Novel methodology for studing oxidative metabolism

研究氧化代谢的新方法

• 批准号: 7169909
• 负责人: Ravinder Reddy
• 金额: $ 33.81万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-10 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7169909
• 关键词: Affect; Alzheimer' s Disease; Animal Model; Animals; Arteries; Blood; Blood Volume; Blood flow; Blood specimen; Brain; Breathing; Carotid Arteries; Cell Respiration; Cerebral Ischemia; Cerebrovascular Circulation; Cerebrum; Clinical Research; Condition; Coupled; Data; Detection; Development; Equation; Evaluation; Family suidae; Gases; Goals; Gold; Human; Image; Imaging Techniques; Invasive; Literature; Lung Capacity; Magnetic Resonance Imaging; Maps; Measurement; Measures; Metabolic; Methodology; Methods; Modeling; NMR Spectroscopy; Neurons; Organ; Oxygen Consumption; Parkinson Disease; Physiology; Positron-Emission Tomography; Principal Investigator; Procedures; Production; Property; Protons; Radiation; Radioisotopes; Rate; Rattus; Reaction; Research; Research Personnel; Resolution; Respiratory System; Safety; Schizophrenia; Source; Spin Labels; Standards of Weights and Measures; System; Techniques; Testing; Time; Tissues; Water; Weight; base; cost; design; efficacy evaluation; human study; improved; in vivo; magnetic field; nervous system disorder; novel; programs; research study; soft tissue; tool; wasting

DESCRIPTION (provided by applicant): Oxygen consumption provides vital information about neuronal activity. Neurological disorders such as Alzheimer's disease, Parkinson's disease, and schizophrenia are associated with hampered enzymatic activity that catalyzes the reaction of oxidative metabolism. Oxygen consumption also has the potential for detecting regions of viable tissue following cerebral ischemia. Quantitative mapping of cerebral oxygen consumption contributes to the better understanding of the patho-physiology of several neurological disorders. A current method for such measurements is positron emission tomography (PET), which provides a low-resolution image and involves radioactive isotopes. Current 17O magnetic resonance imaging (MRI) based methods, have limitations such as low sensitivity and requirement of invasive procedure and requirement of ultra-high magnetic fields. These limitations, coupled with the high cost of 17O2 gas, limit the applicability of direct 17O MRI methods to small animal studies. Consequently, there are no non-invasive methods for measuring oxygen consumption in humans in vivo combining safety with high spatial and temporal resolution. This proposal deals with the development of an integrated approach that combines an efficient 17O2 gas delivery system with improved, noninvasive, MRI strategies for computing cerebral metabolic rate of oxygen consumption (CMRO2). Specifically, an efficient 17O2 gas delivery system, that reduces the 17O2 gas requirement by an order of magnitude will be designed and optimized for use on large animals and in humans. Efficacy of this system will be tested on a swine model. MRI methods will be designed to measure arterial input function of metabolically produced water (mpH217O) and cerebral blood flow. Finally, the above-mentioned system and MRI techniques will be integrated into an improved MRI strategy for measuring mpH217O to compute CMRO2 in the brain in vivo. Once the aims are accomplished, a noninvasive tool will become available to measure CMRO2 with high spatial resolution, which can be immediately extended to in vivo human studies. This approach will have substantial impact on the both scientific and clinical studies of neurological disorders and in the development and evaluation of novel therapies.

描述（由申请人提供）：氧气消耗提供关于神经元活动的重要信息。神经系统疾病，如阿尔茨海默病、帕金森病和精神分裂症，与催化氧化代谢反应的酶活性受阻有关。氧消耗也有可能检测脑缺血后存活组织的区域。脑氧消耗的定量映射有助于更好地理解几种神经系统疾病的病理生理学。目前的一种测量方法是正电子发射断层扫描（PET），它提供低分辨率的图像，并涉及放射性同位素。目前基于磁共振成像（MRI）的方法存在灵敏度低、对侵入性操作要求低、对超高磁场要求等局限性。这些局限性，加上17O2气体的高成本，限制了直接17O MRI方法在小动物研究中的适用性。因此，目前还没有一种既安全又具有高时空分辨率的无创人体体内耗氧量测量方法。本提案涉及一种综合方法的开发，该方法将高效的17O2气体输送系统与改进的无创MRI策略相结合，用于计算脑代谢耗氧量（cmor2）。具体来说，将设计和优化一种高效的17O2气体输送系统，将17O2气体的需求减少一个数量级，用于大型动物和人类。该系统的有效性将在猪模型上进行测试。将设计MRI方法来测量代谢产生的水（mpH217O）和脑血流的动脉输入功能。最后，将上述系统和MRI技术整合到一种改进的MRI策略中，用于测量mpH217O，以计算体内大脑中的cmor2。一旦目标实现，一种非侵入性工具将可用于测量CMRO2的高空间分辨率，这可以立即扩展到体内人体研究。这种方法将对神经系统疾病的科学和临床研究以及新疗法的开发和评估产生重大影响。