Rocco Gogliotti, PhD
Title/s: <p>Assistant Professor</p> <p>Molecular Pharmacology and Neuroscience</p>
Office #: Bldg 115 Room 423
Email: rgogliotti@luc.edu
Title/s: <p>Assistant Professor</p> <p>Molecular Pharmacology and Neuroscience</p>
Office #: Bldg 115 Room 423
Email: rgogliotti@luc.edu
Among the biggest challenges facing neuroscience drug discovery is the failure of promising preclinical data sets to translate into clinical efficacy. One potential contributing factor is an overreliance on mouse models during target identification, particularly knockout mice, which do not often represent the subtleties of clinically pathogenic mutations. The Gogliotti lab uses a multifaceted strategy that integrates pharmacology, genomics, and neuroscience, and emphasizes the use of human autopsy samples early in the discovery process with the goal of enriching drug targets for autism and autism-associated disorders with those that are translationally relevant. The main projects within the lab fall under three categories:
Using a large set of autopsy samples from patients diagnosed with the neurodevelopmental disorder Rett syndrome (RTT), we have discovered that distinct pathogenic mutations have unique effects on gene expression patterns. RTT is caused by loss of function mutations in the methyl CpG binding protein 2 (MeCP2) gene, and our findings complement clinical data demonstrating that the type and location of MeCP2 mutation is predictive of disease severity. Since target identification for RTT is almost exclusively driven by data from Mecp2 knockout mice, these data indicate that patient subpopulations could have unique responses to compounds currently being advanced for clinical use. Our goal is to 1) determine how common mutations impact the safety and efficacy profiles of these compounds across the spectrum of MeCP2 mutations and 2) examine how mutation-specific patterns of gene expression alter disease severity.
In Gogliotti et al. 2018, we conducted an RNA-sequencing experiment on motor cortex and cerebellar samples from RTT patient autopsies, which uncovered that four of the five mAChRs had significantly affected gene expression relative to matched controls. mAChRs are widely considered to be valuable drug targets based on their signaling properties and location within the brain; however, mAChR drug discovery has been plagued by adverse effects, and only recently have clinically viable compounds become available. Using these compounds, which target mAChR receptors allosterically, we have now demonstrated efficacy in mouse models of RTT, CDKL5-disorder, and Pitt Hopkins Syndrome. We are currently examining how the loss of mAChR signaling impacts neurodevelopment and the mechanisms underlying the observed efficacy.
95% of RTT cases result from mutations in MeCP2; however, despite sharing sufficient symptomatic overlap to support a RTT diagnosis, the remaining 5% are MeCP2 mutation-negative. Working under the hypothesis that the pathways whose disruption is conserved between both populations will likely be the most critical to disease manifestation, we recently performed differential sequencing analysis of the transcriptomes in temporal cortex samples from mutation-positive and negative patients. These experiments suggest that pathways associated with activity-dependent gene regulation may be implicated in the disorder. We are currently exploring this using a combination of neurobehavioral assays, transcriptomics, and pharmacology.