Genetic Processes Commons^™

Effect Of Nedd4 Haploinsufficiency On Insulin Sensitivity, Adiposity And Neuronal Behaviors, Jingjing Li

Theses and Dissertations (ETD)

The neural precursor cell expressed developmentally down-regulated gene 4 (NEDD4) is a HECT-type E3 ubiquitin ligase that has received broad attention in recent years. Many of its reported substrates are active players in metabolism, implying a potential role of NEDD4 itself in metabolic regulation. Since homozygous Nedd4 deletion leads to embryonic or perinatal lethality, we investigated the function of NEDD4 in metabolic regulation in vivo, using Nedd4- haploinsufficient mice in a high fat diet-induced obesity (HFDIO) model.

Our studies show that Nedd4-haploinsufficient mice fed a normal diet (ND) exhibited decreased body weight in both genders and proportionally reduced tissue mass …

Cryptorchidism And Infertility In Rats With Targeted Disruption Of The Adamts16 Locus, Shakila Abdul-Majeed, Blair Mell, Surya M. Nauli, Bina Joe

Pharmacy Faculty Articles and Research

A Disintegrin And Metalloproteinase with ThromboSpondin motifs16 (ADAMTS-16) is a member of a family of metalloproteinases. Using a novel zinc-finger nuclease based gene-edited rat model harboring a targeted mutation of the Adamts16 locus, we previously reported this gene to be linked to blood pressure regulation. Here we document our observation with this model that Adamts16 is essential for normal development of the testis. Absence of Adamts16 in the homozygous Adamts16(mutant) males resulted in cryptorchidism and male sterility. Heterozygous Adamts16(mutant) males were normal, indicating that this is a recessive trait. Testes of homozygous Adamts16(mutant) males were significantly smaller with significant histological …

The Histone Methyltransferase Activity Of Mll1 Is Dispensable For Hematopoiesis And Leukemogenesis, Bibhu Mishra, Kristin M. Zaffuto, Erika L. Artinger, Tonis Org, Hannah K. A. Mikkola, Chao Cheng, Malek Djabali

Dartmouth Scholarship

Despite correlations between histone methyltransferase (HMT) activity and gene regulation, direct evidence that HMT activity is responsible for gene activation is sparse. We address the role of the HMT activity for MLL1, a histone H3 lysine 4 (H3K4) methyltransferase critical for maintaining hematopoietic stem cells (HSCs). Here, we show that the SET domain, and thus HMT activity of MLL1, is dispensable for maintaining HSCs and supporting leukemogenesis driven by the MLL-AF9 fusion oncoprotein. Upon Mll1 deletion, histone H4 lysine 16 (H4K16) acetylation is selectively depleted at MLL1 target genes in conjunction with reduced transcription. Surprisingly, inhibition of SIRT1 is sufficient …

Antioxidant Gene Therapy Against Neuronal Cell Death, Juliana Navarro-Yepes, Laura Zavala-Flores, Anandhan Annadurai, Fang Wang, Maciej Skotak, Namas Chandra, Ming Li, Aglaia Pappa, Daniel Martinez-Fong, Luz Maria Del Razo, Betzabet Quintanilla-Vega, Rodrigo Franco

Department of Psychology: Faculty Publications

Oxidative stress is a common hallmark of neuronal cell death associated with neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, as well as brain stroke/ischemia and traumatic brain injury. Increased accumulation of reactive species of both oxygen (ROS) and nitrogen (RNS) has been implicated inmitochondrial dysfunction, energy impairment, alterations in metal homeostasis and accumulation of aggregated proteins observed in neurodegenerative disorders, which lead to the activation/modulation of cell death mechanisms that include apoptotic, necrotic and autophagic pathways. Thus, the design of novel antioxidant strategies to selectively target oxidative stress and redox imbalance might represent important therapeutic approaches against neurological disorders. …

Epigenetic Remodeling In An Imr-32 Cell Line And Transgenic Mouse Model Of Alzheimer's Disease, Matthew S. Baker

Senior Honors Theses

The pathological features of Alzheimer’s disease (AD) have been researched and documented extensively, however the causes of these features are still unknown. The following studies sought to determine if epigenetic methylation alterations contribute to AD. Two studies were sequentially carried out, first using an IMR-32 model and then using a transgenic mouse model overexpressing beta-amyloid. A few assay and confirmation methods were carried out to determine the promoter regions in disease state models undergoing drastic change, and the genes linked to these promoter regions were analyzed to determine significant gene ontology being altered by this epigenetic modification. This data was …

Analysis Of The Regulation And Function Of Cip2a To Identify Candidate Biomarkers For Prostate Cancer, Diana Savoly

Graduate School of Biomedical Sciences Theses and Dissertations

Protein Phosphatase 2A (PP2A) is a tumor suppressor involved in the regulation of several signaling pathways and the cell cycle. PP2A becomes inactivated by several inhibitors, including Cancerous Inhibitor of PP2A (CIP2A). CIP2A has been identified as an oncogene, which is over-expressed in cancers and inhibits PP2A through direct interaction. CIP2A is recognized as a biomarker for cancer; however, it is not cancer-specific. Therefore, we identified and examined the use of CIP2A-regulated proteins as potential biomarkers in prostate cancer to better diagnose prostate cancer in patients. Currently, Prostate Specific Antigen (PSA) is widely used to detect prostate cancer; however, it …

Relating The Metatranscriptome And Metagenome Of The Human Gut, Eric A. Franzosa, Xochitl C. Morgan, Nicola Segata, Levi Waldron, Joshua Reyes, Ashlee M. Earl, Georgia Giannoukos, Matthew R. Boylan, Dawn Ciulla, Dirk Gevers, Jacques Izard, Wendy S. Garrett, Andrew T. Chan, Curtis Huttenhower

Department of Food Science and Technology: Faculty Publications

Although the composition of the human microbiome is now well-studied, the microbiota’s > 8 million genes and their regulation remain largely uncharacterized. This knowledge gap is in part because of the difficulty of acquiring large numbers of samples amenable to functional studies of the microbiota. We conducted what is, to our knowledge, one of the first human microbiome studies in a well-phenotyped prospective cohort incorporating taxonomic, metagenomic, and metatranscriptomic profiling at multiple body sites using self-collected samples. Stool and saliva were provided by eight healthy subjects, with the former preserved by three different methods (freezing, ethanol, and RNAlater) to validate self-collection. …

Genetics Of Peripheral Vestibular Dysfunction: Lessons From Mutant Mouse Strains, Sherri M. Jones, Timothy A. Jones

Department of Special Education and Communication Disorders: Faculty Publications

Background

A considerable amount of research has been published about genetic hearing impairment. Fifty to sixty percent of hearing loss is thought to have a genetic cause. Genes may also play a significant role in acquired hearing loss due to aging, noise exposure, or ototoxic medications. Between 1995 and 2012, over 100 causative genes have been identified for syndromic and nonsyndromic forms of hereditary hearing loss (see Hereditary Hearing Loss Homepage http://hereditaryhearingloss.org). Mouse models have been extremely valuable in facilitating the discovery of hearing loss genes, and in understanding inner ear pathology due to genetic mutations or elucidating fundamental mechanisms …

Chmp1 Negatively Regulates Epidermal Growth Factor Signaling In The Drosophila Wing, Meagan Elisabeth Valentine

Theses, Dissertations and Capstones

A critical step in cellular signaling through transmembrane receptors is the down-regulation of activated receptors through the multivesicular body (MVB) pathway to the lysosome. MVB generation is mediated by the highly conserved ESCRT (0, I, II, and III) protein complexes. Though the ESCRT-III complex provides the core function of the ESCRT machinery, it is the least characterized of the ESCRT complexes. The Chmp1 protein is an ESCRT-III component and a putative tumor suppressor that has been linked to pancreatic and renal cancers in humans. However, published data on Chmp1 activity are conflicting and its role during tissue development is not …

Mapping Genes With Longitudinal Phenotypes Via Bayesian Posterior Probabilities, Anthony Musolf, Alejandro Q. Nato Jr., Douglas Londono, Lisheng Zhou, Tara C. Matise, Derek Gordon

Biochemistry and Microbiology

Most association studies focus on disease risk, with less attention paid to disease progression or severity. These phenotypes require longitudinal data. This paper presents a new method for analyzing longitudinal data to map genes in both population-based and family-based studies. Using simulated systolic blood pressure measurements obtained from Genetic Analysis Workshop 18, we cluster the phenotype data into trajectory subgroups. We then use the Bayesian posterior probability of being in the high subgroup as a quantitative trait in an association analysis with genotype data. This method maintains high power (>80%) in locating genes known to affect the simulated phenotype …

Chemopreventive Effects Of Pterostilbene In Metastatic Prostate Cancer Cells, Phillip A. Zook

PCOM Biomedical Studies Student Scholarship

Recent studies find that pterostilbene (PTS) exhibits more favorable drug properties and similar chemopreventive effects to its structural analogue resveratrol (RSV). However, few studies describe the activity of PTS in prostate cancer (PCa). Here, we conducted cell count experiments to assess the effects of PTS on metastatic PCa cell viability and to compare the potency of PTS to RSV in this respect. We also performed experiments to assess the effects of PTS on the androgen receptor (AR) and AR-mediated events. We used qPCR to measure the mRNA levels of the androgenresponsive gene (ARG), prostate-specific antigen (PSA), and Western blots to …

Effect Of Heme Oxygenase-1 On Matrix Metalloproteinase-3 Expression In Human Fibroblasts, Theresa A. Stangl

PCOM Biomedical Studies Student Scholarship

Heme oxygenase-1(HO-1) is an enzyme that plays a very important role in the resolution of inflammation. HO-1-based therapies are effective in a number of disease conditions. However, HO-1 also increases tumor growth, angiogenesis, metastasis and chemoresistance. Matrix metalloproteinase-3 (MMP-3) is an enzyme involved in physiological and pathophysiological tissue remodeling. Unbalanced expression of MMPs is a key feature of connective tissue destruction in chronic inflammatory conditions. Previously shown in this laboratory, the HO-1 inducer, hemin, increased MMP-3 mRNA expression in some HGF cultures. To assess whether HO-1 and/or its products regulate expression of MMP-3 in human fibroblasts, the effect of HO-1 …

Conformational Changes And Translocation Of Tissue-Transglutaminase To The Plasma Membranes: Role In Cancer Cell Migration, Ambrish Kumar, Jianjun Hu, Holly A. Lavoie, Kenneth B. Walsh, Donald J. Dipette, Ugra S. Singh

Faculty Publications

Background

Tissue-transglutaminase (TG2), a dual function G-protein, plays key roles in cell differentiation and migration. In our previous studies we reported the mechanism of TG2-induced cell differentiation. In present study, we explored the mechanism of how TG2 may be involved in cell migration.

Methods

To study the mechanism of TG2-mediated cell migration, we used neuroblastoma cells (SH-SY5Y) which do not express TG2, neuroblastoma cells expressing exogenous TG2 (SHY_TG2), and pancreatic cancer cells which express high levels of endogenous TG2. Resveratrol, a natural compound previously shown to inhibit neuroblastoma and pancreatic cancer in the animal models, was utilized to …

Analysis Of The Role Of Astrocyte Elevated Gene-1 In Normal Liver Physiology And In The Onset And Progression Of Hepatocellular Carcinoma, Chadia L. Robertson

Theses and Dissertations

First identified over a decade ago, Astrocyte Elevated Gene-1 (AEG-1) has been studied extensively due to early reports of its overexpression in various cancer cell lines. Research groups all over the globe including our own have since identified AEG-1 overexpression in cancers of diverse lineages including cancers of the liver, colon, skin, prostate, breast, lung, esophagus, neurons and neuronal glia as compared to matched normal tissue. A comprehensive and convincing body of data currently points to AEG-1 as an essential component, critical to the progression and perhaps onset of cancer. AEG-1 is a potent activator of multiple pro-tumorigenic signal transduction …