Preclinical evaluation of IGF1 therapy for traumatic brain injury

描述(由申请者提供)：据估计，美国每年有150万人患有创伤性脑损伤(TBI)。幸存者经常遭受持续性的神经功能障碍，损害了他们的生活质量和生产力。尽管关于脑外伤复杂的病理生理机制的知识基础不断扩大，但还没有临床证明的治疗干预措施被确定。创伤性脑损伤导致急性神经血管损伤和细胞死亡，导致早期功能缺陷。功能的恢复可能受到受损大脑无法充分利用内源性修复机制的限制。这一建议的中心假设是，胰岛素样生长因子-1(IGF-1)的治疗将通过减轻神经血管损伤、增强创伤后神经再生和血管生成来改善神经行为功能。我们之前的研究表明，给予重组人IGF-1(rhIGF-1)可以改善脑损伤大鼠的运动和认知功能。然而，还没有研究检验IGF-1在受创伤的大脑中的神经保护或神经恢复能力。我们建议对IGF-1行为功效背后的多种潜在协同机制进行首次全面调查。重要的是，我们将评估在临床相关的8小时治疗窗口内开始的重组人IGF-1治疗的有效性，并展示持续保护至损伤后5周。在脑外伤的治疗中，IGF-1是一个很有前途的候选治疗药物，因为它具有神经保护特性，有助于维持或增强髓鞘形成。因此，在目标1中证明了在损伤后15分钟、3小时或8小时开始的7天系统输注重组人胰岛素样生长因子-1可以改善皮质撞击脑损伤小鼠的运动和认知功能之后，在目标2中，我们将检验IGF-1保护神经元丢失和轴突退化的假设。IGF-1还可以刺激祖细胞的增殖，促进神经元、少突胶质细胞和内皮细胞的分化，并增加大脑中的血管生成。因此，在目标3中，我们将检验这样一种假设，即注射重组人胰岛素样生长因子-1增强了颗粒下和脑室下区的神经发生。在目标4中，我们将使用新的血管灌流技术来量化使用重组人IGF-1或赋形剂治疗的脑损伤小鼠的总血管和血管生成密度，以验证IGF-1有效促进创伤后血管生成的假设。最后，在目标5中，我们将检验这样一个假设，即延迟48小时给药可以选择性地促进神经发生和血管形成，从而在缺乏急性神经保护的情况下导致认知恢复。这些数据将为了解受损大脑中IGF-1的神经血管靶点提供独特而有价值的见解。通过建立长期(损伤后长达5周)的组织学益处并将其与行为反应相关联，拟议的研究具有很高的临床影响的潜力。最终，我们的目标是提供一种催化剂，以加速将IGF-1疗法转化为临床应用，以改善脑外伤患者的健康和福祉。 公共卫生相关性：项目叙述鉴于创伤性脑损伤的高发病率和破坏性的社会经济成本，制定有效的治疗策略至关重要。我们建议的研究将提供多条证据，证明在临床可行的治疗窗口内开始使用胰岛素样生长因子-1治疗可以改善功能预后，减少脑挫伤后的脑损伤。这些研究将为这种生长因子如何保护受损的大脑提供新的见解，产生对将这种治疗方法转化为临床试验至关重要的信息。

DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) afflicts an estimated 1.5 million people each year in the US. Survivors often suffer persistent neurological dysfunction, compromising their quality of life and productivity. Despite the expanding base of knowledge regarding the complex pathophysiology of TBI, no clinically proven therapeutic interventions have been identified. TBI produces acute neurovascular damage and cell death, resulting in early functional deficits. Recovery of function may be limited by the inability of the injured brain to adequately harness endogenous repair mechanisms. The central hypothesis of this proposal is that treatment with insulin-like growth factor-1 (IGF-1) will improve neurobehavioral function through the attenuation of neurovascular damage and the augmentation of posttraumatic neurogenesis and angiogenesis. We previously showed that administration of recombinant human IGF-1 (rhIGF-1) improves motor and cognitive function in brain-injured rats. However, no studies have examined the neuroprotective or neurorestorative capabilities of IGF-1 in the traumatized brain. We propose to conduct the first comprehensive investigation of the multiple, potentially synergistic mechanisms underlying the behavioral efficacy of IGF-1. Importantly, we will evaluate the efficacy of rhIGF-1 treatment initiated within a clinically relevant therapeutic window of 8 hr and demonstrate sustained protection up to 5 weeks postinjury. In the setting of TBI, IGF-1 is a promising therapeutic candidate, as it has neuroprotective properties and helps to sustain or enhance myelination. Therefore, after demonstrating in Aim 1 that a 7 day systemic infusion of rhIGF-1, initiated at 15 min, 3 hr or 8 hr postinjury, improves motor and cognitive function in mice subjected to cortical impact brain injury, in Aim 2 we will test the hypothesis that IGF-1 protects against neuronal loss and axonal degeneration. IGF-1 is also known to stimulate proliferation of progenitor cells, promote neuronal, oligodendroglial and endothelial differentiation, and increase angiogenesis in the brain. Therefore, in Aim 3 we will test the hypothesis that infusion of rhIGF-1 enhances neurogenesis in the subgranular and subventricular zones. In Aim 4, we will employ novel vascular perfusion techniques to quantify densities of total and angiogenic vessels in brain- injured mice treated with rhIGF-1 or vehicle to test the hypothesis that IGF-1 effectively enhances posttraumatic angiogenesis. Finally, in Aim 5 we will test the hypothesis that rhIGF-1 administration delayed 48 hr can selectively enhance neurogenesis and angiogenesis resulting in cognitive recovery in the absence of acute neuroprotection. These data will provide unique and valuable insights into the neurovascular targets for IGF-1 in the injured brain. By establishing long term (up to 5 wks postinjury) histological benefits and correlating these with behavioral responses, the proposed studies have the potential for high clinical impact. Ultimately our goal is to provide a catalyst to accelerate the translation of IGF-1 therapy into clinical application in order to improve the health and well-being of individuals burdened with TBI. PUBLIC HEALTH RELEVANCE: Project Narrative In light of the high incidence and devastating socioeconomic costs of traumatic brain injury, development of an effective treatment strategy is of utmost importance. Our proposed studies will provide multiple lines of evidence that treatment with insulin-like growth factor-1 initiated within a clinically feasible therapeutic window improves functional outcome and reduces brain damage following contusion brain injury. These studies will provide new insights into how this growth factor protects the traumatized brain, yielding information critical to translating this treatment into clinical trials.