IGF::OT::IGF SBIR TOPIC 85 TO SUPPORT THE DEVELOPMENT OF TARGET SPECIFIC MOLECULAR IMAGING AGENTS IN COMBINATION WITH EXISTING IMAGING MODALITIES TO DETECT HIGH RISK ATHEROSCLEROTIC PLAQUE.

本项目的长期目标是开发一种用于检测和表征易损斑块的超声造影剂。易损斑块是导致心肌梗死和中风的原因。易损斑块的早期检测将使干预能够在心脏病发作或中风发生之前进行。在第一阶段，我们希望在小鼠模型中显示可行性，并验证在人类易损斑块标本中相同表位的表达。在目的1中，将制备靶向易损斑块中存在的表位的微泡（MB）：VCAM-1、失调的VWF多聚体、P-选择素和LOX-1。MB将在晚期炎性斑块的小鼠模型中使用对比增强超声分子成像读数进行测试。在目的2中，我们将在小鼠和人颈动脉内膜切除术标本中用VCAM-1、GPIB-α、P-选择素和LOX-1的抗体测试表位的存在。我们预期靶向VCAM-1、VWF、P选择素或LOX-1的一种或多种MB将增强易损斑块的超声检测，并且抗体研究将证实在鼠和人易损斑块中表达相同的表位。在第二阶段，我们将开发专门针对人类表位的微泡。

The long-term objective of this project is to develop an ultrasound contrast agent for detecting and characterizing vulnerable plaque. Vulnerable plaque is responsible for myocardial infarction and stroke. Early detection of vulnerable plaque would enable intervention to be performed before heart attack or stroke has occurred. In Phase I we expect to show feasibility in a mouse model and also to verify expression of the same epitopes in human specimens of vulnerable plaque. In Objective 1 microbubbles (MB) will be prepared targeted to epitopes present in vulnerable plaque: VCAM-1, dysregulated VWF multimers, P-selectin and LOX-1. MB will be testing using contrast enhanced ultrasound molecular imaging readout in a murine model of advanced inflammatory therosclerotic plaque. In Objective 2 we will test for presence of epitopes with antibodies to VCAM-1, GPIB-alpha, P-selectin and LOX-1 in the mice and also in human carotid endarterectomy specimens. We expect that one or more of the MB targeted to either VCAM-1, VWF, Pselectin or LOX-1 will enhance vulnerable plaque for detection by ultrasound and that the antibody studies will confirm expression of the same epitopes in both murine and human vulnerable plaque. In Phase II we will develop microbubbles specifically targeted to human epitopes.