Investigating the role of mast cells in neonatal germinal matrix hemorrhage

研究肥大细胞在新生儿生发基质出血中的作用

基本信息

批准号：
9452501
负责人：
Jiping Tang
金额：
$ 23.7万
依托单位：
LOMA LINDA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-15 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9452501
关键词：
Acute Adolescent Adverse effects Affect Affective Alpha Cell Animal Model Animals Anxiety Anxiety Disorders Astrocytes Attention deficit hyperactivity disorder Attentional deficit Attenuated Autistic Disorder Behavior Birth Rate Blood Brain Brain Injuries Brain hemorrhage Breathing Cells Cerebral Palsy Cerebrospinal Fluid Cerebrum Chymase Cicatrix Clinical Cognitive Development Disease Dose Down-Regulation Encephalitis Exposure to Female Gender Goals Health Personnel Hemorrhage Human Hydrocephalus Hydrogen Hyperactive behavior Impaired cognition Impairment Infant Infarction Infiltration Inflammation Inflammatory Inflammatory Response Injection of therapeutic agent Injury Interleukin-17 Interleukin-6 Intervention Learned Helplessness Learning Lesion Low Birth Weight Infant Measures Mediating Mediator of activation protein Mental Depression Mental Retardation Mental disorders Modeling Molecular Mood Disorders Motor Movement Neonatal Nervous System Physiology Neurologic Neurologic Deficit Neurologic Dysfunctions Neurological outcome Obsessive compulsive behavior Obsessive-Compulsive Disorder Pathologic Pathway interactions Patients Perinatal subependymal hemorrhage Pharmaceutical Preparations Phase Premature Birth Premature Infant Process Production Quality of life Rattus Recombinants Reporting Risk Risk Factors Risk-Taking Role Schizophrenia Short-Term Memory Signal Transduction Social Dominance Source Stroke Sucrose Swimming TGFB1 gene Testing Time Training Transforming Growth Factor beta Tryptase Ventricular Water absorption attenuation autism spectrum disorder brain cell cerebral atrophy cytokine depressive symptoms disability emergency service responder field study gain of function gender difference high risk improved loss of function male mast cell mental function motor disorder neonatal brain nervous system disorder neuroinflammation neuropathology novel novel therapeutics omalizumab patient population preference preterm newborn pup response socioeconomics therapeutic target

项目摘要

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.

在拟议的项目中，我们将研究肥大细胞在炎症中的作用，导致脑损伤和新生儿出血性中风后的精神和神经系统疾病，特别是生发性疾病基质出血（GMH）。最重要的是，我们将测试GMH后肥大细胞的稳定减弱GMH引起的脑损伤和改善心理和神经功能。 GMH是毁灭性的每年影响超过12,000名早产婴儿的疾病，导致脑积水和脑瘫，导致智力低下和终生残疾。 GMH，发生在几乎一半的低出生体重婴儿中显着增加了抑郁症和强迫症的风险。另外，GMH诱导实质性病变和心室膨胀会增加注意力不足和多动症的风险紊乱。无残障生存的GMH患者将具有引起注意力的风险明显更高赤字，焦虑和情绪障碍。 GMH诱导的大脑心室膨胀是强大而重要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在这种动物模型中观察到的新生大鼠和神经后遗症的GMH模型与在人类早产临床上可见。在GMH幼崽中，我们观察到发育的显着延迟，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（水迷宫测试），多动症（开放式测试）以及少年期间的运动功能障碍发展阶段。在此模型中，我们证明了TGFβ1的积累和TGFβ的激活 GMH后，途径显着导致脑损伤。但是，该模型中有源TGFβ1的来源仍然不清楚。在拟议项目的AIM 1中，我们将确定肥大细胞是否是GMH-的主要参与者诱导的TGFβ途径激活。最重要的是，我们将确定肥大细胞稳定是否会减少 GMH引起的脑损伤和改善的心理功能。在上面提到的测试中，记录重复刻板印象运动的观察将提供类似自闭症和/或痴迷的测量强迫行为。情感行为，包括动画和冒险行为，将通过零迷宫和抑郁/学习性的类似抑郁症的行为将使用强制游泳，和蔗糖偏好测试。最后，社会统治力，方法和稀缺标记将由记录与接触新女性和男性有关的观察结果。对于肥大细胞稳定，我们将使用1）Omalizumab，该药物已批准用于治疗与病理肥大细胞有关的疾病人类的激活和2）氢吸入，这是一种安全的治疗，没有报道的副作用。在AIM 2中，我们将研究肥大细胞稳定引起的脑部保护的机制。我们假设抑制肥大细胞介质会衰减TGFβ激活，从而通过下调IL-来减少脑感染 17，导致GMH后脑损伤和神经系统防御的衰减。