Preclinical evaluation of IGF1 therapy for traumatic brain injury

IGF1治疗创伤性脑损伤的临床前评价

• 批准号: 8485697
• 负责人: KATHRYN E SAATMAN
• 金额: $ 36.41万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-15 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8485697
• 关键词: Acute; Age; Attenuated; Axon; Behavioral; Blood Vessels; Brain; Brain Injuries; Bromodeoxyuridine; Cause of Death; Cell Death; Cells; Cerebral Ischemia; Cessation of life; Clinical; Clinical Trials; Cognition; Cognitive; Complex; Contusions; Cortical Contusions; Data; Demyelinations; Enrollment; Evaluation; Functional disorder; Goals; Health; Hippocampus (Brain); Human; IGF1 gene; Individual; Infusion procedures; Injury; Insulin-Like Growth Factor I; Investigation; Isolectin; Label; Learning; Measurement; Memory; Motor; Mus; Myelin; Nerve Degeneration; Neurologic Dysfunctions; Neurons; Outcome; Patients; Perfusion; Personal Satisfaction; Productivity; Proliferating; Property; Quality of life; Rattus; Recombinants; Recovery of Function; Research; Silver Staining; Spinal cord injury; Staining method; Stains; Stem cells; Survivors; Techniques; Testing; Therapeutic; Therapeutic Intervention; Time; Translations; Traumatic Brain Injury; angiogenesis; attenuation; axonal degeneration; brain repair; catalyst; cell injury; cell type; central nervous system injury; clinical application; clinically relevant; cognitive function; cognitive recovery; cognitive rehabilitation; controlled cortical impact; density; disability; functional outcomes; improved; injured; insight; knowledge base; myelination; neurobehavioral; neurogenesis; neuron loss; neuronal survival; neuroprotection; neurorestoration; novel; preclinical evaluation; rehabilitation strategy; repaired; response; stem; subventricular zone; tissue repair; tomato lectin

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.

描述（由申请人提供）：据估计，美国每年有 150 万人遭受创伤性脑损伤 (TBI) 的折磨。幸存者经常遭受持续的神经功能障碍，影响他们的生活质量和生产力。尽管关于 TBI 复杂病理生理学的知识基础不断扩大，但尚未确定经过临床证明的治疗干预措施。 TBI 会产生急性神经血管损伤和细胞死亡，导致早期功能缺陷。受损大脑无法充分利用内源性修复机制，可能会限制功能的恢复。该提案的中心假设是，胰岛素样生长因子-1 (IGF-1) 治疗将通过减轻神经血管损伤和增强创伤后神经发生和血管生成来改善神经行为功能。我们之前表明，给予重组人 IGF-1 (rhIGF-1) 可改善脑损伤大鼠的运动和认知功能。然而，尚无研究检验 IGF-1 在受创伤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 8 小时临床相关治疗窗口内开始的 rhIGF-1 治疗的疗效，并证明在受伤后长达 5 周的持续保护作用。在 TBI 中，IGF-1 是一种有前途的治疗候选药物，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，在损伤后 15 分钟、3 小时或 8 小时开始全身输注 rhIGF-1 7 天，可以改善遭受皮质冲击性脑损伤的小鼠的运动和认知功能，在目标 2 中，我们将测试IGF-1 可以防止神经元丢失和轴突变性的假设。 IGF-1 还可以刺激祖细胞增殖，促进神经元、少突胶质细胞和内皮细胞分化，并增加大脑中的血管生成。因此，在目标 3 中，我们将检验输注 rhIGF-1 增强颗粒下区和脑室下区神经发生的假设。在目标 4 中，我们将采用新型血管灌注技术来量化经 rhIGF-1 或媒介物治疗的脑损伤小鼠的总血管和血管生成血管的密度，以检验 IGF-1 有效增强创伤后血管生成的假设。最后，在目标 5 中，我们将测试以下假设：延迟 48 小时给予 rhIGF-1 可以选择性地增强神经发生和血管生成，从而在缺乏急性神经保护的情况下导致认知恢复。这些数据将为受损大脑中 IGF-1 的神经血管靶点提供独特且有价值的见解。通过建立长期（受伤后长达 5 周）的组织学益处并将其与行为反应相关联，拟议的研究具有产生巨大临床影响的潜力。我们的最终目标是提供催化剂，加速 IGF-1 疗法转化为临床应用，以改善 TBI 患者的健康和福祉。