1999 — 2002 |
Fatemi, S. Hossein |
P50Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These grants differ from program project grants in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes. |
Pilot Study--Bupropion Hcl and Placebo Treatment of Smoking in Schizophrenics @ University of Minnesota Twin Cities
Schizophrenia is a debilitating and chronic brain disorder which affects 1% of the world population. There is significant evidence to indicate high rates of smoking in this patient population causing additional health problems for this group of individuals. There is a scarcity of studies examining the effects of psychopharmacologic interventions in helping schizophrenic patients to either reduce or stop their tobacco intake. Recent evidence shows superiority of bupropion HCl to placebo in cigarette smoking cessation. Although cessation of smoking should be the ultimate goal, many schizophrenics are unwilling or unable to quit. We would like to test the hypothesis that bupropion will cause reductions in nicotine use by schizophrenic patients. We propose to do a double blind randomized placebo-controlled within subject cross-over study in 10 subjects to establish the feasibility and acceptability of bupropion in this population. We hope that this study will provide pilot data to undertake a subsequent larger, clinical trial.
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0.977 |
2005 — 2009 |
Fatemi, Seyyed Hossein |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Prenatal Virally Induced Brain Disorder in Mouse @ University of Minnesota
DESCRIPTION (provided by applicant): Schizophrenia, which affects 1% of the world's population, has been linked epidemiologically to prenatal exposure to human influenza virus. Experimental animal data supporting this linkage are lacking. Our long-range goal is to understand how prenatal human influenza viral infection affects brain development adversely, leading to the genesis of schizophrenia. The objective of this application is to determine how prenatal infection of mice with human influenza virus causes subsequent brain structural and behavioral abnormalities in adult animals. The central hypothesis of the application is that prenatal viral infection at critical periods during embryogenesis causes permanent changes in brain structure and function, leading to the development of postnatal behavioral abnormalities. The rationale for the proposed research is that, once the pathogenesis of influenza virus-induced behavioral abnormalities is understood in mice, similar pathogenic mechanisms can be selectively sought for schizophrenia. We are uniquely prepared to undertake the proposed research, because we have succeeded in performing pilot studies, indicating that infection of mice on day 9 of pregnancy with a sublethal dose of human influenza virus causes abnormal corticogenesis and changes in levels of several important brain markers in postnatal life. Additionally, infection on day 9 of pregnancy leads to development of abnormal behavioral responses on prepulse inhibition in the affected adult mice. The central hypothesis will be tested and the objective of the application accomplished by pursuing three specific aims: 1) identify neuroanatomical molecular profiles for postnatal brain development that result from the effects of prenatal human influenza viral infection in mice using DMA microarray, 2) characterize morphometric abnormalities that are produced in the offspring following prenatal human influenza viral infection in mice by diffusion tensor microimaging and magnetic resonance volumetric studies, and 3) characterize behavioral abnormalities that are produced in mice by brain lesions that are comparable to those in patients with schizophrenia. The proposed work is innovative, because it capitalizes on our new animal model, which links a viral insult to abnormal brain development. It is our expectation that we will link the onset of post-viral structural changes in the brains of mice with the subsequent development of specific biochemical, behavioral and structural changes in affected animals. Such outcomes will be significant, because they are expected to provide a rational explanation for the epidemiological data supporting the link between human influenza viral infection, and the subsequent rise in births that lead to schizophrenia. In addition, it is expected that the results will provide clues that will lead to fundamental advances in our knowledge of the pathogenesis of schizophrenia and, therefore, of how it can be prevented and treated.
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0.839 |
2007 — 2011 |
Fatemi, Seyyed Hossein |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Gabaergic Dysfunction in Autism @ University of Minnesota Twin Cities
[unreadable] DESCRIPTION (provided by applicant): Autism is a severe neurodevelopmental disorder with genetic and environmental etiologies and a prevalence rate of 16 per 10,000, which appears to result from altered development of nervous tissue pre- and postnatally. The central hypothesis of this application is that certain gene families involved in cell growth and migration and GABAergic neurotransmission will be altered in autism. This central hypothesis will be tested and the objectives of this application accomplished by pursuing two Specific Aims: 1) Determine the mRNA [unreadable] and protein levels for Reelin, its receptors, and downstream molecules in the Reelin signaling system in cerebellar, hippocampal, and frontal cortices of autistic subjects and matched controls; and 2) Determine the mRNA and protein levels for GAD 65 and 67 kDa proteins and GABA receptors in cerebellar, hippocampal, and frontal cortices of autistic subjects and matched controls. We will employ previously established qRTPCR, SDS-PAGE and western blotting, and in situ hybridization techniques to quantify various mRNA and protein species. It is our expectation that we will demonstrate gene and protein alterations in brains of autistics involving GABAergic markers, Reelin and its downstream components, linking GABAergic dysfunction to autistic brain structural abnormalities. Such outcomes will be significant, because they are expected to identify biochemical mechanisms responsible for abnormal brain development in early childhood, as seen in autism. [unreadable] [unreadable] [unreadable] [unreadable]
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0.839 |
2009 — 2010 |
Fatemi, Seyyed Hossein |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Varenicline and Smoking Cessation in Schizophrenia @ University of Minnesota
DESCRIPTION (provided by applicant): Schizophrenia is a major debilitating brain disorder that affects 1% of the world's population. There is a 90% prevalence rate of comorbid nicotine addiction in schizophrenic patients leading to high morbidity and mortality rate in this vulnerable population. The smoking cessation agent bupropion HCl has been tested in schizophrenics, but the results on its efficacy are inconclusive. Recent works by different laboratories have shown the safety and efficacy of varenicline, a partial 1422 and full 17 nicotinic acetylcholine receptor agonist, as a smoking cessation agent. However, to date, no published studies have tested the safety and efficacy of varenicline in treatment of nicotine dependence in schizophrenic patients. As varenicline appears to be a promising treatment in non-psychiatric patients, it would be beneficial to examine its effects in schizophrenic patients. The central hypothesis of this application is that treatment with varenicline will safely increase smoking abstinence rates in schizophrenic patients when compared to those receiving placebo. This central hypothesis will be tested and the objectives of this application accomplished by pursuing two Specific Aims: 1) Treatment with varenicline or bupropion HCl for a period of three months will increase smoking abstinence rates in schizophrenic patents when compared to placebo;and 2) Treatment with varenicline or bupropion HCl for a period of three months will not increase psychosis in schizophrenic patients when compared to placebo. We will employ a double-blind randomized placebo controlled study to assess varenicline's safety and efficacy. It is our expectation that we will demonstrate that varenicline is safe and effective in decreasing smoking rates in schizophrenic patients without exacerbating psychotic symptoms. Such outcomes will be significant, because they will offer a new treatment for smoking cessation in this vulnerable population. PUBLIC HEALTH RELEVANCE: Schizophrenia is a major debilitating brain disorder that affects 1% of the world's population with a 90% prevalence rate of comorbid nicotine addiction in schizophrenic patients, leading to high morbidity and mortality rate in this vulnerable population. As varenicline appears to be a promising treatment in non-psychiatric patients, it would be beneficial to examine its effects in schizophrenic patients. The central hypothesis of this application is that treatment with varenicline will safely increase smoking abstinence rates in schizophrenic patients when compared to those receiving placebo. It is our expectation that we will demonstrate that varenicline is safe and effective in decreasing smoking rates in schizophrenic patients without exacerbating psychotic symptoms. Such outcomes will be significant, because they will offer a new treatment for smoking cessation in this vulnerable population.
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0.839 |
2010 — 2014 |
Fatemi, Seyyed Hossein |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Gabaergic and Reelin Deficits in Schizophrenia @ University of Minnesota
DESCRIPTION (provided by applicant): Schizophrenia is a neurodevelopmental disorder that affects young adults and is manifested by a disruption in cognition and emotion, along with negative (i.e., apathy, poor or nonexistent social functioning) and positive (presence of hallucinations, delusions) symptoms, and a lifetime prevalence of 1%. Our proposal will evaluate the degree of involvement of GABAergic receptor families, Reelin, and GAD65 and GAD67 kDa and their constituent signaling systems in postmortem brain samples of subjects with schizophrenia vs. subjects with bipolar disorder, major depression, and matched controls. The central hypothesis of this application is that expression of molecules involved in the Reelin and GABAergic signaling pathways are altered in subjects with schizophrenia, bipolar disorder, and major depression resulting in dysfunctional signaling and consequent brain abnormalities in these disorders. We plan to test our central hypothesis and accomplish the objectives of this application by pursuing the following three Specific Aims: 1) Systematically determine mRNA and protein levels for members of the Reelin signaling system in frontal cortex, anterior hippocampus, and lateral cerebellum of subjects with schizophrenia vs. subjects with bipolar disorder, major depression, and matched controls; 2) Determine the mRNA and protein levels of GAD65, GAD67, and selected GABA receptors in frontal cortex, anterior hippocampus, and lateral cerebellum of subjects with schizophrenia vs. subjects with bipolar disorder, major depression, and matched controls; and 3) Characterize microRNA and miRNA target gene expression in frontal cortex, hippocampus, and cerebellum of subjects with schizophrenia vs. subjects with bipolar disorder, major depression, and controls. We will employ previously established qRT-PCR, western blotting, immunocytochemistry, in situ hybridization and miRNA microarray techniques to quantify various mRNA and protein species. This proposal has the potential to accomplish multiple objectives: 1) Discover systematic changes in Reelin, its receptors, and downstream molecules, in key abnormal structures in schizophrenia, bipolar disorder and major depression: frontal cortex (Brodman's area (BA) 6), anterior hippocampus, and lateral cerebellum; 2) Determine coordinated changes in molecules and identifying relationships among molecules of the Reelin signaling system; 3) Characterize changes in the mRNA and protein levels for GABA receptors, GAD65 and GAD67 kDa molecules in anterior hippocampal, lateral cerebellar, and frontal cortices of subjects with schizophrenia vs. matched bipolar, depressed, and healthy controls; 4) Discover relationships among Reelin and GABAergic signaling system molecules that explain dysfunction of these two systems in the pathology of schizophrenia, bipolar disorder, and major depression; and 5) Test whether miRNAs may be responsible for altered expression of Reelin and GABAergic signaling molecules in subjects with schizophrenia, bipolar disorder, and major depression.
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0.839 |