Understanding of a neurophenotype in hemophilia A

因子缺乏症(血友病A)导致的出血可能发生在任何组织，包括大脑。当前 治疗，包括第八因子(FVIII)替代和最近的新疗法，主要集中在关节 健康。尽管在治疗选择方面取得了进步，但残疾仍然存在。患有血友病的人患有 与年龄和性别匹配的对照组相比，精神健康障碍的发生率(45%比18.5%)更高。而当 血友病相关关节和肌肉疾病的防治取得重大进展 在目前的护理标准下，对血友病A缺乏了解、治疗或预防的研究 脑部疾病。长期目标是找到解决这种机制的诊断和治疗方法。 和血友病A的神经系统疾病的结构。这项建议的目的是检查 神经功能和结构上的FVIII缺乏症。中心假说是大脑微出血和 神经炎症导致大脑结构改变，导致血友病A小鼠的行为改变。这个 这一提议背后的理论基础是，完成这项工作将确定导致神经功能不佳的机制 血友病A的结果将通过追求三个具体目标来检验中心假设：目标1) 检测血友病A小鼠的脑微出血和神经解剖学表型。目的2)研究神经胶质细胞 血友病A小鼠的激活和神经炎症。目标3)确定FVIII替换在 血友病A小鼠的神经精神行为表型。我们将以创新的方式追求这些目标 定量神经成像和基因转移技术评估血友病患者的脑结构和功能 随着时间的推移，动物模型。这项拟议的研究具有重要意义，因为我们将深入了解 在FVIII缺乏模型中，神经解剖学改变和神经炎性通路受到影响。这个 这项工作的预期结果是，FVIII的缺乏将导致显著的神经异常。结果是 将产生重要的积极影响，因为他们将建立对发展中的 FVIII缺乏症的脑结构和功能，长期服用会改善认知、精神和素质 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.