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

 描述(申请人提供)：在儿童中，创伤性脑损伤(TBI)是导致死亡和发病的主要原因，对受影响的个人、他们的父母和整个社会来说是一个主要的健康负担，医疗保健费用超过10亿美元。可悲的是，尽管 发病率和数十年的研究，到目前为止还没有新的治疗方法改善儿童脑损伤的预后。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)是一种促炎症脂质，在中枢神经系统损伤后高度产生，并有助于组织和神经损伤。令人信服的数据显示，重型颅脑损伤后成年患者脑脊液(CSF)中LPA显著升高，特定的LPA亚型可能是脑损伤的标志。在死后的人脑中，脑损伤后胶质细胞和室管膜细胞上调了LPA受体，这意味着LPA信号的增强。使用特定的抗LPA单抗(MAb)Lpathomab(Tm)治疗神经创伤动物模型中的LPA信号抑制，延迟病理过程，包括神经炎症。因此，LPA是与神经创伤后中枢神经系统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，我们在这里调查了LPA在儿童脑外伤中的参与，特别是弥漫性脑损伤。这些初步数据对于了解成人和儿童脑外伤之间的异同，以便制定有针对性的干预措施至关重要。我们将采用临床和实验双重研究的方法，目的如下：1)测定重型颅脑损伤儿童脑脊液和血浆中LPA亚型的时间分布，并验证脑脊液中是否存在高于血浆的LPA水平；2)确定在儿童标本中观察到的LPA变化是否有效地模拟为弥漫性脑损伤后幼年大鼠脑脊液和血浆中LPA的升高；3)确定脑脊液和血浆中LPA水平的变化 观察损伤大鼠脑内产生LPA的脑区，并评估LPA与神经炎症(星形胶质细胞增多、小胶质细胞激活和细胞因子产生)的关系。通过定义脑脊液和血浆LPA脉冲对儿童脑外伤的反应，这项研究将补充我们最近在成人脑外伤中的发现。实验数据将(1)证明幼年脑外伤患者体内LPA的产生；(2)揭示LPA与弥漫性脑损伤之间的潜在联系，弥漫性脑损伤是儿童最常见的脑损伤类型；(3)证实LPA升高与细胞和体液神经炎之间的联系。如果我们的初步结果在儿童和青少年弥漫性脑损伤模型中都是令人鼓舞的，我们将开始一项研究，以确定阻断LPA信号在减少继发性脑损伤方面的效果。在未来，LPA可能成为减少儿童颅脑损伤继发性脑损伤的治疗靶点。

 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.