Aptameric Modulation of Relaxivity in MRI Contrast Agents

描述（由申请人提供）：本项目的目标是开发下一代MRI造影剂的高灵敏度、靶向和生物响应性适体调节剂。 这些新试剂将提供体内额外的结构和功能信息，而这些信息是通过其他成像方式无法获得的。 在接下来的两年里，我们将提供金属离子络合物之间三种不同类型相互作用的初步表征（例如， Gd 3 +DOTA）和它们的基于谷胱甘肽的受体（适体），通过以下三个目的： 在目的1中，我们将研究当附着于钆造影剂的小分子与结合到这些分子的适体相互作用时发生的弛豫率的变化。 在目的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率的影响。 在目标3中，我们将针对携带多种造影剂的支架分离适体。 在后续研究中，我们将通过几种可能的机制来表征这些适体增强弛豫的能力。 在这个项目的最后，我们将提供几种方法来修改MRI造影剂弛豫的初步结果。 基于适体的方法是灵活的;单个适体可以容易地被工程化为寡聚体和高度组织化的结构，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。 公共卫生相关性：我们的目标是提供MRI造影剂的高灵敏度、靶向和生物响应性的基于寡核苷酸的（适体）调节剂。 在代谢和受体成像的背景下，这些调节剂将提供当前成像模式不可用的结构和功能信息。 我们将集中展示三种不同类型的相互作用，通过这些相互作用，预测适体调节剂可以增强MRI造影剂的弛豫性。 我们基于适体的方法的一个重要优势是其灵活性;例如，使用DNA纳米技术的原理，可以很容易地将单个受体工程化为寡聚和高度组织化的结构，并且可以使其对其他识别过程敏感。

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.