Discrete Wavelength Frequency Domain Near Infrared Spectroscopy for Non-Invasive Measurement of Cytochrome Oxidation State

项目总结/摘要（描述） 全球十大死亡原因中有四个与氧气供应有关：需求不匹配（2）和两个 涉及感染过程（2）已知影响线粒体，（27）产氧 在哺乳动物中产生大部分ATP的细胞器。尽管氧化的基本功能 磷酸化（OXPHOS）在人类生存中的作用，（28）和OXPHOS的破坏发生在各种 疾病状态，我们对缺氧细胞死亡的确切过程的理解仍然不完全 明白（28 - 30）本提案的目的是构建和实验验证频域 近红外光谱（NIRS）仪器，其能够测量氧化的和 还原形式的细胞色素aa3，电子传递链（ETC）的末端组分。我们漫长 一个长期目标是开发一种能够在线粒体水平检测器官缺血的患者监测器 (ETC功能障碍），以促进预防和治疗主要死因。我们的核心假设是 工程学的新兴进步，特别是先进光子探测器的使用（例如， 硅光电倍增管[SiPM]）以及近红外辐射（NIR）波长的新组合，将 允许准确测量CytOX。我们将测试我们的中心假设，并通过实现我们的目标， 具体目标1：选择波长数和频率。使用计算机模拟， 我们将测试所有可能的商业可用的激光波长的组合，这些激光波长可以在 100 MHz，以确定在准确度（CytOX）之间提供最有吸引力的折衷的组合 针对宽带进行验证）和简单性（最少数量的波长）; 具体目标2：优化光子检测。在实验室环境中，我们将测试近 红外激光和扩展范围的光电倍增管的组合，以确定适合的频率 CytOX（细胞色素aa3的氧化态）的结构域光谱测量;特定目标3：构建体 并测试功能正常的FD-NIRS设备以测量CytOX。我们将构建并测试一个频域 能够测量血红蛋白（氧合、脱氧）绝对浓度的仪器， 细胞色素aa3（氧化，还原）在准生物组织模型。

PROJECT SUMMARY / ABSTRACT (DESCRIPTION) Four of the top 10 worldwide causes of death are related to oxygen supply:demand mismatching,(2) and two involve infectious processes(2) which are known to impact the mitochondria,(27) the oxygen-producing organelles which generate the majority of ATP in mammals. Despite the essential function of oxidative phosphorylation (OXPHOS) in human survival,(28) and the disruption of OXPHOS that occurs in a variety of disease states, our understanding of the exact process of hypoxic cell death remains incompletely understood.(28-30) This proposal’s objective is to construct and experimentally validate a frequency-domain near infrared spectroscopy (NIRS) instrument capable of measuring absolute concentrations of oxidized and reduced forms of cytochrome aa3, the terminal component of the electron transport chain (ETC). Our long term goal is to develop a patient monitor capable of detecting organ ischemia at the level of the mitochondria (ETC dysfunction) to facilitate prevention and treatment of leading causes of death. Our central hypothesis is that combination of emerging advances in engineering, in particular the use of advanced photon detectors (e.g. silicon photomultipliers [SiPM]) as well as novel combinations of near infrared radiation (NIR) wavelengths, will allow for accurate measurement of CytOX. We will test our central hypothesis and achieve our objective via the following specific aims: Specific Aim 1: Select Wavelength Number and Frequency. Using in silico simulation, we will test all possible combinations of commercially available wavelengths of lasers that can be modulated at 100 MHz to determine the combinations which offer the most attractive tradeoff between accuracy (CytOX validated against broadband) and simplicity (least number of wavelengths), using a pre-existing dataset; Specific Aim 2: Optimize Photon Detection. In a laboratory environment, we will test combinations of near infrared laser light and extended range photomultiplier tubes to identify a combination suitable for frequency domain spectroscopy measurement of CytOX (the oxidation state of cytochrome aa3); Specific Aim 3: Construct and Test a Functioning FD-NIRS Device to Measure CytOX. We will construct and test a frequency domain instrument capable of measuring absolute concentrations of hemoglobin (oxygenated, de-oxygenated) and cytochrome aa3 (oxidized, reduced) in a quasi-biological tissue phantom.