• Ganglioside metabolism in a transgenic mouse model of Alzheimer's disease: expression of Chol-1a antigens in the brain

      Ariga, Toshio; Yanagisawa, Makoto; Wakade, Chandramohan; Ando, Susumu; Buccafusco, Jerry J; McDonald, Michael P; Yu, Robert K.; Institute of Molecular Medicine and Genetics; Department of Pharmacology and Toxicology (2010-10-4)
      The accumulation of Ab (amyloid b-protein) is one of the major pathological hallmarks in AD (Alzheimer’s disease). Gangliosides, sialic acid-containing glycosphingolipids enriched in the nervous system and frequently used as biomarkers associated with the biochemical pathology of neurological disorders, have been suggested to be involved in the initial aggregation of Ab. In the present study, we have examined ganglioside metabolism in the brain of a double- Tg (transgenic) mouse model of AD that co-expresses mouse/ human chimaeric APP (amyloid precursor protein) with the Swedish mutation and human presenilin-1 with a deletion of exon 9. Although accumulation of Ab was confirmed in the double-Tg mouse brains and sera, no statistically significant change was detected in the concentration and composition of major ganglio-N-tetraosyl-series gangliosides in the double-Tg brain. Most interestingly, Chol-1a antigens (cholinergic neuron-specific gangliosides), such as GT1aa and GQ1ba, which are minor species in the brain, were found to be increased in the double-Tg mouse brain. We interpret that the occurrence of these gangliosides may represent evidence for generation of cholinergic neurons in the AD brain, as a result of compensatory neurogenesis activated by the presence of Ab.
    • Gap Junctionâ mediated Cellâ Cell Communication Modulates Mouse Neural Crest Migration

      Huang, G.Y.; Cooper, E.S.; Waldo, K.; Kirby, M.L.; Gilula, N.B.; Lo, C.W.; Institute of Molecular Medicine and Genetics (1998-12-14)
      Previous studies showed that conotruncal heart malformations can arise with the increase or decrease in a1 connexin function in neural crest cells. To elucidate the possible basis for the quantitative requirement for a1 connexin gap junctions in cardiac development, a neural crest outgrowth culture system was used to examine migration of neural crest cells derived from CMV43 transgenic embryos overexpressing a1 connexins, and from a1 connexin knockout (KO) mice and FC transgenic mice expressing a dominant-negative a1 connexin fusion protein. These studies showed that the migration rate of cardiac neural crest was increased in the CMV43 embryos, but decreased in the FC transgenic and a1 connexin KO embryos. Migration changes occurred in step with connexin gene or transgene dosage in the homozygous vs. hemizygous a1 connexin KO and CMV43 embryos, respectively. Dye coupling analysis in neural crest cells in the outgrowth cultures and also in the living embryos showed an elevation of gap junction communication in the CMV43 transgenic mice, while a reduction was observed in the FC transgenic and a1 connexin KO mice. Further analysis using oleamide to downregulate gap junction communication in nontransgenic outgrowth cultures showed that this independent method of reducing gap junction communication in cardiac crest cells also resulted in a reduction in the rate of crest migration. To determine the possible relevance of these findings to neural crest migration in vivo, a lacZ transgene was used to visualize the distribution of cardiac neural crest cells in the outflow tract. These studies showed more lacZ-positive cells in the outflow septum in the CMV43 transgenic mice, while a reduction was observed in the a1 connexin KO mice. Surprisingly, this was accompanied by cell proliferation changes, not in the cardiac neural crest cells, but in the myocardium - an elevation in the CMV43 mice vs. a reduction in the a1 connexin KO mice. The latter observation suggests that cardiac neural crest cells may have a role in modulating growth and development of non-neural crest- derived tissues. Overall, these findings suggest that gap junction communication mediated by a1 connexins plays an important role in cardiac neural crest migration. Furthermore, they indicate that cardiac neural crest perturbation is the likely underlying cause for heart defects in mice with the gain or loss of a1 connexin function.
    • Genetic and Molecular Basis of QTL of Diabetes in Mouse: Genes and Polymorphisms.

      Gao, Peng; Jiao, Yan; Xiong, Qing; Wang, Cong-Yi; Gerling, Ivan; Gu, Weikuan; Center for Biotechnology and Genomic Medicine (2009-05-27)
      A systematic study has been conducted of all available reports in PubMed and OMIM (Online Mendelian Inheritance in Man) to examine the genetic and molecular basis of quantitative genetic loci (QTL) of diabetes with the main focus on genes and polymorphisms. The major question is, What can the QTL tell us? Specifically, we want to know whether those genome regions differ from other regions in terms of genes relevant to diabetes. Which genes are within those QTL regions, and, among them, which genes have already been linked to diabetes? whether more polymorphisms have been associated with diabetes in the QTL regions than in the non-QTL regions.Our search revealed a total of 9038 genes from 26 type 1 diabetes QTL, which cover 667,096,006 bp of the mouse genomic sequence. On one hand, a large number of candidate genes are in each of these QTL; on the other hand, we found that some obvious candidate genes of QTL have not yet been investigated. Thus, the comprehensive search of candidate genes for known QTL may provide unexpected benefit for identifying QTL genes for diabetes.
    • Genetic enhancement of memory and long-term potentiation but not CA1 long-term depression in NR2B transgenic rats.

      Wang, Deheng; Cui, Zhenzhong; Zeng, Qingwen; Kuang, Hui; Wang, Lei Phillip; Tsien, Joe Z.; Cao, Xiaohua; Brain & Behavior Discovery Institute; Department of Neurology (2009-10-19)
      One major theory in learning and memory posits that the NR2B gene is a universal genetic factor that acts as rate-limiting molecule in controlling the optimal NMDA receptor's coincidence-detection property and subsequent learning and memory function across multiple animal species. If so, can memory function be enhanced via transgenic overexpression of NR2B in another species other than the previously reported mouse species? To examine these crucial issues, we generated transgenic rats in which NR2B is overexpressed in the cortex and hippocampus and investigated the role of NR2B gene in NMDA receptor-mediated synaptic plasticity and memory functions by combining electrophysiological technique with behavioral measurements. We found that overexpression of the NR2B subunit had no effect on CA1-LTD, but rather resulted in enhanced CA1-LTP and improved memory performances in novel object recognition test, spatial water maze, and delayed-to-nonmatch working memory test. Our slices recordings using NR2A- and NR2B-selective antagonists further demonstrate that the larger LTP in transgenic hippocampal slices was due to contribution from the increased NR2B-containing NMDARs. Therefore, our genetic experiments suggest that NR2B at CA1 synapses is not designated as a rate-limiting factor for the induction of long-term synaptic depression, but rather plays a crucial role in initiating the synaptic potentiation. Moreover, our studies provide strong evidence that the NR2B subunit represents a universal rate-limiting molecule for gating NMDA receptor's optimal coincidence-detection property and for enhancing memory function in adulthood across multiple mammalian species.
    • Genetic Overexpression of NR2B Subunit Enhances Social Recognition Memory for Different Strains and Species

      Jacobs, Stephanie A.; Tsien, Joe Z.; Brain & Behavior Discovery Institute; Department of Neurology (2012-04-27)
      The ability to learn and remember conspecifics is essential for the establishment and maintenance of social groups. Many animals, including humans, primates and rodents, depend on stable social relationships for survival. Social learning and social recognition have become emerging areas of interest for neuroscientists but are still not well understood. It has been established that several hormones play a role in the modulation of social recognition including estrogen, oxytocin and arginine vasopression. Relatively few studies have investigated how social recognition might be improved or enhanced. In this study, we investigate the role of the NMDA receptor in social recognition memory, specifically the consequences of altering the ratio of the NR2Bâ ¶NR2A subunits in the forebrain regions in social behavior. We produced transgenic mice in which the NR2B subunit of the NMDA receptor was overexpressed postnatally in the excitatory neurons of the forebrain areas including the cortex, amygdala and hippocampus. We investigated the ability of both our transgenic animals and their wild-type littermate to learn and remember juvenile conspecifics using both 1-hr and 24-hr memory tests. Our experiments show that the wild-type animals and NR2B transgenic mice preformed similarly in the 1-hr test. However, transgenic mice showed better performances in 24-hr tests of recognizing animals of a different strain or animals of a different species. We conclude that NR2B overexpression in the forebrain enhances social recognition memory for different strains and animal species.
    • Genetic risk factors for cerebrovascular disease in children with sickle cell disease: design of a case-control association study and genomewide screen.

      Adams, Gaye T; Snieder, Harold; McKie, Virgil C; Clair, Betsy; Brambilla, Donald; Adams, Robert J; Kutlar, Ferdane; Kutlar, Abdullah; Comprehensive Sickle Cell Center; Georgia Institute for Prevention of Human Diseases and Accidents; et al. (2004-05-10)
      BACKGROUND: The phenotypic heterogeneity of sickle cell disease is likely the result of multiple genetic factors and their interaction with the sickle mutation. High transcranial doppler (TCD) velocities define a subgroup of children with sickle cell disease who are at increased risk for developing ischemic stroke. The genetic factors leading to the development of a high TCD velocity (i.e. cerebrovascular disease) and ultimately to stroke are not well characterized. METHODS: We have designed a case-control association study to elucidate the role of genetic polymorphisms as risk factors for cerebrovascular disease as measured by a high TCD velocity in children with sickle cell disease. The study will consist of two parts: a candidate gene study and a genomewide screen and will be performed in 230 cases and 400 controls. Cases will include 130 patients (TCD > or = 200 cm/s) randomized in the Stroke Prevention Trial in Sickle Cell Anemia (STOP) study as well as 100 other patients found to have high TCD in STOP II screening. Four hundred sickle cell disease patients with a normal TCD velocity (TCD < 170 cm/s) will be controls. The candidate gene study will involve the analysis of 28 genetic polymorphisms in 20 candidate genes. The polymorphisms include mutations in coagulation factor genes (Factor V, Prothrombin, Fibrinogen, Factor VII, Factor XIII, PAI-1), platelet activation/function (GpIIb/IIIa, GpIb IX-V, GpIa/IIa), vascular reactivity (ACE), endothelial cell function (MTHFR, thrombomodulin, VCAM-1, E-Selectin, L-Selectin, P-Selectin, ICAM-1), inflammation (TNFalpha), lipid metabolism (Apo A1, Apo E), and cell adhesion (VCAM-1, E-Selectin, L-Selectin, P-Selectin, ICAM-1). We will perform a genomewide screen of validated single nucleotide polymorphisms (SNPs) in pooled DNA samples from 230 cases and 400 controls to study the possible association of additional polymorphisms with the high-risk phenotype. High-throughput SNP genotyping will be performed through MALDI-TOF technology using Sequenom's MassARRAY system. DISCUSSION: It is expected that this study will yield important information on genetic risk factors for the cerebrovascular disease phenotype in sickle cell disease by clarifying the role of candidate genes in the development of high TCD. The genomewide screen for a large number of SNPs may uncover the association of novel polymorphisms with cerebrovascular disease and stroke in sickle cell disease.
    • Genetically dependent ERBB3 expression modulates antigen presenting cell function and type 1 diabetes risk.

      Wang, Hongjie; Jin, Yulan; Reddy, M V Prasad Linga; Podolsky, Robert H.; Liu, Siyang; Yang, Ping; Bode, Bruce; Reed, John Chip; Steed, R. Dennis; Anderson, Stephen W.; et al. (2010-07-29)
      Type 1 diabetes (T1D) is an autoimmune disease resulting from the complex interaction between multiple susceptibility genes, environmental factors and the immune system. Over 40 T1D susceptibility regions have been suggested by recent genome-wide association studies; however, the specific genes and their role in the disease remain elusive. The objective of this study is to identify the susceptibility gene(s) in the 12q13 region and investigate the functional link to the disease pathogenesis. A total of 19 SNPs in the 12q13 region were analyzed by the TaqMan assay for 1,434 T1D patients and 1,865 controls. Thirteen of the SNPs are associated with T1D (best p = 4x10(-11)), thus providing confirmatory evidence for at least one susceptibility gene in this region. To identify candidate genes, expression of six genes in the region was analyzed by real-time RT-PCR for PBMCs from 192 T1D patients and 192 controls. SNP genotypes in the 12q13 region are the main factors that determine ERBB3 mRNA levels in PBMCs. The protective genotypes for T1D are associated with higher ERBB3 mRNA level (p<10(-10)). Furthermore, ERBB3 protein is expressed on the surface of CD11c(+) cells (dendritic cells and monocytes) in peripheral blood after stimulation with LPS, polyI:C or CpG. Subjects with protective genotypes have significantly higher percentages of ERBB3(+) monocytes and dendritic cells (p = 1.1x10(-9)); and the percentages of ERBB3(+) cells positively correlate with the ability of APC to stimulate T cell proliferation (R(2) = 0.90, p<0.0001). Our results indicate that ERBB3 plays a critical role in determining APC function and potentially T1D pathogenesis.
    • Genome-Wide DNA Methylation Maps in Follicular Lymphoma Cells Determined by Methylation-Enriched Bisulfite Sequencing

      Choi, Jeong-Hyeon; Li, Yajun; Guo, Juyuan; Pei, Lirong; Rauch, Tibor A.; Kramer, Robin S.; Macmil, Simone L.; Wiley, Graham B.; Bennett, Lynda B.; Schnabel, Jennifer L.; et al. (2010-09-29)
      Background: Follicular lymphoma (FL) is a form of non-Hodgkin's lymphoma (NHL) that arises from germinal center (GC) B-cells. Despite the significant advances in immunotherapy, FL is still not curable. Beyond transcriptional profiling and genomics datasets, there currently is no epigenome-scale dataset or integrative biology approach that can adequately model this disease and therefore identify novel mechanisms and targets for successful prevention and treatment of FL.
    • Genome-wide target profiling of piggyBac and Tol2 in HEK 293: pros and cons for gene discovery and gene therapy

      Meir, Yaa-Jyuhn J; Weirauch, Matthew T; Yang, Herng-Shing; Chung, Pei-Cheng; Yu, Robert K.; Wu, Sareina C-Y; Institute of Molecular Medicine and Genetics; Institute of Neuroscience (2011-03-30)
      Background: DNA transposons have emerged as indispensible tools for manipulating vertebrate genomes with applications ranging from insertional mutagenesis and transgenesis to gene therapy. To fully explore the potential of two highly active DNA transposons, piggyBac and Tol2, as mammalian genetic tools, we have conducted a side-by-side comparison of the two transposon systems in the same setting to evaluate their advantages and disadvantages for use in gene therapy and gene discovery.
    • Genomic and Functional Analysis of Vesicular Inhibitory Amino Acid Transporter During Mouse Embryogenesis

      Oh, Won-Jong; Institute of Molecular Medicine and Genetics (2006-01)
      The specification of particular neuronal phenotypes during embryonic development requires the appropriate activation and regulation of genes encoding the proteins required for neurotransmitter synthesis, vesicular packaging and re-uptake from the synaptic cleft. Each neurotransmitter is packaged into synaptic vesicles by its own distinct vesicular transporter. In addition, neurotransmitter packaging is well controlled by other co-factors (reviewed in Ahnert-Hilger et al., 2003). Components of GABAergic neurons GABAergic neurons are the principal inhibitory neurons in the mammalian central nervous system (CNS), where GABA is synthesized from glutamate by two glutamate decarboxylases (GAD), namely GAD65 (Gad2) and GAD67 (Gad1) (Erlander et al., 1991). GABA is then loaded into synaptic vesicles by the vesicular inhibitory amino acid transporter (VIAAT, also known as VGAT). Four GABA transporters (GAT 1-4) are responsible for the re-uptake of GABA from the synaptic cleft through the plasma membrane. Inhibitory GABAergic transmission is mediated by binding of GABA to its ionotropic receptors, GABAA and GABAC, which are ligand-gated chloride channels, and its metabotropic receptor, GABAB (Fig. 1).
    • Genomic Predictions in Uterine Cancers

      Tran, Lynn Kim Hoang; Center for Biotechnology and Genomic Medicine (Augusta University, 2020-05)
      Introduction: Current uterine cancer classification provides suboptimal treatment stratification and often groups together patients with significant differences in survival outcome and/or response. We used transcriptomic information to devise genomic scores for improved prediction of uterine cancer patient outcomes and validated these scores in our institutional cohorts. Project 1: In an early iteration of our gene signature discovery pipeline, we developed USC73, a genomic score for uterine serous carcinoma patients, which grouped patients into a low score (lower 66.7 percentile), good prognosis group and a high score (upper 33.3 percentile), poor prognosis group (5-year overall survival: 83.3% and 13.3%, respectively). USC73 predicts survival independently of stage, and can be combined with stage for further resolution of patient survival. Poor survivors have faster-growing tumors and lower rates of complete response to primary therapy. Project 2: We applied our pipeline to uterine endometrioid carcinoma, the most common histotype of uterine cancer, and developed UEC_IGS, an immune gene score that separates early stage patients into a high lymphocytic infiltration, good prognosis group (IGS 1) and a low lymphocytic infiltration, poor prognosis group (IGS 2). UEC_IGS predicts overall survival independent of grade and treatment. IGS 1 patients have higher levels of CD8+ tumor infiltrating lymphocytes (TILs), more CD45RO+/CD3+ memory T cells, and lower levels of FOXP3+ Tregs compared to IGS 2. Conclusion: Using transcriptomic data, we can reliably stratify uterine cancer patients into good and poor survival groups. This information can be used to facilitate recruitment of only poor prognosis patients into clinical trials, mitigating some heterogeneity in patient response and allowing clinicians to better identify treatments for patients who will not survive on the current therapy. Additionally, biological functions (e.g. cellular proliferation or immune infiltration) are associated with each genomic score, and these can serve as potential pathways to target for improving the outcome of poor survival groups.
    • Georgia Cancer Center Integrated Genomics Resource & HPC Server

      Chang, Chang-Shen (Sam); Georgia Cancer Center
      Georgia Cancer Center at Augusta University is home to a High Performance Computing (HPC) Server. One goal of the HPC server is to host the new Biorepository software, LabVantage. This software is a web-based laboratory information management system, which tracks samples throughout their lifespan. All specimens that the Georgia Cancer Center Biorepository receives is entered into LabVantage, which generates a unique barcode number for each sample. Chain of custody is recorded throughout the sample’s lifespan, from inception to eventual withdrawal. LabVantage organizes data such as patient demographics, diagnosis, organ site, and linked pathology reports. 
LabVantage is compliant with all regulations relevant to patient privacy and satisfies all regulations set forth by The College of American Pathologists (CAP). All Biorepository personnel are trained to maintain confidentiality of patient information according to HIPAA regulations. The HPC Server is also used for the analysis of complex data including Next-Generation Sequencing data (NGS). It is currently used to perform data analysis on datasets such as those obtained from The Cancer Genome Atlas (TCGA). The analyses that used to take several weeks can now be performed in a matter of days. Georgia Cancer Center HPC Server is composed of 544 total compute cores and an aggregated memory of 2.9TB. The system is composed of (15) PowerEdge R430 1U systems (128 GB RAM each), (1) PowerEdge R830 (1024 GB RAM) and a high-speed 10GbE interconnect for intra-node communication. The HPCC also houses 633 TB RAW storage capacity. We will also be integrating existing Cancer Center servers including our Illumina Compute system that collects data directly from the Sequencer housed in the Georgia Cancer Center Integrated Genomics Shared Resource and the existing Bioinformatics HPC (see configuration diagram below). Access to the server is available to all Augusta University employees. There is a nominal fee associated with usage and users are required to undergo training.
    • Global Health Needs Assessment at the Medical College of Georgia

      Tipler, Pam; Wyatt, Tasha R; Medical College of Georgia (Augusta University, 2018-01-19)
    • Glucocorticoid-Induced Leucine Zipper (GILZ) Antagonizes TNF-a Inhibition of Mesenchymal Stem Cell Osteogenic Differentiation

      He, Linlin; Yang, Nianlan; Isales, Carlos M.; Shi, Xing-Ming; Institute of Molecular Medicine and Genetics; Department of Orthopaedic Surgery; Department of Pathology (2012-03-2)
      Tumor necrosis factor-alpha (TNF-a) is a potent proinflammatory cytokine that inhibits osteoblast differentiation while stimulating osteoclast differentiation and bone resorption. TNF-a activates MAP kinase pathway leading to inhibition of osterix (Osx) expression. TNF-a also induces the expression of E3 ubiquitin ligase protein Smurf1 and Smurf2 and promotes degradation of Runx2, another key transcription factor regulating osteoblast differentiation and bone formation. We showed previously that overexpression of glucocorticoid (GC)-induced leucine zipper (GILZ) enhances osteogenic differentiation of bone marrow mesenchymal stem cells (MSCs). We and others also showed that GILZ is a GC effecter and mediates GC anti-inflammatory activity. In this study, we asked the question whether GILZ retains its osteogenic activity while functioning as an anti-inflammatory mediator. To address this question, we infected mouse bone marrow MSCs with retroviruses expressing GILZ and induced them for osteogenic differentiation in the presence or absence of TNF-a. Our results show that overexpression of GILZ antagonized the inhibitory effects of TNF-a on MSC osteogenic differentiation and the mRNA and protein expression of Osx and Runx2, two pivotal osteogenic regulators. Further studies show that these antagonistic actions occur via mechanisms involving GILZ inhibition of TNF-a-induced ERK MAP kinase activation and protein degradation. These results suggest that GILZ may have therapeutic potential as a novel anti-inflammation therapy.
    • Glutamic Acid Decarboxylase Expression And Function In The Developing And Neonatal Mouse

      Maddox, Dennis M; Institute of Molecular Medicine and Genetics (2001-06)
      (First Paragraph) In the mouse, there are two distinct genes that encode isoforms of the enzyme glutamic acid decarboxylase (Gad). The G adl gene encodes the larger isoform that has a molecular mass of 67 kilodaltons and is termed "Gad67" (Erlander et al., 1991; Bu et al., 1992). The Gad2 gene encodes the other isoform that has a molecular mass of 65 kilodaltons and is termed "Gad65" (Erlander et al., 1991; Bu et al., 1992). These two isoforms are often co-expressed in GABAergic neurons (Feldblum et al., 1993; Esclapez et al., 1994; Katarova et al., 2000). The isoforms differ in subcellular localization, with Gad67 being found mainly in the soma and Gad65 being found mainly in axon terminals (Kaufman et al., 1991). Additionally, the two isoforms of Gad differ in their affinity for the required cofactor pyridoxal-5’-phosphate (PLP) (Kaufman et al., 1991). By catalyzing the decarboxylation of L-glutamic acid, the Gad enzymes are the rate-limiting step in the biosynthesis of y-aminobutyric acid (GABA) (Barker et al., 1998).
    • The Gulf War Women’s Health Cohort: Study Design and Protocol

      Ansa, Benjamin E.; Sullivan, Kimberly; Krengel, Maxine H.; Heboyan, Vahé; Wilson, Candy; Lobst, Stacey; Coughlin, Steven S.; Institute of Public and Preventive Health (MDPI, 2020-04-02)
      Military service and deployment affect women differently than men, underscoring the need for studies of the health of women veterans and their receipt of health care services. Despite the large numbers of women who served during the 1990–1991 Gulf War, few studies have evaluated Gulf War illness (GWI) and other medical conditions specifically as they affect women veterans of the 1991 Gulf War. The objectives of the Gulf War Women’s Health Cohort study are: (1) to establish the Gulf War women’s cohort (GWWC), a large sample of women veterans who served in the 1990–1991 Gulf War and a comparison group of women who served in other locations during that period; and (2) to provide current, comprehensive data on the health status of women who served during the 1990–1991 Gulf War, and identify any specific conditions that affect Gulf War women veterans at excess rates. The study will utilize both existing datasets and newly collected data to examine the prevalence and patterns of Gulf War Illness symptoms, diagnosed medical conditions, reproductive health, birth outcomes and other health issues among women who served during the Gulf War. The Gulf War Women’s Health Cohort study will address the need for information about the comprehensive health of women veterans who were deployed to the Gulf War, and other wars during the Gulf War era.
    • Hb J- Meerut [alpha 120 (H3) Ala ->Glu (alpha1)] in a Turkish male.

      Elam, Dedrey; Kutlar, Abdullah; Kutlar, Ferdane; Dinçol, Gunçag; Güvenç, Serkan; Titus H.J. Huisman Hemoglobinopathy Laboratory, Comprehensive Sickle Cell Center, Medical College of Georgia (2006-03-31)
      Hb J Meerut is an infrequently found alpha-globin variant. It has previously been reported in various populations around the world. One particular case reported in 1994 included a Turkish family. In this report, details of a second case of Hb J Meerut in a Turkish male who is unrelated to the first family are described. In the present case a slight increase in the oxygen affinity of Hb J Meerut, relative to that of the normal control, has been observed as detected by low p50 values in arterial whole blood. Additionally, a slight increase in red blood cell count, as compared against a normal individual, was observed.
    • Health related quality of life among African American female breast cancer survivors and survivors of other cancers

      Smith, Selina A.; Ansa, Benjamin E.; Claridy, Mechelle D.; Damus, Francesca; Alema-Mensah, Ernest; School of Medicine; Georgia Regents University; Morehouse College (2014-10-17)
    • Hepatic gene expression profiling reveals key pathways involved in leptin-mediated weight loss in ob/ob mice.

      Sharma, Ashok; Bartell, Shoshana M; Baile, Clifton A; Chen, Bo; Podolsky, Robert H.; McIndoe, Richard A; She, Jin-Xiong; Center for Biotechnology and Genomic Medicine; Department of Medicine; Department of Pathology (2010-09-02)
      BACKGROUND: Leptin, a cytokine-like protein, plays an important role in the regulation of body weight through inhibition of food intake and stimulation of energy expenditure. Leptin circulates in blood and acts on the brain, which sends downstream signals to regulate body weight. Leptin therapy has been successful in treating leptin deficient obese patients. However, high levels of leptin have been observed in more common forms of obesity indicating a state of leptin resistance which limits the application of leptin in the treatment of obesity. If the central effect of leptin could be by-passed and genes which respond to leptin treatment could be regulated directly, new therapeutic targets for the treatment of obesity may be possible. The purpose of this study was to identify genes and subsequent pathways correlated with leptin-mediated weight loss. METHODOLOGY/PRINCIPAL FINDINGS: WE UTILIZED MICROARRAY TECHNOLOGY TO COMPARE HEPATIC GENE EXPRESSION CHANGES AFTER TWO TYPES OF LEPTIN ADMINISTRATION: one involving a direct stimulatory effect when administered peripherally (subcutaneous: SQ) and another that is indirect, involving a hypothalamic relay that suppresses food intake when leptin is administered centrally (intracerebroventricular: ICV). We identified 214 genes that correlate with leptin mediated weight loss. Several biological processes such as mitochondrial metabolic pathways, lipid metabolic and catabolic processes, lipid biosynthetic processes, carboxylic acid metabolic processes, iron ion binding and glutathione S-transferases were downregulated after leptin administration. In contrast, genes involved in the immune system inflammatory response and lysosomal activity were found to be upregulated. Among the cellular compartments mitochondrion (32 genes), endoplasmic reticulum (22 genes) and vacuole (8 genes) were significantly over represented. CONCLUSIONS/SIGNIFICANCE: In this study we have identified key molecular pathways and downstream genes which respond to leptin treatment and are involved in leptin-mediated weight loss. Many of these genes have previously been shown to be associated with obesity; however, we have also identified a number of other novel target genes. Further investigation will be required to assess the possible use of these genes and their associated protein products as therapeutic targets for the treatment of obesity.
    • Heritability of insulin sensitivity and lipid profile depend on BMI: evidence for gene-obesity interaction.

      Wang, X; Ding, Xiuhua; Su, S; Spector, T D; Mangino, M; Iliadou, Anastasia; Snieder, H; Georgia Institute for Prevention of Human Diseases and Accidents (2010-01-21)
      AIMS/HYPOTHESIS: Evidence from candidate gene studies suggests that obesity may modify genetic susceptibility to type 2 diabetes and dyslipidaemia. On an aggregate level, gene-obesity interactions are expected to result in different heritability estimates at different obesity levels. However, this hypothesis has never been tested. METHOD: The present study included 2,180 British female twins. BMI was used as an index of general obesity. Outcome measures were insulin sensitivity (indexed by quantitative insulin-sensitivity check index [QUICKI]) and fasting plasma lipid profile. Structural equation modelling was used to test whether BMI interacted with latent genetic and environmental effects to impact on the outcome measures. RESULTS: Genetic influences on triacylglycerol increased with BMI (p < 0.001) whereas the unique environmental influence on QUICKI decreased with BMI (p < 0.001), resulting in a higher heritability estimate for both measures at higher BMI levels. This was further illustrated by stratified analysis in twin pairs concordant for normal weight and twin pairs concordant for overweight. Heritability was 19 percentage points higher for triacylglycerol (p < 0.001) and 31 percentage points higher for QUICKI (p < 0.01) among twins concordant for overweight than among twins concordant for normal weight. BMI had no moderator effect on the latent genetic and environmental factors for total cholesterol and HDL-cholesterol. CONCLUSIONS/INTERPRETATION: Our results suggest that the expression of genes influencing triacylglycerol and insulin sensitivity can vary as a function of obesity status. The substantial increases in the genetic contribution to the total variance in insulin sensitivity and triacylglycerols at higher BMIs may prove extremely valuable in the search for candidate genes.