Abnormal Bleeding Risk in Female Hemophilia A Carriers

项目摘要/摘要 这份K08临床科学家导师研究职业发展奖申请书详细介绍了为期5年的培训 推进西根博士制定止血独立研究计划的职业目标的计划 重点分析女性甲型血友病携带者的出血倾向。这项科学提案试图调查 甲型血友病(HA)携带者的出血倾向，这在很大程度上仍未得到充分认识 明白了。HA是由于编码凝血因子VIII(FVIII)的F8基因突变所致，并且是 通常认为只影响男性，而女性HA携带者被认为很少有症状。 据估计，每四名女性HA携带者对应一名HA男性，而且越来越多的证据表明 在HA携带者中，FVIII水平降低和出血症状并不罕见。许多人都有大量出血 尽管第VIII因子的活动水平被认为对男性来说是足够的。对出血的认识现状 这方面的趋势是缺乏的，调查女性HA携带者的研究将极大地了解她们 分类管理。该提案寻求开发一个风险预测模型，以预测#年的出血倾向 HA载体，使用标准凝血测试以外的参数。在目标1中，多变量风险预测 模型将被开发和验证。在目标2中，模拟HA载体状态的细胞培养系统将是 X染色体失活(XCI)在改变FVIII和FVIII基础和刺激水平中的作用 将对由此产生的凝血酶进行评估。在目标3中，天然抗凝剂改变止血的作用 并解释与XCI无关的HA携带者之间出血表型的差异。 在获奖期间，西根博士将继续发展他在良性血液学方面的专业知识，并进一步 拓展自己的实验设计和实施能力。一个多学科的指导团队已经 为确保该项目的成功而组装，并包括X染色体生物学方面的专业知识，因子VIII 表现、临床血液学和生物统计学。导师团队包括劳拉·卡雷尔博士、瓦尔德·R博士。 Arruda和M.Elaine Eyster博士；他们将指导Cygan博士通过直接 研究经验、正规教学、参加机构研讨会和初级职业发展 机遇。生物统计学家Lan Kong博士将作为一名 合作者和统计顾问。

Project Summary/Abstract This K08 Mentored Clinical Scientist Research Career Development Award application details a 5-year training program to advance Dr. Cygan’s career goal of developing an independent research program in hemostasis focused on bleeding tendency in female Hemophilia A carriers. The scientific proposal seeks to investigate bleeding tendency in Hemophilia A (HA) carriers, which remains largely underrecognized and poorly understood. HA is due to mutations within the F8 gene encoding coagulation Factor VIII (FVIII), and is commonly thought to affect only men, while female HA carriers are thought to be only rarely symptomatic. There are an estimated four female HA carriers for every one HA male, and increasing evidence indicates that decreased FVIII levels and bleeding symptoms in HA carriers are not rare. Many have significant bleeding events despite Factor VIII activity levels considered adequate in males. Current understanding of bleeding tendency in this area is lacking, and research investigating female HA carriers would greatly inform their classification and management. The proposal seeks to develop a risk prediction model for bleeding tendency in HA carriers, using parameters other than standard coagulation testing. In Aim 1, a multivariable risk prediction model will be developed and validated. In Aim 2, a cell culture system to model the HA carrier state will be developed and the role of X-chromosome inactivation (XCI) in altering basal and stimulated levels of FVIII and resulting thrombin generation will be evaluated. In Aim 3, the role that natural anticoagulants alter hemostasis and explain differences in bleeding phenotypes between HA carriers independent of XCI will be investigated. During the award period, Dr. Cygan will continue to develop his expertise in benign hematology, and further expand his abilities in experimental design and implementation. A multidisciplinary mentorship team has been assembled to ensure the success of this project and includes expertise in X chromosome biology, Factor VIII expression, clinical hematology and biostatistics. The mentorship team includes Dr. Laura Carrel, Dr. Valder R. Arruda and Dr. M. Elaine Eyster; they will guide Dr. Cygan in meeting his training objectives through direct research experience, formal didactics, participation in institutional seminars and junior career development opportunities. Dr. Lan Kong, a biostatistician, will contribute to Dr. Cygan’s research and career plan as a collaborator and statistical advisor.