Projects and Grants
Core A: Administrative
The functions of this core are both administrative and academic, with the overall goal of generating efficiencies and cooperation through coordination and integration of resources and facilities to attain the scientific mission of the center. This core supervises all financial and compliances aspects of the center, manages all committees, work groups, and meetings, takes a lead in education and outreach.
Core B: Clinical/Brain Bank
This core is responsible for the identification of patients who meet inclusion and exclusion criteria for the imaging study as well as their clinical assessment. The clinical component of this core is also responsible for the recruitment of subjects for postmortem studies as well as the clinical diagnosis of subjects who come to autopsy. The Brain Banking component of this core is responsible for the acquisition of brain tissue donations from young as well as elderly persons with mental illness and controls. Fixed and/or frozen tissue specimens are distributed to center and non-center research projects.
Core C: Data Management and Statistics
This core possesses expertise in statistical analyses and database management. All projects and cores utilize the Data Management and Statistics Core. The two databases generated by the longitudinal antemortem assessment of the cohort of schizophrenic patients and the brain bank are quite large, as is the imaging database. With the help of database managers and information technology developers the Conte center data warehouse has grown into a powerful, intuitive, scientific date mining tool as well as an administrative portal through which the activities and progress of the Clinical and Brain Bank cores can be tracked.
Project 1: Oligodendrocyte And Neuron Pathology In Cingulate Cortex
The anterior cingulate cortex plays a significant role in motivation, attention, and behavior and, as a component of the limbic system, in affect and memory. It has been clearly implicated in schizophrenia by studies of cytoarchitectural postmortem changes and functional imaging showing hypermetabolism in this region in schizophrenia. This project performs quantitative analysis of possible relationships between oligodendrocytic pathology and abnormalities in cytoarchitecture in the cingulate cortex of postmortem brains from schizophrenic patients and neuropathologic and brain imaging analyses of relevant mice mutants such as the Quaking mouse, as well as genetically modified mice such as MAG, PTPRZ1/RPTPβ, or Olig2 knock-outs/transgenics. This approach offers a superb opportunity to investigate myelin deficits that have a clinical impact and to determine the molecular, developmental, and morphologic characteristics of the neuronal circuits whose alteration is likely to underlie the pathogenesis and clinical manifestations of schizophrenia.
Project 2: Genetic Dissection of Abnormal Oligodendrocyte And Myelin Function In Schizophrenia
This project identifies etiologically relevant oligodendrocyte and/or myelination related pathways by detailed analysis of oligodendrocyte and/or myelination related candidate genes supplemented by whole genome association. Alleles showing replicated evidence for association with schizophrenia will be examined: 1) for functional effects to guide construction of appropriate mouse models; 2) for evidence for association to phenotypes beyond schizophrenia; and, 3) in individuals who have had neuroimaging and cognitive evaluations in order to identify possible mechanisms linking genotype to phenotype.
Project 3: PTPRZ1/RPTP Signaling In Schizophrenia
Neuregulin1 (NRG1) and the NRG1 receptor ERBB4 are associated with schizophrenia. We have identified a signaling complex comprised of ERBB4, a receptor phosphotyrosine phosphatase (PTPRZ1), and a MAGI scaffolding protein and showed that these proteins are expressed in oligodendrocytes. We have observed that PTPRZ1 expression is altered in schizophrenia and represents a genetic risk factor for schizophrenia. We hypothesize that the PTPRZ1 is involved in oligodendrocyte development, and disruption of PPRZ1 signaling can thereby contribute to schizophrenia susceptibility. Therefore: 1) PTPRZ1 and PTPRZ1-associated proteins will be characterized as risk factors for schizophrenia. These proteins will be analyzed for their role in oligodendrocytes and the effects of perturbation of these pathways in cell and animal models will be determined.
Project 4: Structure And Function of White Matter In Schizophrenia
Using diffusion tensor imaging and positron emission tomography imaging modalities we are exploring the hypothesis that white matter tract structure is fixed at disease onset in schizophrenia but that gray and white matter volume loss continues over time. Earlier imaging work conducted by this center has demonstrated regionally-specific areas of white matter with relatively high metabolic rates in patients with schizophrenia. We are working to replicate these findings through the imaging of unmedicated patients with schizophrenia. In addition, using tract-tracing methods, the details of specific cingulate-thalamus, cingulate-frontal and fronto-striatal-thalamic pathways will be quantified. These imaging parameters are measured in the same brain regions from which samples are being taken for the postmortem studies in this center. Taken together, the results from these studies will facilitate important inferences regarding the role of oligodendrocytes and myelin-related gene products in imaging findings related to fractional anisotropy and brain metabolism.
Project 5. Mouse Phenotyping
In this center we are developing and characterizing mouse models that recapitulate key aspects of schizophrenia. The most useful mouse models will have disruptions in genes involved in oligodendrocyte development and/or function, which will lead to reduced expression of oligodendrocyte-related genes, oligodendrocyte dysfunction, tract and white matter abnormalities, and specific behavioral deficits with face and construct validity for schizophrenia.