Viral determinants of Cytomegalovirus related hearing loss

先天性巨细胞病毒（CMV）感染是感音神经性听力损失（SNHL）的主要原因， 孩子在每年约40，000名先天性CMV婴儿中，只有约10%的婴儿 SNHL。SNHL的变异率被认为是由宿主对 这个病毒。然而，CMV是一种复杂的病毒，在不同的人中具有有据可查的遗传和表型变异性。 临床CMV毒株。我们推测，特定的病毒编码功能负责不利的 宫内CMV感染的结局和疾病的变异性可以反映在病毒的多样性中， 基因型，因此，CMV分离株的表型变异。我们提出了几个相互关联的 实验方法，以调查的作用，遗传独特的菌株CMV的发展， SNHL。最初，从有听力损失和无听力损失的婴儿中分离出的病毒的生物学行为， 将表征负责这种行为的特定病毒基因。该分析将包括体外 在一组细胞系和原代细胞中的病毒复制和病毒基因表达作为病毒的筛选测定 表型。我们还将确定宿主细胞反应和病毒基因之间是否存在相互关系。 表达可能与疾病表型相关。最后，这些基因的频率 将在来自孔的大量病毒分离物中定义与特定疾病表型相关的病毒 人口特征。候选人的长期目标是成为儿科传染病 院士，并实现独立作为一个研究人员，以促进发现CMV领域 听力损失相关研究环境是理想的导师谁是在该领域的领导者， 先天性CMV感染候选人将有受保护的时间来进行她的研究在国家的艺术 实验室设施与丰富的可用资源。一个结构化的5年计划与密集的教学 在第一年和第二年的组成部分，在第三年和第五年的一些课程和其他教育活动，以及一项研究， 提出了最后三年强调的内容。相关性：先天性CMV感染是 然而，对这种疾病的发病机制知之甚少。的 拟议的研究将提供进一步深入了解这一过程，并希望，确定标记为 SNHL的发展。

ongenital Cytomegalovirus (CMV) infection is a leading cause of sensorineural hearing loss (SNHL) in children. Among the approximately 40,000 infants born with congenital CMV each year, only ~10% develop SNHL. The variable penetrance of SNHL has been argued to result from differences in host responses to this virus. However, CMV is a complex virus with well documented genetic and phenotypic variability among clinical CMV strains. We hypothesize that specific virus-encoded functions are responsible for an adverse outcome of intrauterine CMV infection and the variability in disease could be reflected in the diversity of viral genotypes and therefore, the phenotypic variability of CMV isolates. We propose several interrelated experimental approaches to investigate the role of genetically unique strains of CMV in the development of SNHL. Initially, the biological behavior of viruses isolated from infants with and without hearing loss and specific viral genes responsible for this behavior will be characterized. This analysis will include in-vitro replication and viral gene expression in a panel of cell lines and primary cells as a screening assay of viral phenotype. We will also determine if there is an interrelationship between host cell responses and viral gene expression that can be associated with disease phenotype. Finally, the frequency of these gene(s) associated with particular disease phenotype will be defined in a large number of virus isolates from a well characterized population. The candidate's long-term goal is to be a Pediatric Infectious Diseases academician and achieve independence as an investigator to contribute to the field of discovery in CMV related hearing loss. The research environment is ideal with mentors who are leaders in the field of congenital CMV infection. The candidate will have protected time to carry out her research in state of the art laboratory facilities with a wealth of available resources. A structured 5 year plan with intensive didactic component in years 1 and 2, some classes and other educational activities in year 3-5, and a research component emphasized in the final three years is proposed. Relevance: Congenital CMV infection is the leading infectious cause of hearing loss yet, little is known about the pathogenesis of this disease. The proposed research will provide further insight into this process and hopefully, identify markers for the development of SNHL.