Investigating the role of mast cells in neonatal germinal matrix hemorrhage

在拟议的项目中，我们将研究肥大细胞在导致脑损伤的炎症中的作用， 结果导致新生儿出血性卒中后的精神和神经障碍，特别是老年痴呆症。 基质出血（GMH）。最重要的是，我们将测试GMH后肥大细胞的稳定是否会 减轻GMH诱导的脑损伤，改善精神和神经功能。GMH是一个毁灭性的 这种疾病每年影响12 000多名早产儿，导致脑积水和脑瘫， 导致智力迟钝和终身残疾。GMH发生在近一半的低出生体重婴儿中， 显著增加抑郁症和强迫症的风险。此外，GMH诱导的 脑实质病变和脑室扩大会增加注意力缺陷和多动症的风险 disorder.无残疾存活的GMH患者将有显着更高的发展注意力的风险 缺陷焦虑和情绪障碍GMH引起的脑室扩大是一个强而显著的 自闭症谱系障碍和精神分裂症发展的危险因素。我们最近开发了一个 新生大鼠GMH模型及在该动物模型中观察到的神经系统后遗症与 临床上在人类早产新生儿中观察到。在GMH幼仔中，我们观察到发育明显延迟， 这导致“工作”记忆“的丧失（通过T-迷宫测试评估），空间学习受损（Water 迷宫试验）和多动（旷场试验）以及在青少年运动功能障碍 发展阶段在这个模型中，我们证明了TGFβ1的积累和TGFβ 1的激活， GMH后脑损伤的发生与GMH后脑损伤的发生密切相关。然而，该模型中活性TGFβ1的来源 仍不清楚在拟议项目的目标1中，我们将确定肥大细胞是否是GMH的主要参与者- 诱导TGFβ通路活化。最重要的是，我们将确定肥大细胞的稳定性是否会降低 对GMH引起的脑损伤和改善精神功能。除上述测试外，记录 重复刻板动作的观察将提供自闭症样和/或强迫症的测量， 强迫性行为情感行为，包括焦虑和冒险行为，将被评估与 零迷宫和抑郁/习得性无助样行为将使用强迫游泳来测量， 和蔗糖偏好测试。最后，社会优势，方法和气味标记将被测量， 记录与暴露于新雌性和雄性相关的观察结果。为了稳定肥大细胞，我们将 用途1）奥马珠单抗，临床批准用于治疗病理性肥大细胞相关疾病的药物 2）氢吸入，一种安全的治疗方法，没有报道的副作用。在目标2中， 将研究肥大细胞稳定诱导的脑保护机制。我们假设抑制 肥大细胞介质将减弱TGFβ的活化，从而通过下调IL-10的表达来减少脑炎症。 17，导致GMH后脑损伤和神经功能缺损的减弱。

In the proposed project, we will study the role of mast cells in inflammation leading to brain injury and consequently to mental and neurological disorders after neonatal hemorrhagic stroke, specifically germinal matrix hemorrhage (GMH). Most importantly, we will test whether stabilization of mast cells after GMH will attenuate GMH-induced brain injury and improve mental and neurological functions. GMH is a devastating disease affecting over 12,000 premature infants annually, resulting in hydrocephalus and cerebral palsy, leading to mental retardation and lifelong disabilities. GMH, occurs in nearly half of low birth weight infants, significantly increases risk of depressive and obsessive-compulsive disorders. Additionally, GMH-induced parenchymal lesions and ventricular enlargement increases the risk of attention deficit and hyperactivity disorder. GMH patients who survive without disability will have significantly higher risk of developing attention deficit, anxiety, and mood disorder. GMH induced cerebral ventricular enlargement is a strong and significant risk factor for the development of autism spectrum disorders and schizophrenia. We recently developed a GMH model in neonatal rats and the neurological sequelae observed in this animal model were similar to that seen in human preterm neonates clinically. In the GMH pups, we observed a significant delay in development, which resulted in the loss of `working' memory' (evaluated by T-Maze test), impaired spatial learning (Water Maze test), and hyperactivity (Open Field test) as well as in motor dysfunctions during the juvenile development stage. In this model, we demonstrated that TGFβ1 accumulation and the activation of the TGFβ pathway significantly contributed to brain injury after GMH. However the source of active TGFβ1 in this model remains unclear. In Aim 1 of the proposed project, we will determine if mast cells are a major player in GMH- induced TGFβ pathway activation. Most importantly we will determine if mast cell stabilization will decrease GMH-induced brain injury and improve mental functions. In additional to tests mentioned above, recording observations of repetitive stereotypic movements will provide measures of autism-like and/or obsessive compulsive behaviors. Affective behaviors, including anxiety and risk-taking behaviors, will be assessed with the zero maze, and depression/learned-helplessness-like behaviors will be measured using the forced swim, and sucrose preference tests. Finally, social dominance, approach, and scent marking will be measured by recording observations associated with exposure to novel females and males. For mast cell stabilization we will use 1) Omalizumab, the drug clinically approved for treating the diseases related to pathologic mast cell activation in humans and 2) Hydrogen inhalation, a safe treatment without reported side effects. In Aim 2, we will study the mechanism of mast cell stabilization-induced brain protection. We hypothesize that inhibition of mast cell mediators will attenuate TGFβ activation thus decrease brain inflammation via downregulation of IL- 17, resulting in the attenuation of brain injury and neurological deficits after GMH.