MRI Probes for Mapping Retinal Activity In Vivo

描述：（申请人？s摘要）本提案描述了 用于视网膜活动的三维成像的探针。这些探针是 对膜敏感的磁共振成像（MRI）造影剂 潜力正是水质子的信号提供了图像， 典型的MRI图像和造影剂与水相互作用， 信号了在我们以前的工作中，我们已经表明，通过阻止 我们能“关掉”的造影剂增强，然后 通过移除块来选择性地“打开”增强。在这些以前的 在实验中，我们向造影剂中加入了一个封闭基团， 通过酶切割，因此信号增强依赖于酶 乳沟基于这些结果，我们假设我们可以调节 药剂通过添加敏感基团增强MRI信号的能力 从而使信号增强依赖于膜电位， 活动在我们的研究设计中，我们建议： 1)基于已知的光学指示剂设计和合成一种代理， 膜电位 2)表征新试剂在无细胞环境中增强对比度的能力 和细胞培养系统。 3)进行研究，导致新药物在眼睛中的应用， vivo.这些研究包括确定最佳的交付路线， 制剂，及其在模型动物研究中的生物分布。 这些研究最终将扩展到视网膜病变的啮齿动物模型。 变性，以绘制视网膜活动随时间的丧失，并将 结果与传统方法观察到的结果一致。拟议预算的结果 研究将提供一种非侵入性的方法来成像膜活动在深 组织;这可能有助于视网膜疾病的早期诊断。虽然我们的 最终目标是将这些药物应用于黄斑变性的研究， 这些试剂将用于观察任何系统，其中膜 信号传导活动发挥作用。

DESCRIPTION: (Applicant?s Abstract) This proposal describes the development of probes for three-dimensional imaging of retinal activity. These probes are magnetic resonance imaging (MRI) contrast agents that are sensitive to membrane potentials. It is the signal from water protons that provides the image in typical MRI images and contrast agents interact with water to enhance that signal. In our previous work we have shown that by blocking the interaction of water with the contrast agent we can "turn off? enhancement, and then selectively "turn on" enhancement by removing the block. In these previous experiments we added a blocking group to the contrast agent that is removable by enzyme cleavage, so that signal enhancement was dependent upon enzyme cleavage. Based on these results we hypothesize that we can modulate the ability of an agent to enhance MRI signal by adding a group that is sensitive to membrane potentials, thus making signal enhancement dependent on membrane activity. In our research design we propose to: 1) Design and synthesize an agent based on a known optical indicator of membrane potentials 2) Characterize the ability of the new agent to enhance contrast in cell-free and cell culture systems. 3) Perform studies leading to the application of the new agents in eyes in vivo. These studies include determining the optimal route of delivery for the agent, and its biodistribution in model animal studies. These investigations will ultimately be extended to rodent models of retinal degeneration to map the loss of retinal activity over time and correlate the results with those observed by traditional methods. Results of the proposed studies will provide a noninvasive method to image membrane activity in deep tissues; this may aid in the early diagnosis of retinal disease. While our ultimate goal is to apply these agents in studies of macular degeneration, these agents would be useful for observations of any system in which membrane signaling activity plays a role.