Individual differences in initial sensitivity to ethanol are strongly related to the heritable risk of alcoholism in humans. To elucidate key molecular networks that modulate ethanol sensitivity we performed a systems genetics analysis of ethanol-responsive gene expression in brain regions of the mesocorticolimbic reward circuit (prefrontal cortex, nucleus accumbens and ventral midbrain) across the BXD RI panel, a highly diverse family of isogenic mouse strains before and after treatment with ethanol. Acute ethanol altered the expression of ~2,750 genes in one or more regions and 400 transcripts were jointly modulated in all three. Ethanol-responsive gene networks were extracted with a powerful graph theoretical method that efficiently summarized ethanol's effects. These networks correlated with acute behavioral responses to ethanol and other drugs of abuse. As predicted, networks were heavily populated by genes controlling synaptic transmission and neuroplasticity. Several of the most densely interconnected network hubs, including Kcnma1 and Gsk3-beta, are known to influence behavioral or physiological responses to ethanol, validating our overall approach. Other major hub genes like Grm3 and Nrg3 represent novel targets of ethanol effects. Networks were under strong genetic control by variants that we mapped to a small number of chromosomal loci. Using a novel combination of genetic, bioinformatic and network-based approaches, we identified high priority cis-regulatory candidate genes, including Scn1b, Gria1, Sncb and Nell2. The ethanol-responsive gene networks identified here represent a previously uncharacterized intermediate phenotype between DNA variation and ethanol sensitivity in mice. Networks involved in synaptic transmission were strongly regulated by ethanol and could contribute to behavioral plasticity seen with chronic ethanol. Our novel finding that hub genes and a small number of loci exert major influence over the ethanol response of gene networks could have important implications for future studies regarding the mechanisms and treatment of alcohol use disorders.

Breast cancer (BC) is one of the most common diagnosed malignancies in females. Although 90% of early diagnosed women are expected to survive for at least 5 years, their quality of life is adversely affected by a cluster of symptoms which we collectively named “psychoneurological symptoms’’ (PN). Given that acquired telomere attrition has been speculated to be a causal factor in chronic diseases and the lack in the literature of mechanisms giving rise to PN symptoms, this study was performed to assess telomere length using a chromosome-specific telomere assay before receiving chemotherapy and at the first chemotherapy. We showed significant telomere attrition on the short arm of chromosome 9. In addition, we showed a negative correlation between telomere length and depression. Furthermore, we evaluated several variables as predictors of the change in telomere length and showed that chemotherapy was predictive of shortened telomere length. Taken together, one can speculate that shortened telomeres could result in epigenetic alterations in the genes juxtaposed to the telomeric region, giving rise to the development and persistence of PN symptoms. Knowledge gained from this study will offer hope for the development of therapeutic interventions that could prevent undesirable side effects and ensure a better quality of life for patients with BC.

Treacher Collins Syndrome (TCS) is a rare autosomal dominant disorder characterized by severe craniofacial defects. The syndrome is associated with mutations in the TCOF1 gene, which encodes a nucleolar phosphoprotein called treacle. Model organisms have been generated to model the disease and have revealed knowledge about the etiology and pathogenesis of the disorder. The craniofacial abnormality observed in TCS patients is found to be caused by an increased level of apoptosis in the neuroepithelium and from this it has been suggested that treacle is important for proper formation and proliferation of neural crest cells that will ultimately contribute to the face. The best attempt to rescue the phenotype of TCS was made by inhibiting the expression of p53 in both zebrafish and mouse models. Although both rescues were successful, it resulted in tumor formation in mice which limits the potential of using this type of rescue in humans. Therefore, it is very important to identify p53-downstream genes that were not 5 related to cancer and use them to interrupt the apoptosis pathway and hence rescuing the phenotype.

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Thesis (Sc. D.)--University of Michigan, 1932. / "Reprinted from the Journal of Morphology, vol. 55, no. 1, September, 1933." "Literature cited": p. 178.

Thesis (Ph. D.)--Ohio State University, 2002. / Title from first page of PDF file. Document formatted into pages; contains xi, 115 p.: ill. Includes abstract and vita. Advisor: Shili Lin, Dept. of Statistics. Includes bibliographical references (p. 106-115).

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