Neuroprotective growth factors in traumatic brain injury

创伤性脑损伤中的神经保护性生长因子

• 批准号: 7197169
• 负责人: DEBORAH J WATSON
• 金额: $ 35.76万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-12-01 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7197169
• 关键词: Acute; Adverse effects; Animal Behavior; Area; Behavioral; Bilateral; Brain; Brain Injuries; Brain-Derived Neurotrophic Factor; Candidate Disease Gene; Cell Death; Cells; Cognitive; Craniocerebral Trauma; Critical Pathways; Data; Development; Dose; Experimental Animal Model; Genes; Grant; Growth Factor; Hippocampus (Brain); Human; In Vitro; Infusion procedures; Injury; Learning; Mediating; Memory; Memory Loss; Memory impairment; Molecular; Molecular Analysis; Neurons; Outcome; Pathway interactions; Patients; Purpose; Relative (related person); Research Personnel; Retrograde amnesia; Signal Transduction; Slice; Survivors; Testing; Therapeutic; Traumatic Brain Injury; United States; Up-Regulation; behavior test; cell injury; disability; experience; hippocampal pyramidal neuron; improved; improved functioning; in vivo; insight; neuron loss; neuroprotection; neurotrophic factor; neurotrophin 4; programs; receptor; research study

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.

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。在那些存活下来的人中，每年有8 -9万人经历长期残疾，通常包括逆行性健忘症和由于海马神经元细胞丧失而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的丢失。在人类以及创伤性脑损伤的实验动物模型中，海马体内的锥体神经元特别容易受到脑损伤。尽管认知问题是患者最持久和最衰弱的结果之一，但没有神经保护疗法可用于人类患者的这种类型的损害。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，我们发现了一种对锥体神经元具有神经保护作用的哺乳动物神经营养因子（NT4/5）。相关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nt4 /5介导的海马神经保护的疗效和机制。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局限性。我们的中心假设是：脑外伤后CAS锥体神经元的NT4/5修复通过上调一组特定的神经保护基因来改善海马功能。我们将通过以下方法来验证这一假设：(1)确定NT4/5治疗是否能改善实验性创伤性脑损伤后的海马功能；(2)通过检测11个被NT4/5上调而不被BDNF上调的候选基因，确定NT4/5介导的神经保护机制；(3)确定海马神经元NT4/5抢救的关键参数。我们将使用多个层面的分析（分子，细胞，电路和行为）来详细了解NT4/5神经保护的机制。这些发现将为开发更具体的治疗方法来改善TBI患者的记忆丧失提供见解。