Schizophrenia is a complex and poorly understood disease caused by the interplay of many environmental and genetic factors. It occurs in 1% of the general population and causes delusions, hallucinations, and disorganized behavior. The 22q11.2 deletion syndrome is a disorder that is caused by the microdeletion of part of chromosome 22 leading to a 25-fold greater chance of developing schizophrenia in affected individuals versus the general population. The missing 22q11.2 region contains the DGCR8 gene, which is required for the initial step of miRNA biogenesis. In Dgcr8 knockout mice, the levels of specific miRNAs in the brain are reduced, and these animals show behavioral and cognitive deficits similar to schizophrenia. However, the 22q11.2 deletion itself is not directly the cause of schizophrenia, since 75% of individuals with this deletion do not develop the disease. We hypothesize that the 22q11.2 deletion increases the risk of schizophrenia through alterations in miRNA regulatory networks via depletion of miRNAs which may serve as a protective buffer against the accumulation of deleterious mutations elsewhere in the genome. In healthy individuals, genes associated with schizophrenia may harbor regulatory mutations, but these mutations are not deleterious since the miRNA regulatory system acts as a buffer that maintains gene expression at the required levels. In 22q11.2 deletion syndrome, the same mutation may have pathogenic effects, since miRNA critical for compensating for these mutations are absent. We believe that these unchecked mutations result in the development of schizophrenia. These experiments attempt to characterize which miRNAs are altered in 22q11.2 deletion syndrome. Based on which miRNAs exhibit altered expression, online resources and predictive software can now be used to determine which genes may have altered expression as a result of disruptions to the miRNA regulatory pathway and these genes could potentially be the targets for diagnostic assays or pharmacological intervention. Lastly, experiments using cellular models and luciferase reporter constructs have been performed to validate how a schizophrenia associated SNP in a specific gene, H3F3B, alters miRNA regulation of one specific miRNA, miR-616. To investigate our hypothesis that the 22q11.2 deletion increases the risk of schizophrenia through alterations in miRNA regulatory networks via depletion of miRNAs which may serve as a protective buffer against the accumulation of deleterious mutations, the experiments described in the following chapters have been performed
Subject (authority = RUETD)
Topic
Cell and Developmental Biology
Subject (authority = ETD-LCSH)
Topic
Schizophrenia
Subject (authority = ETD-LCSH)
Topic
MicroRNA
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TitleInfo
Title
Rutgers University Electronic Theses and Dissertations
Identifier (type = RULIB)
ETD
Identifier
ETD_7535
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Form (authority = gmd)
electronic resource
InternetMediaType
application/pdf
InternetMediaType
text/xml
Extent
1 online resource (xi, 227 p. : ill.)
Note (type = degree)
Ph.D.
Note (type = bibliography)
Includes bibliographical references
Note (type = statement of responsibility)
by William Manley
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TitleInfo
Title
Graduate School - New Brunswick Electronic Theses and Dissertations
Identifier (type = local)
rucore19991600001
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PhysicalLocation (authority = marcorg); (displayLabel = Rutgers, The State University of New Jersey)
Rutgers University. Graduate School - New Brunswick
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