Neuroprotective growth factors in traumatic brain injury

在美国，每年有140万人遭受脑外伤。幸存者中 每年有80- 90，000人经历长期残疾，通常包括逆行性遗忘和缺陷 海马神经元细胞的缺失导致学习和记忆能力下降。双侧海马神经元缺失 在85%的致命性人类头部损伤病例中观察到。在海马体中，锥体神经元 在人类以及TBI的实验动物模型中特别容易受到脑损伤。虽然 认知问题是患者最持久和最衰弱的结果之一，不是吗？ 神经保护疗法可用于人类患者的这种类型的损伤。因此，需要 开发旨在保护这些细胞的治疗策略是至关重要的。 在上一个资助周期中，我们发现了一种哺乳动物神经营养因子（NT 4/5）， 锥体神经元一种相关的神经营养因子，脑源性神经营养因子（BDNF）无效。的 本研究旨在详细评价NT 4/5介导的海马神经元凋亡的有效性和机制。 神经保护我们提出的实验将确定这种新疗法的功能效益。 分子以及与其使用相关的限制。我们的中心假设是：NT 4/5拯救 TBI后CAS锥体神经元通过上调一组特定的 神经保护基因我们将通过以下方式研究这一假设：（1）确定NT 4/5治疗是否 改善实验性创伤性脑损伤后海马功能;（2）确定 NT 4/5介导的神经保护作用，通过检测NT 4/5上调但BDNF不上调的11个候选基因; （3）确定NT 4/5拯救海马神经元的关键参数。 我们将使用多个层次的分析（分子，细胞，电路和行为），以获得详细的 了解NT 4/5神经保护的机制。这些发现将为开发提供见解 更具体的治疗，以改善创伤性脑损伤患者的记忆丧失。

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.