责，其余时间致力于临床实践。我的目标是过渡到 career as a successful independent investigator overseeing my own laboratory and research program.到 achieve this, I am seeking a K08 award to provide support for an additional period of mentored research to gain experience with cancer metabolism, biomarker development, and advanced biostatistics, which are all 实现我的研究目标所必需的。 With the guidance of a distinguished mentorship committee, I will have access to the training, resources, and support necessary to establish a successful independent research program focused on identifying metabolic vulnerabilities in melanoma metastasis.