MICROFABRICATED INSTRUMENTATION TO MEASURE SPHINGOLIPID SIGNALING IN HUMAN ACUTE MYELOID LEUKEMIA

用于测量人类急性髓系白血病中鞘脂信号传导的微型仪器

• 批准号: 9926834
• 负责人: Nancy L. Allbritton
• 金额: $ 64.41万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-07 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9926834
• 关键词: Abbreviations; Acute Myelocytic Leukemia; Acute leukemia; Adult; Age; Allogenic; Apoptosis; Apoptotic; Automation; Automobile Driving; Behavior; Biochemical; Biochemical Pathway; Biochemical Process; Biological Assay; Biomedical Engineering; Cell Death; Cell Line; Cell model; Cells; Cellular Assay; Ceramidase; Ceramides; Chemicals; Chemotherapy-Oncologic Procedure; Clinical; Collaborations; Cytogenetics; DNA Sequence; Data; Development; Disease; Drug resistance; Engineering; Enzymes; Epigenetic Process; Equilibrium; Exhibits; Fluorescent Probes; Future; Gene Expression; Genes; Genetic; Glucosylceramides; Goals; Growth; Heterogeneity; Human; Hypoxia; In complete remission; Individual; Knowledge; Lead; Leukemic Cell; Link; Lipids; Lyase; Malignant Neoplasms; Measurement; Measures; Medical; Metabolism; Microfluidics; Modeling; Molecular; Monitor; Multi-Drug Resistance; Mutation; Neoadjuvant Therapy; Oncologist; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phosphoric Monoester Hydrolases; Play; Population; Procedures; Production; Prognosis; Proteins; Recording of previous events; Recurrent disease; Refractory Disease; Regimen; Relapse; Reporter; Research; Risk Assessment; Role; Sampling; Scientist; Signal Pathway; Signal Transduction; Specimen; Sphingolipids; Sphingomyelinase; Sphingomyelins; Sphingosine; Stem cell transplant; Survival Rate; System; Techniques; Testing; Therapeutic; Therapeutic Agents; Treatment Efficacy; Up-Regulation; Work; acute myeloid leukemia cell; arm; biological heterogeneity; cancer cell; ceramide 1-phosphate; ceramide kinase; chemotherapy; comorbidity; desaturase; design; dihydroceramide; dihydroceramide desaturase; drug efficacy; genomic signature; glycosylation; improved; individual patient; innovation; inorganic phosphate; insight; instrumentation; kinase inhibitor; leukemia; microdevice; molecular marker; mortality; multidisciplinary; neoplastic cell; new technology; non-genetic; novel; overexpression; precision medicine; prognostic; response; sphingosine 1-phosphate; sphingosine kinase; targeted treatment; technology development; treatment optimization; treatment response; tumor

An innovative platform to measure the activity of the sphingolipid pathway in single cells from primary, human, acute myeloid leukemia (AML) will be developed. A multidisciplinary group (chemist, bioengineer, oncologist and computational scientist) with a history of successful collaborations will pursue the development of engineered microfluidic instrumentation and supporting hardware using medically relevant probes to answer fundamental questions regarding heterogeneity in single AML cells. Fluorescent probes to track simultaneously the three major pathways comprising the ceramide-sphingosine axis in AML cells will be developed so that a detailed understanding of sphingolipid signaling in the tumor cells is achieved. Electrophoretic separations within a microfabricated device will be optimized for the single-cell measurements as a component of the work flow. Automation and integration will greatly increase throughput to yield a microdevice which is compatible with common clinical workflows. A powerful attribute of the proposal is that these measurements will be performed on single cells from primary samples and will avoid the confounding aspects of population- averaged data yielded by bulk cell assays. Furthermore, by simultaneously tracking all arms of the sphingolipid pathway, we will identify the strategies that AML cells use to dynamically reprogram their growth-promoting pathways via sphingolipid signaling during drug treatment. The proposed microfabricated devices will in the future provide key information concerning the best treatment option(s) for patients as well yielding an assessment of treatment efficacy to contribute fundamental data to the emerging field of precision medicine.

一个创新平台，用于测量单个单元中鞘脂途径的活性 将开发主要，人类，急性髓样白血病（AML）。一个多学科小组 （化学家，生物工程师，肿瘤学家和计算科学家）有成功的历史 合作将追求工程化的微流体仪器的开发，并 使用医学相关探针支持硬件来回答基本问题 关于单个AML细胞的异质性。荧光探针同时跟踪 包括AML细胞中的神经酰胺 - 闪氨酸轴的三个主要途径将是 开发，以使对肿瘤细胞中鞘脂信号传导的详细理解是 成就了。微观生育设备内的电泳分离将被优化 单细胞测量作为工作流程的组成部分。自动化和集成将 大大增加吞吐量以产生与常见临床兼容的微电位 工作流程。该提案的强大属性是将执行这些测量 在主要样品的单个细胞上，将避免种群的混杂方面 散装细胞分析产生的平均数据。此外，通过同时跟踪 鞘脂途径，我们将确定AML细胞动态使用的策略 在药物治疗过程中，通过鞘脂信号传导重新编程其生长途径。 拟议的微型制造设备将来将提供有关该设备的关键信息 患者的最佳治疗选择以及对治疗疗效的评估 为精密医学的新兴领域贡献基本数据。