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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

基本信息

批准号：
8384396
负责人：
Kayvan R Keshari
金额：
$ 8.77万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-01 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8384396
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 Neoplasms 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 rapid detection research clinical testing response skills small molecule tissue culture tissue/cell culture treatment planning

项目摘要

DESCRIPTION (provided by applicant): 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 i 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. PUBLIC HEALTH RELEVANCE: Through this Pathway to Independence Award project, I will gain the necessary knowledge and training to become a faculty member with an independent research program focused on the engineering and implementation of novel 3D cell and tissue culture bioreactors, and the use this platform in conjunction with hyperpolarized MR to better study cancer metabolism.

描述（由申请人提供）：通过获得独立之路奖，我希望获得必要的技能，获得一个独立研究项目的教职职位，该项目专注于生物工程和新型 3D 细胞和组织培养生物反应器的实施，并使用该平台与超极化 (HP) 13C MR 结合更好地研究癌症代谢。由于前列腺癌的生物学和病理学复杂性，临床迫切需要开发更灵敏和特异的成像标记物，以改善前列腺癌患者的特异性治疗计划和治疗失败的早期评估。利用超极化 (HP) 代谢底物的非凡新技术有可能提供这些 MR 生物标志物。最近在细胞和动物模型中进行的 HP MR 研究表明，HP 代谢标志物反映了酶通量，并且可以更准确地测量前列腺癌的存在、进展和治疗反应。然而，现有的小鼠和细胞培养模型不能可靠地模拟人类疾病，因此我们提出了一种 HP 13C MR 和 NMR 兼容的 3D 组织培养生物反应器的新型组合，用于研究活人前列腺组织切片 (TSC) 的实时代谢。这项研究的总体目标是设计一种与 NMR 兼容的 3D 组织培养生物反应器，用于人类 TSC，并用它来识别 HP 分子成像标记，以改进前列腺癌患者的特异性治疗计划和对靶向治疗反应的早期评估。实现这些目标需要在原代细胞和组织培养、前列腺生物化学和病理学、HP 探针开发、微工程、生物转运和药代动力学等领域进行额外的培训。利用这种新的培训，第一个目标是优化在 NMR 兼容的 3D 组织培养生物反应器中维持人类前列腺 TSC 的条件，并验证 TSC 随着时间的推移的代谢完整性。连续 31P 将用于监测生物反应器中组织切片随时间的进展。 HP 13C MR 的动态采集将用于实时计算与丙酮酸和其他探针代谢相关的通量。该数据将与生物反应器中培养前后的组织病理学进行比较，以评估变化。第二个目的是利用这种新的实验模型来比较正常和恶性前列腺组织的代谢，重要的是确定 HP 代谢物是否与病理分级及其与代谢和生物转运的关系相关。第三个目标是利用该平台来识别 PI3K/mTOR 抑制剂治疗反应的 HP 标记物。该提案的目标是开发一种工程系统，该系统可以克服当前小鼠和细胞培养模型的局限性，并有助于开发相关生物标志物以转化为临床。虽然该独立之路奖的研究重点是前列腺癌，但 NMR 兼容的原代组织培养生物反应器平台与高灵敏度 HP MR 探针的结合将在各种疾病和成像模式中具有广泛的适用性。公共健康相关性：通过这个独立之路奖项目，我将获得必要的知识和培训，成为一名独立研究项目的教职人员，该项目专注于新型 3D 细胞和组织培养生物反应器的工程和实施，并结合使用该平台与超极化 MR 来更好地研究癌症代谢。