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： 黑色素瘤是皮肤癌死亡的主要原因，因为它有效地转移到了远处的器官。 转移需要明显的可塑性，以使癌细胞生存与不同的代谢屏障 原始原发性肿瘤部位，包括较高的氧化应激，养分有限和变化 微环境。黑色素瘤经历此过程所需的特定代谢变化很差 理解。我们最近确定了一种新型的黑色素瘤转移抑制因子，即甘油醛3-- 磷酸盐脱氢酶，生精（GAPDHS）。我们表征了GAPDHS在A中的功能作用 患者衍生的异种移植（PDX）模型，并证明了其对糖酵解和丙酮酸羧化酶的影响 活动。在此提案中，我们将研究与驱动器GAPDH相关的代谢变化 转移并确定其表达是否可以用于预测黑色素瘤的肿瘤进展 患者。具体而言，我们将确定中央糖酵解中GAPDH的酶活性是否是 抑制转移所需的（AIM 1），如果其下游抑制丙酮酸羧化酶活性 影响转移（AIM 2），以及GAPDHS表达是否充当黑色素瘤的生物标志物 患者的代谢和转移（AIM 3）。作为大学皮肤病学助理教授 德克萨斯州西南医疗中心，我将80％的时间用于指导下的研究兴趣 Ralph Deberardinis博士的剩余时间致力于临床实践。我的目标是过渡到 作为一个成功的独立研究者的职业，负责我自己的实验室和研究计划。到 实现这一目标，我正在寻求K08奖，以为额外的指导研究提供支持 在癌症代谢，生物标志物发展和先进的生物统计学方面获得经验，这都是 实现我的研究目标所必需的。在杰出的指导委员会的指导下，我将 有必要的培训，资源和支持以建立成功的独立研究 计划着重于识别黑色素瘤转移中的代谢脆弱性。