Schizophrenia is a severely debilitating disease affecting 1% of the population worldwide. Though major progress has been made in the last two decades towards understanding the causes of the disease, we still lack a complete model for the underlying mechanisms. Recently, increases in the number of gene copies in the Vasoactive Intestinal Peptide Receptor 2 (VPAC2R) region were found to be strongly linked to schizophrenia. The VPAC2 receptor is a vasoactive intestinal peptide (VIP) responsive G-protein coupled receptor which signals predominantly through the cAMP signaling pathway. The role of the VPAC2 receptor in the regulation of circadian rhythm has been well studied, but the role and mechanism of VIPR2 in neuronal functions linked to mental health and cognitive function remains unexplored. Using animal models of disease-linked genetic copy number variation, I will address how VPAC2 copy number variations give rise to behavioral changes linked with disease. The VPAC2 receptor is expressed in the hippocampus and its activation enhances synaptic transmission. In hippocampal slices I will determine whether enhanced activation of VPAC2 receptors in the hippocampus presents a disease mechanism in VPACR copy number variation, and if this leads to changes long term potentiation. Finally, using DREADD based modulation, and in-vivo imaging of hippocampal circuitry I will determine the role of VPAC2 receptor signaling in hippocampal circuitry linked to fear conditioning behavior and reveal whether this is disrupted in disease. Through this research I aim to illuminate the mechanisms, from gene to behavior, by which enhanced expression of the VPAC2 receptor can contribute to schizophrenia. These findings will improve our understanding of the underlying mechanisms of VIP interneuron signaling and how this links to disease-related behavior schizophrenia and bring us closer to a more complete model of the biology underlying this disease. My training through this K01 will allow me to 1) learn advanced skills in in-vitro and in-vivo physiology and behavior; 2) gain the knowledge and analysis tools required to interpret these techniques; and 3) acquire the capabilities required of an independent investigator. The application integrates didactic teaching, mentorship from experienced mentors and active research to allow me to achieve these goals. Together the mentorship team I have selected, the institutional support provided a wealth of knowledge and expertise and the support of this K01 Award will allow me to achieve these goals and bring me closer to my long term career goal of becoming an independent investigator dedicated to improving our understanding of mechanisms and therapies in schizophrenia.
Schizophrenia is a debilitating disorder affecting 1% of the population with an economic $60 billion dollars per annum in the US alone. The proposed K01 application aims to identify the neural mechanisms underlying schizophrenia in patients with copy number variations of the gene encoding the G- protein coupled VPAC2 receptor, and by this investigation to reveal pathways that might underlie disease in these individuals and in schizophrenia in general. This project enhances the NIMH's public health mission by responding to Objectives 1 of the NIMH Strategic Plan calling for research to 'determine the mechanisms by which genes influence the development and functioning of neural cells and circuits across the lifespan' in addition to Objective 3 as the development of VPAC2 receptor antagonists provides a promising new therapy for 'better interventions' in schizophrenia.
| Barr, Ian; Weitz, Sara H; Atkin, Talia et al. (2015) Cobalt(III) Protoporphyrin Activates the DGCR8 Protein and Can Compensate microRNA Processing Deficiency. Chem Biol 22:793-802 |
