Molecular and Cellular Biology; Neurobiology; Neuropharmacology
The goal of my research is to elucidate the endogenous role of two neuropeptide systems and their potential as therapeutic targets; urotensin II (UII) and neuropeptide S (NPS). Both of these peptides regulate basal ganglia function through G protein-coupled receptor (GPCR) mediated intracellular signals. The basal ganglia are critical in motivated behavior (e.g. food seeking), voluntary movement, and the expression of habits (e.g. compulsions). Basal ganglia dysfunction results in neurological disorders as diverse as Parkinsonism and drug addiction. GPCRs are proven to be amenable to drug development and are targeted by over 30 percent of present day pharmaceuticals. My goal is to exploit the UII and NPS systems to improve the medical treatment of neurological disorders.
Currently my lab is pursuing the following:
1) Determine the role of UIIR activation and the UIIR expressing neurons in reward-related behaviors:. Our results support the need for further investigation of the UII-system as a therapeutic target for treating drug abuse disorders. In addition, we are investigating the i) bias-signaling properties of the endogenous UIIR ligands, and ii) the impact of UIIR single-nucleotide polymorphisms on receptor signaling.
2) We designed a toxin that selectively targets UIIR expressing neurons (cholinergic PPT). In rats the toxin-mediated lesion mimics Progressive Supranuclear Palsy (the most common atypical parkinsonism) on multiple fronts: selective ablation of cholinergic PPT neurons, impaired motor function, and deficits in acoustic startle reaction (MacLaren et al, 2014a; MacLaren et al, 2014b). Our selective cholinergic depletion and a viral-mediated tauopathy rat models are the first to specifically model PSP, and we are further characterizing these models in hope of using them for future drug discovery.
3) During my graduate and post-doctoral training it was found that the central brain administration of neuropeptide S (NPS) in mice enhances memory, is anxiolytic-like (reduced anxiety) and produces hyperlocomotor (increased movement) (Xu et al., 2004; Jungling et al., 2008; Duangdao et al., 2009; Okamura et al., 2011). This is a highly unique behavioral profile. Typically drugs that induce activity and arousal increase anxiety-like behaviors, while drugs that are anxiolytic generally have sedative effects and impair memory. Therefore, the NPS-system could be a therapeutic target for disorders for which fast-acting anxiolytics that augment memory formation would be beneficial (e.g. post-traumatic stress disorder (PTSD)).
In collaboration with the Drug Discovery Center at Research Triangle Institute, we are testing new small molecule NPSR-targeted drug-like compounds.