Arteriogenesis by Ultrasonic Microbubble Destruction

描述（由申请人提供）：动脉生成的靶向刺激（定义为小动脉和动脉的形成和管腔扩张）是闭塞性血管疾病引起的缺血的有前景的治疗方法。迄今为止，在创建治疗性动脉生成的尝试集中在选定的生长因子基因和蛋白质的交付：最近，我们已经开发出一种创新的新技术，基于造影剂微泡破坏与超声，刺激动脉生成和周围地区的缺血。这种动脉生成反应可以使用超声波束靶向选定的组织区域，伴随着治疗组织中充血能力的增加，从而证明了这种技术用于恢复受动脉闭塞影响的器官的血流的潜力。在临床环境中，这种方法有可能以最小的侵入性进行。该提案包括4个具体目标，广泛阐述了超声微泡技术增强血流的临床潜力以及合理操作该技术以增强和潜在延长动脉生成。第一个和第二个具体目标将分别测试超声微泡破坏用于增强流向长期受血管闭塞影响的肌肉的血流的功效，并确定哪些微血管重塑事件产生了血流增强。第三个具体目标的研究将确定如何通过改变用户控制因素（即微泡尺寸、微泡剂量、超声频率和应用时间）来控制动脉生成和血流恢复。有了这些信息，我们将开发一种优化的协议，用于在临床相关的微泡剂量下产生动脉生成。在第四个具体目标中，我们将向动脉闭塞的肌肉递送携带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联合收割机一个国家的最先进的细胞转染的方法与超声靶向输送策略，与合理操纵的幅度和寿命的动脉生成反应的目标。鉴于这种靶向基因递送方法的广泛适用性，这些研究可能会对许多其他病理和病症的研究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.