Arteriogenesis by Ultrasonic Microbubble Destruction

描述（申请人提供）：靶向刺激动脉生成，即小动脉和动脉的形成和管腔扩张，是治疗闭塞性血管疾病引起的缺血的一种很有前景的方法。迄今为止，创造治疗性动脉生成的尝试主要集中在选择生长因子基因和蛋白质的递送上：最近，我们开发了一种创新的新技术，基于超声造影剂微泡破坏，用于刺激缺血区域及其周围的动脉生成。这种动脉生成反应，可以使用超声束靶向选定的组织区域，伴随着治疗组织充血能力的增加，从而证明了该技术在恢复受动脉闭塞影响的器官的血液流动方面的潜力。在临床环境中，这种方法具有微创的潜力。本提案包括4个具体目标，广泛地解决超声微泡技术在增强血流量和合理操作技术以放大和潜在地延长动脉生成方面的临床潜力。第一个和第二个具体目标将分别测试超声微泡破坏对增强长期受血管闭塞影响的肌肉的血流量的功效，并确定哪些微血管重塑事件会产生血流量增强。第三个具体目标的研究将确定如何通过改变用户控制的因素来控制动脉发生和血流恢复，即微泡大小、微泡剂量、超声频率和应用时间。有了这些信息，我们将在临床相关的微泡剂量下制定一个优化的方案来产生动脉生成。在第四个具体目标中，我们将向动脉闭塞的肌肉输送含有促动脉生成生长因子（bFGF）或促动脉生成细胞因子（MCP-1）基因的聚乙烯亚胺（PEI）纳米复合物。这些最终的研究将结合最先进的细胞转染方法和超声靶向递送策略，目的是合理地控制动脉生成反应的大小和寿命。鉴于这种靶向基因传递方法的广泛适用性，很可能这些研究将对许多其他病理和疾病的调查和治疗产生重大影响。

DESCRIPTION (provided by applicant): The targeted stimulation of arteriogenesis, which is defined as the formation and lumenal expansion of the arterioles and arteries, is a promising treatment for ischemia caused by occlusive vascular disease. To date, attempts at creating therapeutic arteriogenesis have centered on the delivery of selected growth factor genes and proteins: Recently, we have developed an innovative new technique, based on contrast agent microbubble destruction with ultrasound, for stimulating arteriogenesis in and around regions of ischemia. This arteriogenic response, which may be targeted to selected tissue regions using the ultrasound beam, is accompanied by an increase in hyperemic capacity in the treated tissue, thereby demonstrating the potential of this technique for restoring blood flow to organs affected by arterial occlusion. In the clinical setting, this method has the potential to be performed with minimal invasiveness. This proposal consists of 4 specific aims that broadly address the clinical potential of the ultrasound- microbubble technique for enhancing blood flow and the rational manipulation of the technique for amplifying and potentially prolonging arteriogenesis. The first and second specific aims will respectively test the efficacy of ultrasonic microbubble destruction for enhancing blood flow to muscle that is chronically affected by vascular occlusion and establish which microvascular remodeling events create the flow enhancement. Studies for the third specific aim will determine how arteriogenesis and flow restoration can be controlled through alterations in user-controlled factors, namely microbubble size, microbubble dosage, ultrasound frequency, and application time. With this information, we will then develop an optimized protocol for generating arteriogenesis at a clinically relevant microbubble dosage. In the fourth specific aim, we will deliver polyethylenimine (PEI) nanocomplexes bearing genes for either a pro-arteriogenic growth factor (bFGF) or a pro-arteriogenic cytokine (MCP-1) to the arterially occluded muscle. These final studies will combine a state-of-the-art approach for cell transfection with an ultrasound targeted delivery strategy, with the goal of rationally manipulating the magnitude and longevity of the arteriogenesis response. Given the broad applicability of this targeted gene delivery method, it is likely these studies will have a significant impact on the investigation and treatment of many other pathologies and conditions.