Aptameric Modulation of Relaxivity in MRI Contrast Agents

描述（由申请人提供）：该项目的目标是开发下一代高灵敏度、靶向性和生物反应性的核磁共振造影剂适配体调节剂。这些新试剂将提供体内额外的结构和功能信息，否则无法通过其他成像方式获得。在接下来的两年里，我们将提供金属离子配合物（例如Gd3+DOTA）与其寡核苷酸受体（适配体）之间三种不同类型相互作用的初步表征，通过以下三个目标：在目标1中，我们将研究附着在钆造影剂上的小分子与与这些分子结合的适配体相互作用时发生的弛豫变化。在Aim 2中，我们将首先分离与MRI造影剂结合的寡核苷酸受体，然后研究适体结合对弛豫的影响。在Aim 3中，我们将分离适合体对抗携带多种造影剂的支架。在后续研究中，我们将通过几种可能的机制来描述这些适体增强弛豫性的能力。在本项目结束时，我们将提供几种改变MRI造影剂弛豫度的方法的初步结果。基于适体的方法是灵活的；单个适配体可以很容易地设计成寡聚和高度有组织的结构，并且可以对其他识别过程敏感。因此，该项目的主要意义在于我们将为受体和代谢成像开辟全新的场所。

DESCRIPTION (provided by applicant): The goal of this project is to develop the next generation of highly-sensitive, targeted, and bio- responsive aptameric modulators of MRI contrast agents. These new reagents would provide in vivo additional structural and functional information, not otherwise available through other imaging modalities. Over the next two years we will provide initial characterization of three different types of interactions between metal ion complexes (e.g., Gd3+DOTA) and their oligonucleotide-based receptors (aptamers), through the following three aims: yIn Aim 1 we will study changes in relaxivity that occur when small molecules attached to gadolinium contrast agents interact with aptamers binding to those molecules. yIn Aim 2 we will first isolate oligonucleotide receptors binding to MRI contrast agents, and then study the impact of aptamer binding on relaxivity. yIn Aim 3 we will isolate aptamers against scaffolds carrying multiple contrast agents. In a follow- up study we will characterize the ability of these aptamers to enhance relaxivity by several possible mechanisms. At the end of this project we will provide preliminary results for several approaches to modify the relaxivity of MRI contrast agents. The approaches based on aptamers are flexible; individual aptamers can be readily engineered into oligomeric and highly-organized structures, and can be made sensitive to other recognition processes. Thus, the main significance of this project is that we will open completely new venues for receptor and metabolic imaging. PUBLIC HEALTH RELEVANCE: Our goal is to provide highly-sensitive, targeted, and bio-responsive oligonucleotide-based (aptameric) modulators of MRI contrast agents. In the context of metabolic and receptor imaging these modulators will provide structural and functional information not available with current imaging modalities. We will focus on demonstrating three different types of interactions through which aptameric modulators are predicted to enhance the relaxivity of MRI contrast agents. An important advantage of our approach based on aptamers is in its flexibility; for example, individual receptors can be readily engineered into oligomeric and highly-organized structures using principles of DNA nanotechnology, and can be made sensitive to other recognition processes.