For much of her scientific research career, Dr. Cowell has studied the cellular mechanisms underlying neuronal cell death and injury. However, she has recently made a significant change in long-term research interests and is in the process of entering the field of mental health research. This proposal outlines a strategy for didactic and technical training and exposure to emerging concepts in translational schizophrenia research, with the goal of promoting Dr. Cowell's success as an independent, extramurally funded, academic investigator in mental health. Dr. Cowell's development plan involves the completion of coursework and attendance at research conferences, workshops in career development and ethical conduct in research, and a program of research that will contribute technically and intellectually to her progress towards independence. Based on preliminary data suggesting that peroxisome proliferator activated receptor g (PPARg) coactivator 1a (PGC-1a) is involved in metabolic homeostasis in inhibitory neurons, experiments are designed to test the hypotheses that 1) PGC-1a regulates metabolism and synaptic plasticity in GABAergic neurons in vitro and in vivo, 2) adverse perinatal events (hypoxia) have a long-term effect on the maturation of GABAergic circuits by disrupting normal PGC-1a expression and histone acetylation in development, and 3) the expression levels of PGC-1a and related metabolic genes are altered in inhibitory interneurons in the cortex of schizophrenic patients. To test these hypotheses, Dr. Cowell has chosen a panel of consultants with extensive experience in cell culture, rodent models of perinatal hypoxia, assessment of chromatin acetylation/methylation status, and laser capture microdissection from human postmortem brain tissue. This plan will equip the applicant with the knowledge and technical expertise to address key issues in mental health research, while elucidating the mechanisms by which disturbances in brain development contribute to the pathogenesis of schizophrenia. Schizophrenia is a significant health concern; it has been estimated that 1% of the general population and 14% of the homeless population has schizophrenia. In 1990 alone, schizophrenia accounted for $32.5 billion in medical costs. New treatments are needed to improve the lives of those with schizophrenia and to prevent the emergence of schizophrenia in high-risk populations. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01MH077955-02
Application #
7478119
Study Section
Synapses, Cytoskeleton and Trafficking Study Section (SYN)
Program Officer
Wynne, Debra K
Project Start
2007-08-01
Project End
2012-04-30
Budget Start
2008-05-12
Budget End
2009-04-30
Support Year
2
Fiscal Year
2008
Total Cost
$129,807
Indirect Cost
Name
University of Alabama Birmingham
Department
Psychiatry
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
McMeekin, Laura J; Li, Ye; Fox, Stephanie N et al. (2018) Cell-Specific Deletion of PGC-1? from Medium Spiny Neurons Causes Transcriptional Alterations and Age-Related Motor Impairment. J Neurosci 38:3273-3286
McMeekin, Laura J; Lucas, Elizabeth K; Meador-Woodruff, James H et al. (2016) Cortical PGC-1?-Dependent Transcripts Are Reduced in Postmortem Tissue From Patients With Schizophrenia. Schizophr Bull 42:1009-17
Lucas, Elizabeth K; Dougherty, Sarah E; McMeekin, Laura J et al. (2014) PGC-1? provides a transcriptional framework for synchronous neurotransmitter release from parvalbumin-positive interneurons. J Neurosci 34:14375-87
Lucas, Elizabeth K; Reid, Courtney S; McMeekin, Laura J et al. (2014) Cerebellar transcriptional alterations with Purkinje cell dysfunction and loss in mice lacking PGC-1?. Front Cell Neurosci 8:441
Dougherty, S E; Bartley, A F; Lucas, E K et al. (2014) Mice lacking the transcriptional coactivator PGC-1? exhibit alterations in inhibitory synaptic transmission in the motor cortex. Neuroscience 271:137-48
Jiang, Zhihong; Cowell, Rita M; Nakazawa, Kazu (2013) Convergence of genetic and environmental factors on parvalbumin-positive interneurons in schizophrenia. Front Behav Neurosci 7:116
Jiang, Zhihong; Rompala, Gregory R; Zhang, Shuqin et al. (2013) Social isolation exacerbates schizophrenia-like phenotypes via oxidative stress in cortical interneurons. Biol Psychiatry 73:1024-34
Lucas, Elizabeth K; Dougherty, Sarah E; McMeekin, Laura J et al. (2012) Developmental alterations in motor coordination and medium spiny neuron markers in mice lacking pgc-1ýý. PLoS One 7:e42878
Lucas, Elizabeth K; Markwardt, Sean J; Gupta, Swati et al. (2010) Parvalbumin deficiency and GABAergic dysfunction in mice lacking PGC-1alpha. J Neurosci 30:7227-35
Cowell, Rita M; Talati, Pratik; Blake, Kathryn R et al. (2009) Identification of novel targets for PGC-1alpha and histone deacetylase inhibitors in neuroblastoma cells. Biochem Biophys Res Commun 379:578-82