Understanding of a neurophenotype in hemophilia A

凝血因子VIII缺乏（血友病A）导致的出血可发生在任何组织，包括大脑。电流 治疗，包括因子VIII（FVIII）替代和最近的新疗法，主要集中在关节炎， 健康尽管在治疗选择方面取得了进展，但残疾仍然存在。血友病患者患有 与年龄和性别匹配的对照组相比，精神健康障碍的发生率增加（45%对18.5%）。而 在预防和治疗血友病相关的关节和肌肉疾病方面已经取得了重大进展 在目前的治疗标准下，缺乏对血友病A的研究来了解、治疗或预防 脑部疾病长期目标是找到诊断和治疗方法，解决机制 和血友病A神经系统疾病的结构。本建议的目的是审查 凝血因子VIII缺乏对神经功能和结构的影响。中心假设是大脑微出血和 神经炎症导致大脑结构的变化，引起血友病A小鼠的行为变化。的 该建议的基本原理是，完成将确定导致神经功能不良的机制， 血友病A的结局。中心假设将通过追求三个具体目标来检验：目标1） 检查血友病A小鼠的脑微出血和神经解剖表型。目的2）研究胶质细胞 活化和神经炎症。目的3）确定FVIII替代在以下方面的作用： 血友病A小鼠的神经精神行为表型。我们将利用创新的方法来实现这些目标。 定量神经影像学和基因转移技术评估血友病患者的脑结构和功能 动物模型随着时间的推移。拟议的研究意义重大，因为我们将深入了解 神经解剖学变化和神经炎性通路在FVIII缺乏模型中受到影响。的 这项工作的预期结果是缺乏FVIII将导致显著的神经异常。结果 将产生重要的积极影响，因为他们将建立一个更好的了解发展中国家的 大脑结构和功能在FVIII缺乏，长期将改善认知，精神，和质量 血友病A患者的生活结局。

Bleeding resulting from factor VIII deficiency (hemophilia A) can occur in any tissue including the brain. Current treatments, including factor VIII (FVIII) replacement and recent novel therapeutics, focus primarily on joint health. In spite of advancements in treatment options, disabilities remain. People with hemophilia suffer from increased rates of mental health disorders compared to age and sex matched controls (45% vs. 18.5%). While significant progress has been made in prevention and treatment of hemophilia-related joint and muscle disease with current standards of care, there is a paucity of research in hemophilia A to understand, treat, or prevent brain disease. The long-term goal is to find diagnostic and treatment approaches that address the mechanism and structure of neurologic disease in hemophilia A. The objective of this proposal is to examine the role of FVIII deficiency on neurologic function and structure. The central hypothesis is that cerebral microbleeds and neuroinflammation lead to changes in brain structure, causing behavioral changes in hemophilia A mice. The rationale underlying this proposal is that completion will identify mechanisms causing poor neurologic outcomes in hemophilia A. The central hypothesis will be tested by pursuing three specific aims: Aim 1) Examine cerebral microbleeds and neuroanatomy phenotypes in hemophilia A mice. Aim 2) Investigate glial activation and neuroinflammation in hemophilia A mice. Aim 3) Identify the role of FVIII replacement in neuropsychiatric behavioral phenotypes in hemophilia A mice. We will pursue these aims using innovative quantitative neuroimaging and gene transfer techniques to evaluate brain structure and function in hemophilia animal model over time. The proposed research is significant because we will gain insights into the neuroanatomic changes and neuroinflammatory pathways impacted in a model of FVIII deficiency. The expected outcome of this work is that lack of FVIII will result in significant neurologic abnormalities. The results will have an important positive impact because they will establish a better understanding of the developing brain structure and function in FVIII deficiency, and long-term will improve cognitive, psychiatric, and quality of life outcomes for people with hemophilia A.