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.
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