Genetic causes as co-factors in cytomegalovirus associated hearing loss

描述(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，是导致感音神经性耳聋(SNHL)和其他神经后遗症的主要非遗传原因。尽管疾病负担很高，但对巨细胞病毒相关性听力损失的发病机制知之甚少。此外，只有大约15%的先天性巨细胞病毒感染的儿童会发展为听力，而在那些出现这些缺陷的儿童中，听力损失的严重程度、偏侧性和时间差异很大。上一次 研究表明，在CMV相关SNHL的儿童中，GJB2突变的频率增加，这增加了遗传因素可能解释先天性CMV感染中听力损失的变异性。NIDCD研究职业提升奖(K18)的总体目标是由一位知名的研究人员申请，目的是获得遗传学领域的先进科学知识和工具，重点关注儿童听力损失。候选人是一名临床科学工作者，在过去20年中，在先天性巨细胞病毒(CMV)感染和CMV相关性听力损失领域，拥有经过证明的外部资金和科学生产力方面的记录。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的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)通过分析正在进行的CHEMS研究队列的样本子集(外周血和干血点)来确定遗传原因是否是CMV相关性听力损失的辅助因素，4)继续在CMV相关性耳聋领域做出学术贡献，以及5)发展合作并寻求外部资金，以开展研究，以阐明CMV相关性听力损失的机制。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，进行分子遗传学方面的实践培训，正规课程，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举行的系列研讨会，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CHAMES研究的儿童子集，以确定CMV相关性听力损失的遗传基础。此外，还将探讨利用干血斑点进行外显子全序列测定的可行性。BWH和其他哈佛附属机构有出色的资源来完成培训，患者群体的听力与定义的听力结果一致，标本确保成功完成拟议的培训和研究。除了莫顿博士作为主要导师外，其他三位顶尖专家(雷姆博士、肯纳博士和沈阳博士)也同意作为候选人的联合导师参加该项目。建议的研究不仅将加深我们对CMV相关性听力损失机制的理解，还将使候选人准备将其研究计划扩展到研究听力损失的遗传基础，并提高UAB的听力研究能力。

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.