Genetic causes as co-factors in cytomegalovirus associated hearing loss

描述（由申请人提供）：先天性巨细胞病毒（CMV）感染是最常见的病毒感染，也是感音神经性听力损失（SNHL）和其他神经系统后遗症的主要非遗传原因。尽管疾病负担很高，但对CMV相关性听力损失的发病机制和机制知之甚少。此外，只有约15%的先天性CMV感染的儿童发展听力，并且在那些发展这些缺陷的儿童中，损失在严重程度，偏侧性和时间方面差异很大。先前 一项研究表明，CMV相关SNHL儿童中GJB2突变频率增加，这增加了遗传因素可能解释CMV感染所致听力损失变异性的可能性。这个NIDCD研究职业提升奖（K18）申请的总体目标是获得遗传学领域的先进科学知识和工具，重点是儿童听力损失。候选人是一名临床科学家，在过去二十年中，在先天性巨细胞病毒（CMV）感染和CMV相关听力损失领域的校外资金和科学生产力方面有着良好的记录。这项建议的具体目标包括：1）加强他在分子遗传学和听力损失遗传基础方面的知识和技能，2）接受分子遗传学和生物信息学方面的高级教学培训，3）通过分析样本子集，进行研究以确定遗传原因是否是CMV相关听力损失的辅助因素（外周血和干血斑），4）继续在CMV相关性耳聋领域做出学术贡献，和5）发展合作并寻求校外资金进行研究，以阐明巨细胞病毒相关听力损失的机制。拟议的培训计划包括在布里格姆妇女医院辛西娅·莫顿博士的实验室休假，进行分子遗传学的实践培训，正式的课程，并参加各种学习机会，包括在布罗德研究所和其他哈佛附属机构的系列研讨会，实验室会议和参加国家会议。还提出了一个研究项目，以检查参与CHIMES研究的儿童的一个子集，以确定CMV相关听力损失的遗传基础。此外，将探索使用干血点进行全外显子组测序的可行性。在BWH和其他哈佛附属机构完成培训所需的优秀资源、来自CHIMES的具有明确听力结果的患者人群以及样本的可用性确保了拟议培训和研究的成功完成。除了莫顿博士作为主要导师外，其他三位领先的专家（雷姆博士、肯纳博士和沈博士）已同意作为候选人的共同导师参加该项目。拟议的研究不仅将提高我们对CMV相关听力损失机制的理解，还将为候选人扩展其研究计划以调查听力损失的遗传基础并提高UAB的听力研究能力做好准备。

DESCRIPTION (provided by applicant): Congenital cytomegalovirus (CMV) infection is the most common viral infection and a leading non-genetic cause of sensorineural hearing loss (SNHL) and other neurological sequelae. Despite the high disease burden, little is known about the pathogenesis and mechanisms of CMV-associated hearing loss. In addition, only about 15% of children with congenital CMV infection develop hearing and in those who develop these deficits, the losses are quite variable with respect to severity, laterality and timing. A previous study showed increased frequency of GJB2 mutations in children with CMV-related SNHL raising the possibility that genetic factors may explain the variability in hearing loss in congenial CMV infection. The overall goal of this NIDCD Research Career Enhancement Award (K18) application by an established investigator is to acquire advanced scientific knowledge and tools in the field of genetics, focusing on hearing loss in children. The candidate is a clinician scientst with a proven track record for extramural funding and scientific productivity in the area of congenital cytomegalovirus (CMV) infection and CMV-associated hearing loss over the past two decades. Specific objectives of this proposal include: 1) Strengthening his knowledge and skills in molecular genetics and genetic basis of hearing loss, 2) Undergo advanced didactic training in molecular genetics and bioinformatics, 3) Conduct a study to determine whether genetic causes are co-factors in CMV-associated hearing loss by analyzing a subset of samples (peripheral blood and dried blood spots) from the cohort participating in the ongoing CHIMES study, 4) Continue to make scholarly contributions in area of CMV-associated deafness, and 5) Develop collaborations and seek extramural funding to carry out studies to elucidate mechanisms of CMV- associated hearing loss. The training plan proposed consists of a sabbatical in Dr. Cynthia Morton's laboratory at the Brigham and Women's Hospital for hands-on training in molecular genetics, formal coursework, and participating in a variety of learning opportunities including seminar series at the Broad Institute and other Harvard affiliated institutions, lab meetings and attending national meetings. A research project to examine a subset of children participating in the CHIMES study to determine genetic basis for CMV-associated hearing loss is also proposed. In addition, the feasibility of whole exome sequencing using dried blood spots will be explored. The availability of excellent resources to complete the training at BWH and other Harvard affiliated institutions, patient population from CHIMES with defined hearing outcomes, and specimens ensures successful completion of the proposed training and research. In addition to Dr. Morton as the primary mentor, three other leading experts (Drs. Rehm, Kenna and Shen) have agreed to participate in the program as co- mentors for the candidate. The proposed studies will not only improve our understanding of the mechanisms of CMV-associated hearing loss but also prepare the candidate to expand his research program to investigating genetic basis of hearing loss and to enhance hearing research capacity at UAB.