Development of Quantitative Multi-Contrast Molecular Imaging

关于细胞和分子在体内是如何活动的，有许多重要但尚未得到解答的生物学问题。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，已经发现了大量的信息，但在许多情况下，我们仍然不了解细胞群体在体内的实际相互作用和行为。已经开发了几种成像技术，可以随着时间的推移在体内监测细胞，但是提供最佳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成像各种不同类型的造影剂，如钆（Gd）或氧化铁的技术，但几乎所有的研究一次只使用一种造影剂。磁共振成像（MRI）以其对从人体组织到混凝土等多种材料进行成像的能力而闻名。它还可以用来追踪被造影剂标记的单个细胞和分子。该项目将开发和评估基于mri的生物制剂的定量测量，这些生物制剂被超顺磁性氧化铁（SPIO）与一种特殊的Gd制剂联合使用，可以指示细胞何时死亡，也称为凋亡。我的项目将分为三个不同的步骤。在第一步，我们将优化一种特殊类型的MRI脉冲序列，称为磁共振指纹（MRF）。我们的实验室已经将这种技术用于SPIO和Gd的成像，但目前还不够快，无法在体内临床前使用。因此，我们将努力使这项技术更快，甚至更准确。该计划的第二步将使用磁共振成像来观察spio标记的细胞和测量细胞凋亡的Gd造影剂。由于这种试剂在垂死的细胞中被修饰，它有两种独特的形式——a)只被困在垂死的细胞中，b)探针的前体形式可以进入任何细胞，但最终会被清除。我们将使用核磁共振成像来区分不同版本的探针，并测量标记的细胞，看看是否对癌症治疗有反应。程序的最后一部分将是优化这个项目的专业数据分析。我们将研究一种新兴的自动分析技术，称为放射组学，它可以用来自动从大量的成像数据中挑选出人眼不明显的重要特征。该研究项目描述了一个连贯的项目序列，将开发和验证新工具，用于同时基于mri的两种类型的细胞和标记为SPIO或Gd的分子的定量。这项工作将产生先进的成像技术，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.