Neuroprotective growth factors in traumatic brain injury

描述（由申请人提供）：在美国，每年有140万人遭受创伤性脑损伤。在那些幸存者中，每年有80- 90，000人经历长期残疾，通常包括逆行性遗忘症和海马神经元细胞丢失导致的学习和记忆缺陷。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丢失。在海马内，锥体神经元特别容易受到人类以及TBI实验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衰弱的结果之一，但对于人类患者的这种类型的损伤，没有神经保护治疗。因此，开发旨在保护这些细胞的治疗策略的需求至关重要。在上一个资助周期中，我们鉴定了一种哺乳动物神经营养因子（NT 4/5），它对锥体神经元具有神经保护作用。一种相关的神经营养因子，脑源性神经营养因子（BDNF）无效。本研究旨在详细评价NT 4/5介导的海马神经保护作用及其机制。我们提出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：TBI后NT 4/5拯救CAS锥体神经元通过上调一组特定的神经保护基因改善海马功能。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）通过检查NT 4/5上调但BDNF不上调的11个候选基因来确定NT 4/5介导的神经保护机制;（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）来详细了解NT 4/5的神经保护机制。这些发现将为开发更具体的治疗方法以改善TBI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.