Human Tissue Culture Bioreactor and Hyperpolarized MR for Biomarker Discovery

用于生物标志物发现的人体组织培养生物反应器和超极化 MR

• 批准号: 8670990
• 负责人: Kayvan R Keshari
• 金额: $ 24.9万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8670990
• 关键词: Affect; Animal Model; Area; Award; Benign; Biochemistry; Bioenergetics; Biological Markers; Biomedical Engineering; Bioreactors; Cancer Patient; Cell Culture Techniques; Cell model; Cells; Clinic; Clinical; Data; Development; Disease; Drug Kinetics; Encapsulated; Engineering; Experimental Models; Faculty; Failure; Gases; Gene Expression; Genetic Markers; Goals; Histopathology; Hour; Human; Image; Imaging Techniques; Individual; Knowledge; Label; Life; Malignant - descriptor; Malignant neoplasm of prostate; Measures; Metabolic; Metabolic Marker; Metabolism; Methods; Modeling; Monitor; Mus; Oncogenic; Pathologic; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacotherapy; Phase; Physiological Processes; Positioning Attribute; Prostate; Prostate Cancer therapy; Proteins; Pyruvate; Pyruvate Metabolism Pathway; Research; Signal Transduction; Slice; System; Techniques; Therapeutic; Therapeutic Agents; Time; Tissues; Training; Translating; Translations; Work; cellular pathology; human FRAP1 protein; human disease; human tissue; imaging modality; improved; in vivo; inhibitor/antagonist; mTOR Inhibitor; member; molecular imaging; novel; pharmacodynamic model; programs; prostate cancer model; public health relevance; rapid detection; research clinical testing; response; skills; small molecule; tissue culture; tissue/cell culture; treatment planning; tumor metabolism

Project Summary Through this Pathway to Independence Award, I hope to acquire the skills necessary to obtain a faculty position with an independent research program focused on the bioengineering and implementation of novel 3D cell and tissue culture bioreactors, and the use this platform in conjunction with hyperpolarized (HP) 13C MR to better study cancer metabolism. Due to the biologic and pathologic complexity of prostate cancer, there is an urgent clinical need to develop more sensitive and specific imaging markers for improved prostate cancer patient-specific treatment planning and early assessment of therapeutic failure. An extraordinary new technique utilizing hyperpolarized (HP) metabolic substrates has the potential to provide these MR biomarkers. Recent HP MR studies in cell and animal models suggest that HP metabolic markers reflect enzymatic fluxes and may provide a more accurate measure of prostate cancer presence, progression and response to therapy. However, available murine and cell culture models don't reliably mimic human disease, thus we propose a novel combination of HP 13C MR and NMR-compatible 3D tissue culture bioreactors to study the real-time metabolism of living human prostate tissue slices (TSCs). The overall objective of this research are to engineer an NMR-compatible, 3D Tissue Culture Bioreactor for use with human TSCs and use it to identify HP molecular imaging markers for improved prostate cancer patient- specific treatment planning and early assessment of response to targeted therapy. Accomplishing these aims will require additional training in the areas of primary cell and tissue cultures, prostate biochemistry and pathology, HP probe development, micro-engineering, biotransport, and pharmacokinetics. Utilizing this new training, the first aim is to optimize conditions for maintaining human prostate TSCs in an NMR-compatible, 3D tissue culture bioreactor and to verify the metabolic integrity of TSCs over time. Continuous 31P will be used to monitor the progression of tissue slices in the bioreactor with time. Dynamic acquisitions of HP 13C MR will be used to calculate fluxes associated with metabolism of pyruvate and other probes in real time. This data will be compared to histopathology before and after culture in the bioreactor to assess changes. The second aim is to use this new experimental model to compare normal and malignant prostate tissues metabolism, and importantly, determine whether HP metabolites correlate with pathologic grade and their relationship to metabolism and biotransport. The third aim is to use this platform to identify HP markers of therapeutic response to PI3K/mTOR inhibitors. It is the goal of this proposal to develop an engineered system, which can overcome the limitations of current murine and cell cultures models and aid in the development of relevant biomarkers for translation to the clinic. While the focus of the research in this Pathway to Independence Award is on prostate cancer, the combination of NMR-compatible primary tissue culture bioreactor platform combined with high sensitivity HP MR probes would have wide applicability across a variety of diseases and imaging modalities.

项目总结