MR & Optical Diagnosis of Mitochondrial Metabolism and Dysfunction

先生

• 批准号: 8116600
• 负责人: KEVIN E CONLEY
• 金额: $ 52.22万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-02-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8116600
• 关键词: Achievement; Age; Aging; Blood; Blood Vessels; Cells; Chemicals; Clinical; Coupling; Cytochromes; Defect; Degenerative Disorder; Diabetes Mellitus; Diagnosis; Diagnostic; Diagnostic Procedure; Electron Transport; Enzymes; Functional disorder; Goals; Grant; Health; Heme aa3 Cytochrome Oxidase; Human; Hybrids; Limb structure; Magnetic Resonance; Magnetic Resonance Spectroscopy; Measurement; Measures; Metabolic Diseases; Metabolism; Methods; Mitochondria; Muscle; Nature; Nerve Degeneration; Noise; Optics; Oxidases; Phosphorylation; Positioning Attribute; Signal Transduction; Skeletal Muscle; Spectrum Analysis; Surface; Testing; Time; Translating; age related; analytical method; analytical tool; base; design; design and construction; in vivo; innovation; mitochondrial dysfunction; muscle aging; novel; tool; uptake

DESCRIPTION (provided by applicant): This application builds on our recent innovations involving a novel combination of magnetic resonance (MRS) and optical (OS) spectroscopic approaches for studying mitochondrial energetics in human muscle. Muscle provides a unique window on the mitochondrial defects that are at the center of a growing number of metabolic and degenerative diseases (e.g., diabetes, neurodegeneration and aging). In this competing renewal, we use the dual OS/MRS spectroscopy approach applied to skeletal muscle to develop diagnostic procedures for identifying defects in mitochondrial function. The proposed studies build on progress made over the tenure of this grant that have led to two key achievements: 1) a combined OS/MRS strategy for measuring chemical content and dynamics that yield energy fluxes and 2) new optical analytical tools that open the visible spectrum for exploitation in vivo. This progress has led to the first quantitative measurement of Oz uptake, which combined with ATP flux, measures mitochondrial coupling non-invasively in vivo. Aim #1 expands on this mitochondria! functional measurement and capitalizes on our ability to use the visible spectrum to develop a measurement of mitochondrial capacity based on cytochrome aas content. To achieve this, we will exploit new analytical methods that permit extending our optical spectroscopy into the visible wavelengths. Aim #2 combines new optical and MRS methods to determine cellular and vascular oxygenation in vivo. A novel optical wavelength shift analysis combined with quantification by MRS yields cellular oxygenation ([oxy-Mb]/total [Mb]) and blood oxygenation ([oxy-Hb]/total [Hb]). These oxygenation measurements have the potential to reveal vascular dysfunction, as well as calibrate our O2 uptake determinations. Aim #3 proposes to design, fabricate and implement a multimodal apparatus that will integrate optical spectroscopy with interleaved, multinuclear 1H and 31P MR spectroscopy. This apparatus uses the technological advances in Aims #1 and #2 to permit new measurements and increased signal-to- noise that will allow studies of mitochondrial function in human muscle in a single session of <90 min. Aim #4 translates this diagnostic tool to aging, which is accompanied by significant mitochondrial dysfunction and is a malady of considerable importance to the health of the nation. The ability to conduct such a complete analysis in a clinically feasible session will provide a unique diagnostic probe of the nature and extent of dysfunction in metabolic and degenerative disorders. Upon completion of this project we will be in position to translate our tools to standard wide bore 3T or other human magnets for use in a clinical setting.

描述（由申请人提供）：此申请基于我们最近的创新，涉及磁共振（MRS）和光学（OS）光谱方法的新型组合，用于研究人类肌肉中的线粒体能量。肌肉在线粒体缺陷上提供了一个独特的窗口，这是越来越多的代谢和退化性疾病（例如糖尿病，神经变性和衰老）的中心。在这种竞争的续订中，我们使用应用于骨骼肌的双OS/MRS光谱方法来开发诊断程序，以识别线粒体功能中的缺陷。拟议的研究基于该赠款的任期取得的进展，这导致了两个关键成就：1）OS/MRS的合并OS/MRS策略，用于测量产生能量通量的化学含量和动力学，以及2）新的光学分析工具，可以在体内开放可见的频谱。这一进展导致了OZ摄取的第一个定量测量，该测量与ATP通量结合使用，在体内测量了线粒体偶联的测量。目标＃1扩展了这个线粒体！功能测量并利用我们使用可见光谱以基于细胞色素AAS含量来开发线粒体能力的测量能力。为了实现这一目标，我们将利用新的分析方法，允许将光谱扩展到可见的波长中。 AIM＃2结合了新的光学和MRS方法，以确定体内细胞和血管氧合。一种新型的光波长移位分析与MRS的定量结合产生细胞氧合（[[oxy-Mb]/总[MB]）和血液氧合（[[oxy-hb]/total [hb]）。这些氧合测量值有可能揭示血管功能障碍，并校准我们的O2摄取测定。 AIM＃3提出了设计，制造和实施多模式的设备，该设备将将光谱与交织的，多核1H和31p MR光谱学整合在一起。该设备在目标＃1和2中使用技术进步来允许新的测量和增加信号噪声，从而可以在一个<90分钟的一次疗程中研究人类肌肉中的线粒体功能。 AIM＃4将这种诊断工具转化为衰老，伴随着严重的线粒体功能障碍，并且对国家健康非常重要。在临床上可行的会话中进行这样的完整分析的能力将为代谢和退化性疾病中功能障碍的性质和功能障碍提供独特的诊断探测。该项目完成后，我们将可以将我们的工具转换为标准的宽孔3T或其他人类磁铁，以用于临床环境。

项目成果

Gradient-enhanced FAWSETS perfusion measurements.

梯度增强 FAWSETS 灌注测量。

• DOI: 10.1016/j.jmr.2005.04.002
• 发表时间: 2005
• 期刊: Journal of magnetic resonance (San Diego, Calif. : 1997)
• 作者: Marro,KennethI;Lee,Donghoon;Hyyti,OutiM
• 通讯作者: Hyyti,OutiM

Shaking up glycolysis: Sustained, high lactate flux during aerobic rattling.

摇动糖酵解：有氧运动期间持续的高乳酸通量。

• DOI: 10.1073/pnas.98.2.723
• 发表时间: 2001
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: Kemper,WF;Lindstedt,SL;Hartzler,LK;Hicks,JW;Conley,KE
• 通讯作者: Conley,KE

Noninvasive in vivo small animal MRI and MRS: basic experimental procedures.

无创体内小动物 MRI 和 MRS：基本实验程序。

• DOI: 10.3791/1592
• 发表时间: 2009
• 期刊: Journal of visualized experiments : JoVE
• 作者: Lee,Donghoon;Marcinek,David
• 通讯作者: Marcinek,David

FAWSETS perfusion measurements in exercising skeletal muscle.

骨骼肌运动中的 FAWSETS 灌注测量。

• DOI: 10.1002/nbm.963
• 发表时间: 2005
• 期刊: NMR in biomedicine.
• 作者: Marro,KennethI;Hyyti,OutiM;Kushmerick,MartinJ
• 通讯作者: Kushmerick,MartinJ

Minimal shortening in a high-frequency muscle.

高频肌肉的最小缩短。

• DOI: 10.1242/jeb.00253
• 发表时间: 2003
• 期刊: The Journal of experimental biology
• 作者: Moon,BradR;Conley,KevinE;Lindstedt,StanL;Urquhart,MichaelR
• 通讯作者: Urquhart,MichaelR