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: 8185414
• 负责人: KATHRYN E SAATMAN
• 金额: $ 32.48万
• 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/8185414
• 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; Wound Healing; 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; 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. 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.

描述（由申请人提供）：在美国，脑外伤（TBI）每年遭受约150万人的折磨。幸存者经常遭受持续的神经功能障碍，损害了他们的生活质量和生产力。尽管关于TBI复杂的病理生理学知识的基础不断扩大，但尚未确定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。功能的恢复可能会受到受伤的大脑无法充分利用内源性修复机制的限制。该提议的中心假设是，胰岛素样生长因子1（IGF-1）的治疗将通过衰减神经血管损伤和创伤后神经发生和血管生成的增强来改善神经行为功能。我们先前表明，重组人IGF-1（RHIGF-1）的给药可改善脑损伤大鼠的运动和认知功能。然而，尚无研究检查IGF-1在受创伤性大脑中的神经保护性或神经遗传能力。我们建议对IGF-1行为疗效的多重，潜在的协同机制进行首次全面研究。重要的是，我们将评估在8小时的临床相关治疗窗口内启动的RHIGF-1治疗的疗效，并在损伤后长达5周证明持续的保护。在TBI的环境中，IGF-1是具有神经保护特性的有前途的治疗候选者，有助于维持或增强髓鞘质量。因此，在AIM 1中证明了7天的系统性输注RHIGF-1在15分钟，3小时或8小时后发起的启动，改善了受皮质影响脑损伤的小鼠的运动和认知功能，在AIM 2中，我们将测试IGF-1的假设，即IGF-1可以预防神经元丧失和轴突变性。已知IGF-1还可以刺激祖细胞的增殖，促进神经元，寡头和内皮分化，并增加大脑的血管生成。因此，在AIM 3中，我们将检验以下假设：RHIGF-1的输注增强了粒状和脑室下区域的神经发生。在AIM 4中，我们将采用新型的血管灌注技术来量化用RHIGF-1或媒介物处理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AIM 5中，我们将检验以下假设：RHIGF-1给药延迟48小时可以选择性增强神经发生和血管生成，从而在没有急性神经保护的情况下导致认知恢复。这些数据将为受伤大脑中IGF-1的神经血管靶靶标提供独特而有价值的见解。通过建立长期（最多5周后）的组织学益处并将其与行为反应相关联，提出的研究可能会产生高临床影响。最终，我们的目标是提供一种催化剂，以加快IGF-1治疗为临床应用，以改善负担TBI负担的个人的健康和福祉。 公共卫生相关性：鉴于创伤性脑损伤的高发和毁灭性的社会经济成本，有效治疗策略的发展至关重要。我们提出的研究将提供多种证据，表明在临床上可行的治疗窗口内启动的胰岛素样生长因子1治疗可改善功能结果，并减少挫伤脑损伤后脑损伤。这些研究将为这种生长因子如何保护受创伤的大脑提供新的见解，从而产生将该治疗转化为临床试验至关重要的信息。