Neuroprotective growth factors in traumatic brain injury

描述(申请人提供)：在美国，每年有140万人遭受创伤性脑损伤。在那些幸存下来的人中，每年有8-90,000人经历长期残疾，通常包括逆行性健忘症和由于海马神经细胞丢失而导致的学习和记忆障碍。在85%的致命性人类头部损伤病例中，观察到双侧海马神经元的丢失。在海马区，锥体神经元特别容易受到人类和实验性脑损伤动物模型的脑损伤的影响。虽然认知问题是患者中最持久和最虚弱的结果之一，但对于人类患者的这种类型的损伤，还没有可用的神经保护疗法。因此，开发旨在保护这些细胞的治疗策略是至关重要的。在之前的资助周期中，我们鉴定了一种哺乳动物神经营养因子(NT4/5)，它对锥体神经元具有神经保护作用。相关的神经营养因子脑源性神经营养因子(BDNF)无效。本研究的目的是详细评价NT4/5介导的海马神经保护作用及其机制。我们提议的实验将确定这种新的治疗分子的功能益处以及与其使用相关的限制。我们的中心假设是：NT4/5挽救脑损伤后的CAS锥体神经元通过上调一组特定的神经保护基因来改善海马区的功能。我们将从以下几个方面探讨这一假说：(1)确定NT4/5治疗是否改善了实验性脑损伤后的海马神经元功能；(2)通过检测11个受NT4/5上调但不受BDNF上调的候选基因，确定NT4/5介导的神经保护机制；以及(3)确定NT4/5拯救海马神经元的关键参数。我们将使用多层次的分析(分子、细胞、电路和行为)来详细了解NT4/5的神经保护机制。这些发现将为开发更具体的治疗方法来改善脑外伤患者的记忆丧失提供见解。

DESCRIPTION (provided by applicant): In the United States, 1.4 million people each year suffer a traumatic brain injury. Of those who survive, 80-90,000 people per year experience long-term disabilities, often including retrograde amnesia and deficits in learning and memory due to hippocampal neuronal cell loss. Bilateral loss of hippocampal neurons has been observed in 85% of fatal human head injury cases. Within the hippocampus, pyramidal neurons are particularly vulnerable to brain injury in humans as well as experimental animal models of TBI. Although the cognitive problems are among the most long-lasting and debilitating outcomes in patients, no neuroprotective therapy is available for this type of damage in human patients. Therefore, the need for the development of therapeutic strategies aiming at protecting these cells is critical. In the previous grant cycle, we identified a mammalian neurotrophin (NT4/5) that is neuroprotective for pyramidal neurons. A related neurotrophin, brain-derived neurotrophic factor (BDNF) was ineffective. The purpose of this proposal is to evaluate in detail the efficacy and mechanism of NT4/5-mediated hippocampal neuroprotection. Our proposed experiments will determine the functional benefit of this new theraputic molecule as well as the limitations associated with its use. Our Central Hypothesis is: NT4/5 rescue of CAS pyramidal neurons after TBI improves hippocampal function via upregulation of a specific set of neuroprotective genes. We will investigate this hypothesis by: (1) Determining whether NT4/5 treatment improves hippocampal function after experimental traumatic brain injury; (2) Determining the mechanism of NT4/5-mediated neuroprotection by examining 11 candidate genes upregulated by NT4/5 but not by BDNF; and (3) Determining the critical parameters for NT4/5 rescue of hippocampal neurons. We will use multiple levels of analysis (molecular, cellular, circuit and behavioral) to gain a detailed understanding of the mechanism of NT4/5 neuroprotection. These findings will provide insight for developing more specific therapies to ameliorate memory loss in TBI patients.