National Vulvodynia Association

Terry Morgan M.D., of the Oregon Health Sciences University, as well as Andrea Nackley PhD and Denniz Zolnoun M.D., of the University of North Carolina, are the recipients of the 2014 NVA Research Award.

 

Terry K. Morgan, MD, PhD – Oregon Health & Science University

Terry Morgan, MD, PhD, a pathologist at Oregon Health Sciences University, was awarded an NVA research grant titled, Heritability and Proteomic Pathway Analysis of Vestibulodynia. Prior research, including Morgan’s, has shown that inflammation and nerve growth (neurogenic inflammation) are involved in the pathophysiology of vestibulodynia (aka provoked localized vulvodynia, or PLV). Although PLV is not currently considered to be a genetic disease, Dr. Morgan hypothesizes there is a genetic predisposition that can be tested using the Utah Population Database (UPDB). The UPDB takes advantage of large Mormon families with documented genealogies linked to their diagnostic codes. It has been employed in a number of studies to determine whether a disease runs in families (familiality), by comparing the frequency of the diagnosis in related versus non-related women. If PLV is familial, it will be more common among blood relatives of women with confirmed disease. The goal will be to identify distantly related affected women for subsequent NIH-funded whole genome sequencing and “shared haplotype analysis,” which is a proven method to identify key candidate genes that cause common diseases. Dr. Morgan will also screen fresh frozen vestibular biopsies for expression differences that may be involved in inflammation and nerve growth.

For this pilot experiment, Dr. Morgan will use pooled samples from each diagnostic group: case-control matched samples from negative controls (n=12), primary PLV (n=6), and secondary PLV (n=6). He will use protein expression analysis (proteomics) to test for differences in key regulators like the JAK-STAT pathway that is known to play a role in neurogenic inflammation. Analysis of pooled samples from multiple women within each of the three diagnostic groups will washout natural differences between individuals and amplify shared molecular pathways. It improves the signal:noise result without candidate gene selection bias. Future studies will compare expression levels in individuals within and between groups to validate reproducible differences. The hope is to provide more objective tests to better diagnose PLV and to develop more effective patient-based treatments.

 

Andrea Nackley, PhD and Denniz Zolnoun, MD – University of North Carolina

Vestibulodynia (VBD) represents a significant healthcare problem that is ineffectively treated due to its unclear etiology and heterogeneous clinical presentation. To reduce the complexity of VBD and improve standards of care, the identification of unique biological signatures and pathways that map onto distinguishing clinical features is required. Emerging evidence implicates that microRNAs, non-coding molecules that regulate gene expression, control molecular pathways linked to pain, mood, and inflammation. Yet little is known about their role in chronic pain conditions such as VBD. In a recent case-control study, the investigators evaluated the relationship between pain, psychological traits, inflammatory cytokines and microRNAs in women with VBD alone and those with VBD and chronic overlapping pain conditions (COPCs). Women with VBD had localized pain, normal self-reported pain and psychological profiles, and increased levels of anti- as well as pro-inflammatory cytokines. Those with VBD+COPCs had pain at remote bodily sites, enhanced self-reported pain and somatization, and no compensatory increase in anti-inflammatory cytokines. Women with VBD and VBD+COPCs displayed a dysregulation of 10 and 11 microRNAs, respectively, that were correlated with pain-relevant phenotypes and cytokine levels. These results suggest microRNAs represent a valuable tool for differentiating VBD subtypes (localized pain with apparent peripheral neurosensory disruption versus widespread pain with a central sensory contribution) that may require different treatment approaches.

Investigators will perform in silico pathway analysis to generate a list of predicted targets for the 21 microRNAs dysregulated in women with VBD and VBD+COPCs. Next, they will measure expression levels of the proteins corresponding to the predicted targets in banked blood samples from VBD, VBD+COPCs, and controls using custom protein microarrays. Finally, protein expression levels will be correlated with previously collected data on case status, intermediate phenotypes, and patient-reported outcomes. Results from the proposed aims will inform the design of a larger population-based study to determine the utility of microRNAs and microRNA targets as screening tools for diagnosis and treatment of VBD subtypes.

 

For information on other NVA-funded research, click here.