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

米诺环素作为镰状细胞病神经炎症和认知缺陷的潜在疗法

• 批准号: 10530629
• 负责人: Hyacinth Idu Hyacinth
• 金额: $ 61.02万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-15 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10530629
• 关键词: Address; Adult; Age; Age of Onset; Agonist; Anemia; Anxiety; Behavioral; Biological Factors; Blood Vessels; Blood flow; Bone Density; Bone Marrow; Brain; Cerebral Infarction; Cerebral Ischemia; Cerebrum; Child; Chronic; Clinical Trials; Cognitive; Cognitive deficits; Communication; Complication; Cross-Sectional Studies; Dendrites; Dendritic Spines; Development; Drug Targeting; Economics; Educational Status; FDA approved; Genes; Golgi Apparatus; Healthcare; Hippocampus; Histologic; Histology; Image; Immunohistochemistry; Individual; Infarction; Inflammation; Inflammatory; Injury; Intelligence quotient; Intervention; Job loss; Knowledge; Laser Scanning Microscopy; Learning; Life; Link; Magnetic Resonance Angiography; Magnetic Resonance Imaging; Mediating; Mediator; Memory; Mental Depression; Microglia; Minocycline; Modeling; Molecular; Morphology; Mus; Neuronal Plasticity; Neurons; Neurotrophic Tyrosine Kinase Receptor Type 2; Outcome; PTPRC gene; Pathologic; Pathologic Processes; Patients; Peripheral; Pharmaceutical Preparations; Pilot Projects; Prevention; Prevention strategy; Quality of life; Randomized; Reporting; Research; Research Design; Resources; Role; Severities; Sickle Cell; Sickle Cell Anemia; Signal Transduction; Source; Stroke; Testing; Therapeutic; Unemployment; Vascular Diseases; Vertebral column; aged; cerebral ischemic injury; cerebral microinfarct; cognitive function; cohort; cytokine; density; design; disability; improved; in vivo; low socioeconomic status; neuroinflammation; neuronal survival; neurotrophic factor; novel therapeutic intervention; novel therapeutics; pre-clinical; prevent; prospective; receptor; small molecule; systemic inflammatory response; treatment strategy; two-photon

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.

项目摘要 认知和行为（焦虑和抑郁）缺陷是镰状细胞病的两种可能改变生活的并发症 细胞疾病（SCD）。全面智商 (IQ) 丧失、就业能力受到干扰、 医疗资源和整体生活质量是 SCD 患者认知缺陷的一些后果。 介导这些并发症发生的分子和细胞因素仍然很大程度上未知。 该提案旨在定义神经炎症在异常神经可塑性发展中的作用以及如何 两者在时间上与 SCD 认知和行为缺陷的发生有关。我们还将尝试识别 一些小分子和治疗策略可用于预防和/或治疗 SCD- 相关的认知和行为缺陷。我们的初步研究表明，镰状细胞小鼠发育 随着年龄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 中认知缺陷的发生是由于神经炎症和异常 神经可塑性定义为树突乔木、树突棘的密度降低以及树突棘的比例 未成熟的树突棘。我们还将研究脑梗塞和脑梗塞的潜在作用或贡献 微血管病变。这将通过以下目标进行严格测试 (1) 确定时间 SCD 认知（学习和记忆）缺陷与异常之间的关系 神经可塑性和/或脑梗塞和微血管病变的负担。这将使我们能够 建立认知和行为缺陷的发生与异常发生之间的时间关系 神经可塑性以及脑微梗塞的负担。 (2) 展示神经炎症的作用， 以及米诺环素在治疗 SCD 认知缺陷方面的治疗效果。这将由 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、神经可塑性异常的发生和进展以及认知能力的发展 和行为缺陷。此外，我们将研究阻断神经炎症是否可能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目标。 (3)判断是否 使用神经营养蛋白激动剂或抗神经炎症介质治疗可逆转 SCD 中的神经炎症、神经可塑性异常和认知缺陷。这些研究旨在 使我们能够识别小分子和/或小分子靶点并提供临床前信息 可以支持旨在确定认知和认知障碍的治疗和预防策略的临床试验 SCD 中的行为缺陷。