Development of Quantitative Multi-Contrast Molecular Imaging

问题是，关于细胞和分子在体内的行为，有许多重要但尚未回答的生物学问题。尽管研究人员通过使用尖端工具将单个细胞映射到基因组，发现了大量信息，但在许多情况下，我们仍然不知道细胞群体在体内实际上是如何相互作用和行为的。已经开发了几种成像技术，可以在体内随着时间的推移监测细胞，但提供最高质量图像的技术不能提供定量信息，限制了我们的观察。此外，尽管我们已经开发了各种不同类型的造影剂，如Gd或氧化铁的成像技术，但几乎所有的研究都一次只使用一种造影剂。溶液磁共振成像(MRI)以其对从人体组织到混凝土的各种材料进行成像的能力而闻名。它还可以用来跟踪单个细胞和分子，这些细胞和分子已经被对比剂标记。该项目将开发和评估基于MRI的生物试剂的定量测量，这些生物试剂标记有超顺磁性氧化铁(SPIO)，与一种特殊的Gd试剂相结合，可以指示细胞何时死亡，也称为细胞凋亡。我的项目将有三个不同的步骤。在第一步中，我们将优化一种特殊类型的磁共振脉冲序列，称为磁共振指纹(MRF)。我们的实验室已经实现了这项技术，用于SPIO和Gd的成像，但目前它还不够快，不能在体内临床前使用。因此，我们将努力使这项技术更快、更准确。该计划的第二步将使用MRF来观察SPIO标记的细胞和测量细胞凋亡的Gd造影剂。因为这种试剂在濒临死亡的细胞中被修饰，所以它有两种独特的形式-a)只在濒临死亡的细胞中被捕获的版本，以及b)可以进入任何细胞但最终将被清除的探针的前体形式。我们将使用MRF来区分不同版本的探针，并仍然测量标记的细胞，看看是否对癌症治疗有反应。该计划的最后部分将优化该项目的专业数据分析。我们将看到一种名为放射组学的新兴自动化分析，它可以用来自动从大量成像数据中挑选出人眼看不到的重要特征。这一研究计划的影响描述了一系列连贯的项目，这些项目将开发和验证基于MRI的新工具，用于同时对两种类型的细胞和分子进行SPIO或Gd标记的量化。这项工作将产生先进的成像技术，这些技术在许多生物学领域具有广泛的适用性，并可以提高对基本免疫行为的理解，特别是在癌症治疗方面。

The Problem There are a number of important yet unanswered biological questions about how cells and molecules behave in the body (in vivo). Although researchers have discovered a large amount of information by using cutting edge tools to map individual cells down to the genome, in many cases we still don't understand how populations of cells actually interact and behave in the body. Several imaging techniques have been developed that allow monitoring of cells over time in vivo, but the techniques that offer the best quality images do not provide quantitative information, limiting our observations. Additionally, although we have developed technologies to image various different types of contrast agents like gadolinium (Gd) or iron oxide, almost all studies only use one agent at a time. The Solution Magnetic resonance imaging (MRI) is well known for its ability to image a large variety of materials, from human tissue to concrete. It can also be used to track individual cells and molecules that have been labeled with a contrast agent. This program will develop and evaluate MRI-based quantitative measurements of biological agents tagged with superparamagnetic iron oxide (SPIO) in combination with a special Gd agent that can indicate when cells are dying, also known as apoptosis. My project will have three distinct steps in it. In the first step, we will optimize a special type of MRI pulse sequence called magnetic resonance fingerprinting (MRF). Our lab has implemented this technique for imaging both SPIO and Gd, but right now it is not fast enough to use in vivo preclinically. We will therefore work to make this technique faster and even more accurate. The second step of the program will use MRF to look at SPIO-labeled cells and the Gd contrast agent that measures apoptosis. Because this agent is modified in cells that are dying, it has two unique forms - a) the version that gets trapped only in dying cells, and b) the precursor form of the probe that can get into any cells but will eventually be cleared. We will use MRF to distinguish between the different versions of the probe and still measure the labeled cells to see if there is a response to e.g. cancer therapy. The last part of the program will be to optimize the specialized data analysis for this project. We will look at an emerging type of automated analysis called radiomics, which can be used to automatically pick out important features in large amounts of imaging data that are not obvious to the human eye. The Impact This program of research describes a coherent sequence of projects that will develop and validate novel tools for simultaneous MRI-based quantification of two types of cells and molecules labeled with SPIO or Gd. This work will result in advanced imaging technologies that have broad applicability in a number of biological fields and can improve understanding of basic immunological behavior, particularly with respect to cancer therapies.