Investigating the role of lysophosphatidic acid (LPA) in pediatric brain injury

 描述（由申请人提供）：在儿童中，创伤性脑损伤（TBI）是死亡率和发病率的主要原因，对受影响的个人、他们的父母和整个社会来说是一个重大的健康负担，医疗保健费用超过10亿美元。虽然，尽管高 发病率和数十年的研究，迄今为止，没有新的治疗方法改善儿童TBI的结果。需要进一步了解导致继发性脑损伤的病理生理学，以开发新的治疗方法。 我们的研究表明，溶血磷脂酸（LPA）是一种促炎脂质，在CNS损伤后大量产生，并有助于组织和神经损伤。令人信服的数据显示，LPA在严重TBI后的成年患者的脑脊液（CSF）中显著增加，特定的LPA亚型作为脑损伤的潜在标志。在死后的人脑中，脑外伤后胶质细胞和室管膜细胞的LPA受体上调，这意味着增强的LPA信号传导。用特异性抗LPA单克隆抗体（mAb）Lpathomab（tm）在神经创伤动物模型中治疗性抑制LPA信号传导，延迟病理过程，包括神经炎症。因此，LPA是与神经创伤后CNS炎症和神经变性相关的继发性损伤过程的驱动力。 为了扩展我们在成人和啮齿动物研究中的结果，在这里，我们调查了LPA在儿童TBI中的参与，特别关注弥漫性脑损伤。这些初步数据对于了解成人和儿童TBI之间的相似性和差异至关重要，以便制定有针对性的干预措施。我们将采用临床和实验双重研究方法，目的如下：1）确定严重TBI儿童CSF和血浆中LPA亚型的时间曲线，并验证CSF中LPA水平高于血浆的存在;（二）为了确定在儿童样本中观察到的LPA变化是否有效地模拟了幼年大鼠CSF和血浆中LPA的升高，弥漫性脑损伤;（3）识别 脑区产生LPA在受伤的大鼠脑，并评估LPA与神经炎症（星形细胞增多症，小胶质细胞活化，细胞因子的产生）的关系。 通过定义儿童TBI时的CSF和血浆LPA脉冲，这项研究将补充我们最近在成人TBI中的发现。实验数据将（1）证明青少年TBI中LPA的产生;（2）揭示LPA与弥漫性脑损伤（儿童中最常见的TBI类型）之间的潜在关联;（3）证实LPA增加与细胞和体液神经炎症的联系。如果我们在儿童TBI和青少年弥漫性TBI模型中的初步结果令人鼓舞，我们将开始研究以确定阻断LPA信号传导在减少继发性脑损伤中的功效。在未来，LPA可能成为一个治疗目标，以减少继发性脑损伤的儿童患有TBI。

 DESCRIPTION (provided by applicant): In children, traumatic brain injury (TBI) is the leading cause of mortality and morbidity representing a major health burden for affected individuals, their parents and the society at large with more than $1 billion in healthcare. Sadly, despite high incidence and decades of research, to date no new treatments improve outcome in children with TBI. Further understanding of the pathophysiology leading to secondary brain damage is required to develop new therapies. Our research has demonstrated that lysophosphatidic acid (LPA) is a proinflammatory lipid, highly produced after CNS injury, and contributes to tissue and neurological damage. Compelling data showed that LPA was markedly increased in adult patients' cerebrospinal fluid (CSF) after severe TBI, with specific LPA isoforms serving as potential signatures of brain damage. In postmortem human brain, the LPA receptors were upregulated by glial and ependymal cells after TBI implying enhanced LPA signaling. Therapeutic inhibition of LPA signaling in animal models of neurotrauma with a specific anti-LPA monoclonal antibody (mAb), Lpathomab(tm), delayed pathological processes, including neuroinflammation. Thus, LPA is a driving force for secondary injury processes associated with CNS inflammation and neurodegeneration after neurotrauma. To extend our results in adult human and rodent studies, here we investigate the involvement of LPA in pediatric TBI with a specific focus on diffuse brain injury. These preliminary data are essential to understand the similarities and differences between adult and pediatric TBI, in order to develop targeted interventions. We will use a dual clinical and experimental research approach following the aims below: 1) To determine time profiles of LPA isoforms in CSF and plasma of children with severe TBI, and validate the presence of higher levels of LPA in CSF compared to plasma; 2) To determine whether changes of LPA observed in children's samples are modeled effectively as an elevation of LPA in juvenile rat CSF and plasma after diffuse brain injury; 3) To identify the brain regions producing LPA in the injured rat brain, and assess the relationship of LPA with neuroinflammation (astrocytosis, activation of microglia, and cytokine production). By defining the CSF and plasma LPA pulse in response to pediatric TBI, this study will complement our recent findings in adult TBI. The experimental data will (1) demonstrate LPA production in juvenile TBI; (2) reveal potential associations between LPA that are specific to diffuse brain injury, the most frequent type of TBI in children; and (3) corroborate the link of increased LPA with cellular and humoral neuroinflammation. If our preliminary results are encouraging in both childhood TBI and juvenile diffuse TBI model, we will embark on a study to determine the efficacy of blocking LPA signaling in reducing secondary brain damage. In future, LPA may become a therapeutic target to reduce secondary brain damage in children suffering from TBI.