Abnormal Bleeding Risk in Female Hemophilia A Carriers

项目概要/摘要 K 08指导临床科学家研究职业发展奖申请详细介绍了为期5年的培训 该计划旨在推进Cygan博士的职业目标，即开发止血方面的独立研究计划 关注女性血友病A携带者的出血倾向。这项科学提案旨在调查 血友病A（HA）携带者的出血倾向，这在很大程度上仍然没有得到充分认识， 明白HA是由于编码凝血因子VIII（FVIII）的F8基因内的突变所致， 通常认为只影响男性，而女性HA携带者被认为只有很少的症状。 据估计，每四名女性携带者对应一名男性携带者，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。许多人有严重的出血 尽管在男性中因子VIII活性水平被认为是足够的，但仍发生事件。目前对出血的认识 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告知他们， 分类和管理。该建议旨在开发一个出血倾向的风险预测模型， HA携带者，使用标准凝血试验以外的参数。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，将建立模拟HA载体状态的细胞培养系统。 X染色体失活（XCI）在改变FVIII的基础和刺激水平中的作用， 将评价产生的凝血酶。在目标3中，天然抗凝剂改变止血的作用 并解释独立于XCI的HA携带者之间出血表型的差异。 在获奖期间，Cygan博士将继续发展他在良性血液学方面的专业知识， 扩展他在实验设计和实施方面的能力。一个多学科的指导小组已经 组装，以确保该项目的成功，包括在X染色体生物学，因子VIII的专业知识， 表达、临床血液学和生物统计学。导师团队包括Laura Carrel博士、Valder R. Arruda和M. Elaine Eyster;他们将通过直接指导Cygan博士实现他的培训目标。 研究经验、正规教学法、参加机构研讨会和初级职业发展 机会Lan Kong博士是一名生物统计学家，他将作为一名生物统计学家为Cygan博士的研究和职业规划做出贡献。 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.