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

基本信息

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
项目类别：
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

项目摘要

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.

测量单细胞鞘脂通路活性的创新平台将开发出原发性人类急性髓性白血病（AML）。多学科小组（化学家、生物工程师、肿瘤学家和计算科学家）具有成功的历史合作将致力于开发工程微流体仪器和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。荧光探针同时追踪 AML细胞中构成神经酰胺-鞘氨醇轴的三个主要途径将是开发以便详细了解肿瘤细胞中的鞘脂信号传导实现了。微制造装置内的电泳分离将针对单细胞测量作为工作流程的一部分。自动化和集成将大大提高了生产量，以产生与常见临床兼容的微型设备工作流程。该提案的一个强大属性是这些测量将被执行对来自初级样本的单细胞进行分析，将避免群体的混淆方面大量细胞测定产生的平均数据。此外，通过同时跟踪所有手臂通过鞘脂途径，我们将确定 AML 细胞动态地使用的策略在药物治疗期间通过鞘脂信号重新编程其生长促进途径。所提出的微加工设备将在未来提供有关为患者提供最佳治疗方案，并对治疗效果进行评估为新兴的精准医学领域贡献基础数据。