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: 7997165
• 负责人: DEBORAH J WATSON
• 金额: $ 33.87万
• 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 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7997165
• 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; Relative (related person); Research Personnel; Retrograde amnesia; Signal Transduction; Slice; Survivors; Testing; Traumatic Brain Injury; United States; Up-Regulation; behavior test; cell injury; comparative efficacy; disability; experience; hippocampal pyramidal neuron; improved; improved functioning; in vivo; insight; neuron loss; neuroprotection; neurotrophic factor; neurotrophin 4; oxidative damage; programs; receptor; research study; therapeutic development

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.

在美国，每年有140万人遭受创伤性脑损伤。在那些幸存的人中， 每年有8万至9万人患有长期残疾，通常包括逆行性健忘症和缺陷 海马神经细胞丢失所致的学习记忆障碍。双侧海马神经元的丢失 在85%的致命的人类头部损伤病例中观察到了这种情况。在海马区，锥体神经元 在人类以及脑外伤的实验动物模型中特别容易受到脑损伤的影响。尽管 认知问题是患者最持久和最虚弱的结果之一，没有 对于人类患者的这种类型的损伤，神经保护疗法是可用的。因此，有必要对 开发旨在保护这些细胞的治疗策略至关重要。 在之前的资助周期中，我们确定了一种哺乳动物神经营养素(NT4/5)，它对 锥体神经元。相关的神经营养因子脑源性神经营养因子(BDNF)无效。这个 本研究的目的是详细评价NT4/5介导的海马神经元损伤的疗效和机制。 神经保护。我们提议的实验将确定这种新疗法的功能益处。 分子以及与其使用相关的限制。我们的中心假设是：NT4/5拯救 颅脑损伤后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NT4/5治疗 改善实验性颅脑损伤后的海马区功能；(2)明确其作用机制 NT4/5通过检测11个被NT4/5上调但不受BDNF上调的候选基因而介导的神经保护； (3)确定NT4/5挽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)来获得详细的 对NT4/5神经保护机制的理解。这些发现将为发展提供洞察力 改善脑外伤患者记忆丧失的更具体的治疗方法。

项目成果

Identification of potentially neuroprotective genes upregulated by neurotrophin treatment of CA3 neurons in the injured brain.

鉴定通过神经营养素治疗受损大脑中 CA3 神经元上调的潜在神经保护基因。

• DOI: 10.1089/neu.2010.1487
• 发表时间: 2011
• 期刊: Journal of neurotrauma
• 影响因子: 4.2
• 作者: Malik,SaafanZ;Motamedi,Shahab;Royo,NicolasC;LeBold,David;Watson,DeborahJ
• 通讯作者: Watson,DeborahJ

Neural stem cells as biological minipumps: a faster route to cell therapy for the CNS?

• DOI: 10.2174/157488807779317044
• 发表时间: 2007
• 期刊: Current stem cell research & therapy
• 影响因子: 2.7
• 作者: H. Isaac Chen;Asha Bakshi;N. Royo;S. Magge;D. Watson;Nicolas C. Royo;Suresh N. Magge;Deborah J. Watson