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Articles 61 - 88 of 88
Full-Text Articles in Medical Genetics
Approaches For Enhancing Therapeutic Efficacy Of A Novel Il-10 Gene Family Member: Mda-7/Il-24, Belal Azab
Approaches For Enhancing Therapeutic Efficacy Of A Novel Il-10 Gene Family Member: Mda-7/Il-24, Belal Azab
Theses and Dissertations
Melanoma differentiation associated gene-7 (mda-7) was discovered in the Fisher laboratory by subtraction hybridization of temporally spaced subtracted cDNA libraries prepared from terminally differentiated human melanoma cells treated with human fibroblast interferon (IFN-β) and the protein kinase C activator mezerein (MEZ), an approach called ‘differentiation induction subtraction hybridization’ (DISH). mda-7 is located in human chromosome 1q32–33 and based on sequence homology, chromosomal localization, and its functional properties, the mda-7 gene is now classified as a member of the IL-10 family of cytokines and named IL-24. The mda-7/IL-24 cDNA encodes a protein of 206-amino acids with a predicted size of ~24-kDa, …
Pediatrician Perceptions Of The Patient-Centered Medical Home Model, Christopher Ray
Pediatrician Perceptions Of The Patient-Centered Medical Home Model, Christopher Ray
Theses and Dissertations
The Patient-Centered Medical Home (PCMH) is an emerging model of health care designed to provide a simpler, more effective health care experience. The model places heavy emphasis on the concept of every patient having a "personal physician" who is the point of access for all health care needs and concerns. The personal physician integrates all relevant health care information to provide the patient with a holistic picture of his health. The supposed benefits of the PCMH model include an improved patient experience, increased effectiveness of care, increased efficiency of care, greater access to care, among others. Only now is evidence …
The Effects Of Age And Heterochromatin On Frequencies Of Acquired Chromosomal Aneuploidy In Uncultured Human Leukocytes, Noran Aboalela
The Effects Of Age And Heterochromatin On Frequencies Of Acquired Chromosomal Aneuploidy In Uncultured Human Leukocytes, Noran Aboalela
Theses and Dissertations
While age-related sex chromosomal aneuploidy is a well-characterized phenomenon, the relationship between autosomal loss and age remains unclear. The emergence of the specific and highly sensitive fluorescence in situ hybridization (FISH) technology has enabled investigators to study interphase cells, thereby overcoming problems inherent with the study of metaphase spreads for acquired aneuploidy assessment. Despite all the advantages of this technique, there are some limitations that could be misleading when scoring interphase autosomal aneuploidy. In this study we show that sex chromosomal hypoploidy is correlated with age. By using a twin study design, we evaluated Y chromosome hypoploidy frequencies and found …
Haploinsufficiency Of Rai1 And Its Effect On Bdnf Expression, Sun Kim
Haploinsufficiency Of Rai1 And Its Effect On Bdnf Expression, Sun Kim
Theses and Dissertations
Smith-Magenis Syndrome (SMS) [OMIM, #182290] is a congenital anomaly and mental retardation (MCA/MR) syndrome associated with deletion of chromosome17p11.2 [1]. The clinical phenotype has been well described and includes minor craniofacial anomalies, self-injurious behaviors as well as sleep disturbances, speech delays, and obesity [1,2,3]. The incidence of SMS is estimated to be ~ 1:15,000 - 25,000 births [2,6]. Among SMS patients, ~90% are comprised of 17p11.2 deletions, while ~10% have RAI1 mutations [8]. All 17p11.2 deletions associated with SMS include RAI1 deletion [10]. RAI1 is thought to function as a transcriptional factor although its cellular role is still unclear. First, …
The Mechanism Of Obesity In Rai1+/- Mice, Kristie Schmidt
The Mechanism Of Obesity In Rai1+/- Mice, Kristie Schmidt
Theses and Dissertations
Smith-Magenis syndrome (SMS) is a genetic disorder caused by a deletion or mutation of the retinoic acid induced 1 (RAI1) gene on chromosome 17p11.2 that results in haploinsufficiency. SMS patients with a deletion account for 90% of the cases, while the other 10% have a mutation in RAI1. The syndrome is characterized by cognitive impairment, craniofacial abnormalities, sleep disturbances, developmental delay, obesity, and behavioral phenotypes. SMS is thought to affect 1:25,000 live births, although due to similar infantile phenotypes with Down syndrome and Prader-Willi syndrome, SMS may be mis- or under-diagnosed. In a study of 54 children, it was shown …
Identification And Characterization Of A Second Wolfram Syndrome Gene, Sami Amr
Identification And Characterization Of A Second Wolfram Syndrome Gene, Sami Amr
Theses and Dissertations
Wolfram Syndrome (WFS) is a debilitating autosomal recessive neurodegenerative disorder characterized by juvenile onset insulin dependent diabetes mellitus (DM) and optic atrophy (OA) as well as a number of neurological and endocrine complications that result in early death due to respiratory complications. Previous research has mapped Wolfram syndrome to chromosome 4p16.1 and the disease has been attributed to mutations in the WFS1 gene affecting the WFS1 protein (wolframin), an ER membrane glycoprotein that plays an important role in the unfolded protein response (UPR) and in intracellular Ca2+ homeostasis. An additional locus for WFS on chromosome 4q22-24 was identified by linkage …
Mechanisms Associated With Aging And Age-Related Disease In Drosophila, Melanie Jones
Mechanisms Associated With Aging And Age-Related Disease In Drosophila, Melanie Jones
Theses and Dissertations
Aging is an intrinsic process that is independent of obvious disease. In contrast to normal aging, age-related diseases are conditions that typically manifest at advanced ages, are associated with explicit pathology and cause disability and premature death. We used Drosophila as a model to investigate the molecular-genetic mechanisms associated with aging and age-related disease. Age-related locomotor impairment (ARLI) is a serious condition for the elderly and greatly impacts their quality of life. Toward identifying genes and mechanisms that influence ARLI, we performed a forward genetic screen using Drosophila mutants. This screen identified a loss of function mutant in PDK1, a …
Identification Of Loci Contributing To The Smith-Magenis Syndrome-Like Phenotype And Molecular Evaluation Of The Retinoic Acid Induced 1 Gene, Stephen Williams
Identification Of Loci Contributing To The Smith-Magenis Syndrome-Like Phenotype And Molecular Evaluation Of The Retinoic Acid Induced 1 Gene, Stephen Williams
Theses and Dissertations
Smith-Magenis syndrome (SMS) is a multiple congenital abnormalities intellectual disability syndrome that results from a deletion of chromosome 17p11.2 or mutation of the retinoic acid inducted one gene (RAI1). SMS is characterized by a multitude of phenotypic features including craniofacial defects, short stature, obesity, intellectual disability, self-abusive behavior, sleep disturbance and behavioral abnormalities. Interestingly, although SMS is a clearly defined syndrome with a known molecular change at its foundation, ~40% of all candidate cases sent to the Elsea lab for evaluation do not have a mutation or deletion of RAI1. We hypothesize that at least one other locus must be …
Regulation Of Telomerase Expression In Stem Cell Reprogramming, Patrick Sachs
Regulation Of Telomerase Expression In Stem Cell Reprogramming, Patrick Sachs
Theses and Dissertations
A great need exists for an abundant, easily accessible source of patient-specific cells that will function for use in regenerative medicine. One promising source is the adult stem cell derived from adipose tissue (ASCs). Isolated from waste lipoaspiration, these cells could serve as a readily available source for the regeneration of damaged tissues. To further define the biology of ASCs, we have isolated multiple cell strains from different adipose tissue sources, indicating wide-spread distribution in the body. We find that a widely used set of cell surface markers fail to distinguish ASCs from normal fibroblasts. However, our ASC isolations are …
The Role Of Methyl Cpg Binding Domain Protein 2 (Mbd2) In The Regulation Of Embryonic And Fetal Β-Type Globin Genes, Merlin Nithya Gnanapragasam
The Role Of Methyl Cpg Binding Domain Protein 2 (Mbd2) In The Regulation Of Embryonic And Fetal Β-Type Globin Genes, Merlin Nithya Gnanapragasam
Theses and Dissertations
The reexpression of the fetal γ-globin gene in adult erythrocytes is of therapeutic interest due to its ameliorating effects in β-hemoglobinopathies. We recently showed that Methyl CpG Binding Domain Protein2 (MBD2) contributes to the silencing of the chicken embryonic ρ-globin and human fetal γ-globin genes. We further biochemically characterized an erythroid MeCP1 complex that is recruited by MBD2 to mediate the silencing of these genes. These observations suggest that the disruption of the MeCP1 complex could augment the expression of the fetal/embryonic globin genes. In the studies presented in chapter 2, we have pursued a structural and biophysical analysis of …
Association Tests Of The Opioid Receptor System And Alcohol-Related Traits, Ryan Bennett
Association Tests Of The Opioid Receptor System And Alcohol-Related Traits, Ryan Bennett
Theses and Dissertations
The opioid receptors and their endogenous ligands have long been implicated in a variety of traits including addiction, impulsive behaviors and substance dependence. Using phenotypic measurements collected from the IASPSAD, data from a latent class analysis and data from a SNP array and additional genotyping assays, association and regression tests were performed to determine the effects of common SNPs encoded in the genes of the opioid receptors and ligands on various traits relating to alcohol dependence. Although only one SNP can be reported as significant for substance dependence within alcoholics, there were a few results approaching significance that may offer …
Nonhomologous End-Joining: Tdp1-Mediated Processing, Atm-Mediated Signaling, Amy Hawkins
Nonhomologous End-Joining: Tdp1-Mediated Processing, Atm-Mediated Signaling, Amy Hawkins
Theses and Dissertations
This thesis investigates two separate features of nonhomologous end-joining (NHEJ) DNA repair: end processing, and DNA repair kinase signaling. DNA end processing was investigated in a mouse model of hereditary spinocerebellar ataxia with axonal neuropathy (SCAN1), a congenital neurodegenerative disease. SCAN1 is caused by a homozygous H493R mutation in the active site of tyrosyl-DNA phosphodiesterase (TDP1). To address how the H493R mutation elicits the specific pathologies of SCAN1 and to further elucidate the role of TDP1 in processing DNA end modifications, we generated a Tdp1 knockout mouse and characterized their behavior and specific repair deficiencies in extracts of embryonic fibroblasts …
Genes And Symptoms Of Schizophrenia: Modifiers, Networks, And Interactions In Complex Disease, Sarah Bergen
Genes And Symptoms Of Schizophrenia: Modifiers, Networks, And Interactions In Complex Disease, Sarah Bergen
Theses and Dissertations
Understanding the genetic foundations of schizophrenia and the resultant symptom manifestations is an important step as we work toward development of new prevention and treatment strategies. This work has sought better understanding of this disease through use of three subject cohorts and two studies using simulated data exploring features of complex disease. First, we probed the symptoms of schizophrenia in subjects of African and European ancestry drawn from the Genetic Association Information Network (GAIN) schizophrenia study and found significant differences between groups, particularly in affective symptoms. The genetic basis of symptom variation was then explored in a selection of candidate …
Chaperone Expression And Effects Of Its Inhibition On Breast Cancer Sensitization, Malissa Diehl
Chaperone Expression And Effects Of Its Inhibition On Breast Cancer Sensitization, Malissa Diehl
Theses and Dissertations
Breast cancer is one of the most prevalent and deadly forms of cancer in women and is not restricted by race or ethnicity. Although a wealth of knowledge has been amassed on the biology of breast cancer, including its risk factors, diagnosis, prognosis, prevention, and treatment, it remains a serious health concern and active area of research. Initial response to standard chemotherapeutic and radiotherapeutic regimens is generally strong for many patients, yet breast tumors often recur, leading to more aggressive and resistant tumors. Because recurrence is such a clinical issue, more effective therapeutic approaches are needed to eliminate partial clinical …
Chaperone Association With Telomere Binding Proteins, Amy Depcrynski
Chaperone Association With Telomere Binding Proteins, Amy Depcrynski
Theses and Dissertations
The Hsp90 chaperone complex associates with the telomerase enzyme, facilitating the assembly of the ribonucleoprotein complex. While previous data from our laboratory indicate that Hsp90 and p23 remain stably associated with (functionally active) telomerase, more recent experiments suggest that these chaperones associate with telomeres independent of telomerase, presumably through a specific interaction with telomere binding proteins. The current study examines the novel interactions between TRF2, TRF1, TIN2 and TPP1 and molecular chaperones (Hsp90, Hsp70, p23). In vitro and in cell experiments have shown an interaction between TRF1 and TRF2 and the molecular chaperones Hsp90 and Hsp70. Inhibition of Hsp90 using …
Exploring The Methylation Status Of Rai1 And The Rai1 Consensus Binding Sequence, Eri Kamura
Exploring The Methylation Status Of Rai1 And The Rai1 Consensus Binding Sequence, Eri Kamura
Theses and Dissertations
Smith Magenis Syndrome (SMS) is a multiple congenital anomalies/ mental retardation disorder caused by deletion or mutation of the RAI1 gene on chromosome 17p11.2. The majority of patients with SMS phenotypes have a deletion or mutation of RAI1. However, some patients have been observed with SMS-like phenotypes and yet have no deletions or mutations in the RAI1 gene. One possible explanation could be aberrant methylation of RAI1 since RAI1 is present and yet may be silenced. In order to study this possibility, patient cell lines were treated with 5-Aza-2’-deoxycytidine. RNA was extracted and real-time PCR was used to check the …
Retinoic Acid Induced 1 Gene Analysis In Humans And Zebrafish, Bijal Vyas
Retinoic Acid Induced 1 Gene Analysis In Humans And Zebrafish, Bijal Vyas
Theses and Dissertations
Smith-Magenis syndrome (SMS) is a complex mental retardation syndrome caused by deletion of 17p11.2 region or mutation of the RAI1 gene (retinoic acid induced 1). Individuals with SMS typically exhibit speech and motor delays, mental retardation, characteristic craniofacial and skeletal anomalies, and a distinct neurobehavioral phenotype that includes sleep disturbances, stereotypes, and maladaptive and self-injurious behaviors. RAI1 is thought to be a transcription factor modulating the expression of genes involved in a variety of cellular functions. Previous studies have shown the RAI1 gene being induced by retinoic acid (RA), a derivative of vitamin A. RA plays a significant role in …
Identification Of Apoptosis Pathway In Treacher Collins Syndrome, Khaled Alsayegh
Identification Of Apoptosis Pathway In Treacher Collins Syndrome, Khaled Alsayegh
Theses and Dissertations
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 …
Roles Of Krüppel Like Factors Klf1, Klf2, And Klf4 In Embryonic Beta-Globin Gene Expression, Yousef Alhashem
Roles Of Krüppel Like Factors Klf1, Klf2, And Klf4 In Embryonic Beta-Globin Gene Expression, Yousef Alhashem
Theses and Dissertations
Krüppel like factors (KLFs) are a family of 17 proteins whose main function is gene regulation by binding to DNA elements in the promoters of various genes. KLF transcription factors recognize CACCC-elements and act as activators or repressors of the gene expression. Among the 17 family members, KLF1, KLF2, and KLF4 share high homology to each other. KLF1 is the founding member of the family and is an erythroid-specific protein. KLF2 is expressed in erythroid, endothelial, and other cells. KLF4 is expressed in endothelial, smooth muscle, and other cells. In this thesis, the functions of these KLFs were reviewed in …
Obesity, Adiposity, And Satiety In Mouse Models Of Smith-Magenis Syndrome And Dup(17)(P11.2) Syndrome, Brooke Burns
Obesity, Adiposity, And Satiety In Mouse Models Of Smith-Magenis Syndrome And Dup(17)(P11.2) Syndrome, Brooke Burns
Theses and Dissertations
Smith-Magenis syndrome (SMS) is a complex disorder caused by haploinsufficiency of RAI1 and characterized by sleep disturbances, behavioral abnormalities, mental retardation, and obesity in teens and adults. Rai1+/- mice are obese after 20 weeks. Dup(17)(p11.2) syndrome is a complex disorder associated with overexpression of RAI1. A transgenic mouse model of dup(17)(p11.2) syndrome overexpresses Rai1 and results in a mouse that is growth delayed. In order to characterize the obese phenotypes of mouse models of SMS and the role of RAI1 in obesity, daily food intake and serum levels of insulin, glucose, PPY, and leptin were measured; adiposity was studied by …
Effects Of Altered Superoxide Dismutase Expression On Age-Related Functional Declines And Survival In Drosophila, Ian Martin
Theses and Dissertations
Most organisms experience progressive declines in physiological function as they age. A number of studies in a variety of species support a strong link between oxidative damage, age-related functional declines and life span determination. Here, manipulating the expression levels of superoxide dismutase (SOD) isoenzymes SOD1 and SOD2, resulted in altered functional senescence and survival characteristics in Drosophila. Overexpression of cytosolic Sod1 using the yeast GAL4/UAS system conferred a 30-34% increase in mean life span and resulted in an attenuated senescence of odor avoidance behavior in aging flies. Tissue-specific Sod1 overexpression selectively in the nervous system or muscle failed to reproduce …
Telomerase Inhibition And Sensitization Of Breast Tumor Cells, Kennon R. Poynter
Telomerase Inhibition And Sensitization Of Breast Tumor Cells, Kennon R. Poynter
Theses and Dissertations
Telomerase, a ribonucleoprotein enzyme minimally composed of an RNA template (hTR) and a catalytically active protein subunit (hTERT), synthesizes telomeric repeats onto chromosome ends and is obligatory for continuous tumor cell proliferation, as well as malignant progression of breast cancer cells. Telomerase is an attractive anticancer therapeutic target because its activity is present in over 90% of human cancers, including more than 95% of breast carcinomas, but undetectable in most somatic cells. Traditions chemo- and radio-therapies lack the ability to effectively control and cure breast cancer, in part because residual cells are or become resistant to DNA damaging modalities.While various …
The Quantitative Genetics Of Neurodevelopment: A Magnetic Resonance Imaging Study Of Childhood And Adolescence, James Eric Schmitt
The Quantitative Genetics Of Neurodevelopment: A Magnetic Resonance Imaging Study Of Childhood And Adolescence, James Eric Schmitt
Theses and Dissertations
Understanding the causes of individual differences in brain structure may give clues about the etiology of cognition, personality, and psychopathology, and also may identify endophenotypes for molecular genetic studies on brain development. We performed a comprehensive statistical genetic study of anatomic neuroimaging data from a large pediatric sample (N=600+) of twins and family members from the Child Psychiatry Branch at the NIMH. These analyses included variance decomposition of structural volumetric endophenotypes at several levels of resolution, voxel-level analysis of cortical thickness, assessment of gene by age interaction, several multivariate genetic analyses, and a search for genetically-mediated brain-behavioral relationships. These analyses …
Dual Regulation Of Telomerase Activity By Hsf1 And Its Role In Prostate Cancer Progression, Keith Douglas Ostergaard Jensen
Dual Regulation Of Telomerase Activity By Hsf1 And Its Role In Prostate Cancer Progression, Keith Douglas Ostergaard Jensen
Theses and Dissertations
It has been shown that the key components of the hsp90 chaperone complex, including hsp90, p23, hsp70, hsp40, and HOP (p60), associate with telomerase; however, their specific roles in telomerase function and tumor progression have not yet been defined. HSF1, the primary mammalian heat shock protein transcription factor, may affect telomerase activity and transformation by regulating the expression of several hsp90 chaperone complex proteins in response to stress as well as regulating the transcription of hTERT, the protein subunit of telomerase.In our in vitro model of prostate cancer progression, as cells progress from immortal but non-tumorigenic (P69) to tumorigenic (M2182) …
A Critical Review Of Telomerase Biology And Model Systems For The Study Of Telomerase, Jeremy Charles Aisenberg
A Critical Review Of Telomerase Biology And Model Systems For The Study Of Telomerase, Jeremy Charles Aisenberg
Theses and Dissertations
The study of telomere and telomerase biology holds substantial promise in uncovering the molecular process of aging and the treatment of cancers. Studies have shown that telomere shortening is directly linked to cellular aging and that telomerase expression is found in over 85% of human cancers, including 95% of all advanced malignancies. Development of effective model systems to elucidate the molecular mechanisms underlying the role of telomeres and telomerase in the processes aging and cancer is of particular importance. While inbred strains of mice have provided a wealth of information for a variety of pathways and diseases, the mouse model …
Characterization Of The Tcof1 Gene Using A Neuroblastoma Cell Line And A Mouse Model, Lin Li
Characterization Of The Tcof1 Gene Using A Neuroblastoma Cell Line And A Mouse Model, Lin Li
Theses and Dissertations
Treacher Collins syndrome (TCS) is an autosomal dominant craniofacial development disorder and is caused by mutations in the TCOF1 gene. The TCOFl protein treacle is a nucleolar protein and may function in ribosome biogenesis.Previously, we identified downstream candidate genes using microarray analysis after manipulating Tcofl levels in a murine neuroblastoma (NB) cell line. The list of genes includes cell cycle genes as well as the transcription factors Cnbp and Tbx2, which are known to affect the cell cycle through the c-myc and p19-Mdm2-p53-p21 pathways respectively. To further characterize the cellular effects of Tcofl, stably transfected NB cell lines with overexpression …
A Twin Study Of Antisocial Behavior And Depression: Methodology, Etiology, And Comorbidity, Kelly A. Tracy
A Twin Study Of Antisocial Behavior And Depression: Methodology, Etiology, And Comorbidity, Kelly A. Tracy
Theses and Dissertations
The etiological connection between internalizing and externalizing disorders is poorly understood. This manuscript aims to investigate the roles of genes and then environment in the development of Major Depressive Disorder (MDD) and Antisocial Personality Disorder (ASPD) and the nature of their comorbidity in young adults. Data from a sample of 2,291 young adult male and female twins from the Young Adult Follow Up Study (YAFU) of the Virginia Twin Study of Adolescent Behavioral Development (VTSABD) were used to estimate the proportion of variation in these traits that can be accounted for by additive genetic, shared environmental, and unique environmental factors. …
Genetic Dissection Of Behavioral And Neurogenomic Responses To Acute Ethanol, Aaron Wolen
Genetic Dissection Of Behavioral And Neurogenomic Responses To Acute Ethanol, Aaron Wolen
Theses and Dissertations
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 …