Viral determinants of Cytomegalovirus related hearing loss

生殖器巨细胞病毒(CMV)感染是引起感音神经性耳聋(SNHL)的主要原因 孩子们。在每年大约40,000名出生时患有先天性巨细胞病毒的婴儿中，只有10%的人会患上 SNHL。SNHL的可变外显率被认为是由于寄主对 这种病毒。然而，CMV是一种复杂的病毒，其遗传和表型变异在 临床CMV株。我们假设特定的病毒编码功能导致了 宫内CMV感染的转归和疾病的变异性可以通过病毒的多样性来反映。 因此，CMV分离物的表型变异性。我们提出了几个相互关联的 研究巨细胞病毒基因独特毒株在猪瘟发病过程中作用的实验方法 SNHL。最初，从患有和不患有听力损失的婴儿中分离出的病毒的生物学行为 负责这一行为的特定病毒基因将被描述出来。这项分析将包括体外 在一组细胞系和原代细胞中的复制和病毒基因表达作为病毒筛选试验 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 可能与疾病表型相关的表达。最后，这些基因的频率(S) 与特定疾病表型相关的病毒将在从井中分离的大量病毒中定义 具有特征的人口。候选人的长期目标是成为一名儿科传染病专家 院士和研究员实现自主，为CMV发现领域做出贡献 相关的听力损失。研究环境是理想的，有导师是该领域的领导者 先天性巨细胞病毒感染。候选人将有足够的时间进行最先进的研究 实验室设施，拥有丰富的可用资源。有条理的五年计划和密集的说教 一年级和二年级的部分课程，三到五年级的一些班级和其他教育活动，以及一项研究 提出了最后三年强调的部分。相关性：先天性巨细胞病毒感染是 目前仍是听力损失的主要感染原因，但对这种疾病的发病机制知之甚少。这个 拟议的研究将提供对这一过程的进一步洞察，并有望确定 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.