Minocycline as a potential therapy for neuroinflammation and cognitive deficit in sickle cell disease

项目摘要 认知和行为（焦虑和抑郁）缺陷是两个潜在的改变生活的并发症镰刀 细胞疾病（SCD）。全面智商（IQ）的丧失，就业能力的干扰， 医疗资源和整体生活质量是SCD患者认知缺陷的一些后果。 介导这些并发症发展的分子和细胞因子在很大程度上仍然是未知的。 该建议旨在确定神经炎症在异常神经可塑性发展中的作用，以及如何 这两者与SCD中认知和行为缺陷的发生时间相关。我们还将尝试识别 一些小分子和治疗策略可以用于预防和/或治疗SCD- 相关的认知和行为缺陷。我们的初步研究表明镰状细胞小鼠 随着年龄的增长和神经炎症而发生的认知和行为缺陷，因此我们的中心假设是 SCD中认知缺陷的发展是由于神经炎症和异常 神经可塑性定义为树突乔木、树突棘密度降低， 未成熟的树突棘我们还将研究脑梗死的潜在作用或贡献， 微血管病变这将被严格测试，目的如下：（1）确定时间 SCD中认知（学习和记忆）缺陷的存在与异常 神经可塑性和/或脑梗塞和微血管病的负担。这将使我们能够 在认知和行为缺陷的发作与异常的发作之间建立时间关系， 神经可塑性以及脑微梗死的负担。(2)展示神经炎症的作用， 以及米诺环素在治疗SCD认知缺陷中的治疗益处。会来做这项工作 建立细胞和分子证据的发病和进展之间的基线关系， 神经炎症和异常神经可塑性的发作和进展以及认知功能的发展 和行为缺陷此外，我们还将研究阻断神经炎症是否是一种潜在的治疗方法。 治疗或预防SCD相关认知和行为缺陷的靶点。(3)确定是否 用神经营养素激动剂治疗或抗神经炎性介质治疗逆转了 神经炎症、异常神经可塑性和SCD中的认知缺陷。这些研究旨在 使我们能够识别小分子和/或小分子靶标，并提供临床前信息， 可以支持一项临床试验，旨在确定治疗和预防策略， 行为缺陷

Project Abstract Cognitive and behavioral (anxiety and depression) deficits are two potentially life-altering complications of sickle cell disease (SCD). Loss of full-scale intelligence quotient (IQ), interference with employability, navigation of healthcare resources and overall quality of life are some of the consequences of cognitive deficit in SCD patients. The molecular and cellular factors that mediate the development of these complications are still largely unknown. This proposal aims to define the role of neuroinflammation in development of abnormal neuroplasticity and how the two are temporally related to onset of cognitive and behavioral deficit in SCD. We will also attempt to identify some small molecules and treatment strategies that could have utility in prevention and/or treatment of SCD- associated cognitive and behavioral deficit. Our preliminary studies have shown that sickle cell mice developed cognitive and behavioral deficit that occur with age and neuroinflammation and thus our central hypothesis is that the development of cognitive deficits in SCD is due to neuroinflammation and abnormal neuroplasticity defined by decreased density of dendritic arbors, dendritic spines and, the proportion of immature dendritic spines. We will also examine the potential role or contribution from cerebral infarcts and microvasculopathy. This will be rigorously tested with the following aims (1) Determine the temporal relationship between presence of cognitive (learning and memory) deficit in SCD, and abnormal neuroplasticity and/or the burden of cerebral infarcts and microvasculopathy. This will enable us to establish a temporal relationship between the onset of cognitive and behavioral deficit, and onset of abnormal neuroplasticity as well as the burden of cerebral microinfarct. (2) Demonstrate the role of neuroinflammation, as well as the therapeutic benefit of minocycline in treating cognitive deficits in SCD. This will be done by establishing baseline relationship between onset and progression of cellular and molecular evidence of neuroinflammation and onset and progression of abnormal neuroplasticity as well as development of cognitive and behavioral deficit. Additionally, we will examine whether blocking neuroinflammation could be a potential target for the treatment or prevention of SCD associated cognitive and behavioral deficit. (3) Determine whether treatment with a neurotrophin agonist treatment or anti-neuroinflammatory mediators reverses neuroinflammation, abnormal neuroplasticity and cognitive deficit in SCD. These studies are design to enable us identify small molecule(s) and/or small molecule target(s) and provide the preclinical information that could support a clinical trial geared towards identifying treatment and prevention strategies for cognitive and behavioral deficit in SCD.