Developmental Brain Injury: Characterization, Mechanism and Treatment of Diffuse

描述（由申请人提供）：在拟议的研究中，我打算通过解决每个年龄的病理生理过程和细胞死亡表型来表征不同发育年龄的弥漫性TBI（创伤性脑损伤）。我的研究旨在解决以下假设：弥漫性脑损伤后细胞死亡的机制随发育年龄的变化而不同。Specific Aim #1提出了一种新的弥漫性创伤性脑损伤模型的特征，该模型适用于7天至3个月大的大鼠。目的是确定细胞死亡表型和关键相关分子机制的差异，以及作为发育年龄函数的功能结果。我将验证以下预测：1)年轻大鼠弥漫性TBI倾向于与caspase依赖性凋亡相关的分子机制，2)成年大鼠弥漫性TBI倾向于与坏死相关的分子机制，以及3)弥漫性TBI将导致依赖于发育年龄的功能结果的缺陷。具体目标2提出通过研究半胱天冬酶抑制剂或镁盐治疗对细胞死亡和功能结局的影响来解决这一假设。目的是确定caspase抑制剂或镁盐是否可以保护幼鼠免受弥漫性脑损伤。我们将验证caspase抑制剂，而不是镁盐，将减少年轻大鼠弥漫性脑损伤引起的损伤和神经功能缺损的预测。

DESCRIPTION (provided by applicant): In the proposed studies, I intend to characterize diffuse TBI (traumatic brain injury) at different developmental ages by addressing the pathophysiological processes and cell death phenotype at each age. My studies are intended to address the following hypothesis: mechanisms of cell death after diffuse TBI differ as a function of developmental age. Specific Aim #1 proposes to characterize a new diffuse traumatic brain injury model in rats ranging from 7 days through 3 months of age. This aim is to determine differences with regard to cell death phenotype and key related molecular mechanisms as well as functional outcomes as a function of developmental age. I will test the predictions that 1) diffuse TBI in young rats favors molecular mechanisms associated with caspase dependent apoptosis, 2) diffuse TBI in adult rats favors molecular mechanisms associated with necrosis, and 3) diffuse TBI will result in deficits in functional outcomes that are dependent upon developmental age. Specific Aim #2 proposes to address this hypothesis by studying the effects of treatment with caspase inhibitors or magnesium salts on cell death and functional outcome according to developmental age. This aim is to determine if caspase inhibitors or magnesium salts can protect against diffuse TBI in young rats. We will test the prediction that caspase inhibitors, but not magnesium salts, will decrease damage and neurological deficits induced by diffuse TBI in young rats.