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Intracellular Na+ Concentration ([Na+]I) Is Elevated In Diabetic Hearts Due To Enhanced Na+–Glucose Cotransport, Rebekah Lambert, Sarah Srodulski, Xiaoli Peng, Kenneth B. Margulies, Florin Despa, Sanda Despa

Pharmacology and Nutritional Sciences Faculty Publications

BACKGROUND: Intracellular Na⁺ concentration ([Na⁺]i) regulates Ca²⁺ cycling, contractility, metabolism, and electrical stability of the heart. [Na⁺]i is elevated in heart failure, leading to arrhythmias and oxidative stress. We hypothesized that myocyte [Na⁺]i is also increased in type 2 diabetes (T2D) due to enhanced activity of the Na⁺-glucose cotransporter.

METHODS AND RESULTS: To test this hypothesis, we used myocardial tissue from humans with T2D and a rat model of late-onset T2D (HIP rat). Western blot analysis showed increased Na⁺-glucose cotransporter expression in failing hearts from T2D patients compared …

Novel Human Abcc9/Sur2 Brain-Expressed Transcripts And An Eqtl Relevant To Hippocampal Sclerosis Of Aging, Peter T. Nelson, Wang-Xia Wang, Bernard R. Wilfred, Angela Wei, James Dimayuga, Qingwei Huang, Eseosa T. Ighodaro, Sergey C. Artiushin, David W. Fardo

Sanders-Brown Center on Aging Faculty Publications

ABCC9 genetic polymorphisms are associated with increased risk for various human diseases including hippocampal sclerosis of aging. The main goals of this study were 1 > to detect the ABCC9 variants and define the specific 3′ untranslated region (3′UTR) for each variant in human brain, and 2 > to determine whether a polymorphism (rs704180) associated with risk for hippocampal sclerosis of aging pathology is also associated with variation in ABCC9 transcript expression and/or splicing. Rapid amplification of ABCC9 cDNA ends (3′RACE) provided evidence of novel 3′ UTR portions of ABCC9 in human brain. In silico and experimental studies were performed focusing on …

Platelet-Activating Factor Receptor Affects Food Intake And Body Weight, Wei Li, Thomas M. Mcintyre

Biomedical Sciences

“Let’s Move!” is a comprehensive initiative, launched by the First Lady, Michelle Obama, dedicates to solving problems of obesity, which is growing in child. The life behaviors do affect obesity; however, the mechanistic insight in molecular level is still not clear. In this study, by continually monitoring mouse body weight under chow and high fat western diets as well as metabolic, physical activity and food intake behaviors assessed in a CLAMS Comprehensive Lab Animal Monitoring System, we demonstrated that the platelet-activating factor receptor (PTAFR) contributes to modification of life behaviors. PTAFR does not affect metabolism of ingested dietary fat and …

Dietary Intake And Bio-Activation Of Nitrite And Nitrate In Newborn Infants, Jesica Ann Jones

Loma Linda University Electronic Theses, Dissertations & Projects

Nitrate and nitrite are commonly thought of as inert end products of nitric oxide (NO) oxidation, possibly carcinogenic food additives, or well-water contaminants. However, recent studies have shown that nitrate and nitrite play an important role in cardiovascular and gastrointestinal homeostasis through conversion back into NO via a physiological system involving enterosalivary recirculation, bacterial nitrate reductases, and enzyme-catalyzed or acidic reduction of nitrite to NO. The diet is a key source of nitrate in adults; however, infants ingest significantly less nitrate due to low concentrations in breast milk. In the mouth, bacteria convert nitrate to nitrite, which has gastro-protective effects. …

Week Of August 31, 2015, New York Medical College

InTouch

• NYMC Achieves Top ACCME Accreditation
• CrisisManager Makes Campus Debut
• GSBMS Hosts Fourth Annual STAR Student Research Forum
• Karen Sanders, M.D. '77, deputy chief academic affiliations officer of the U.S. Department of Veterans Affairs, Visits NYMC
• NYMC Joins the Good Food Farmers Network
• High Schoolers Visit NYMC for Insider's View of Medicine

Mitochondrial Activity And Cyr1 Are Key Regulators Of Ras1 Activation Of C. Albicans Virulence Pathways, Nora Grahl, Elora G. Demers, Allia K. Lindsay, Colleen E. Harty, Sven D. Wilger, Amy E. Piispanen, Deborah A. Hogan

Dartmouth Scholarship

Candida albicans is both a major fungal pathogen and a member of the commensal human microflora. The morphological switch from yeast to hyphal growth is associated with disease and many environmental factors are known to influence the yeast-to-hyphae switch. The Ras1-Cyr1-PKA pathway is a major regulator of C. albicans morphogenesis as well as biofilm formation and white-opaque switching. Previous studies have shown that hyphal growth is strongly repressed by mitochondrial inhibitors. Here, we show that mitochondrial inhibitors strongly decreased Ras1 GTP-binding and activity in C. albicans and similar effects were observed in other Candida species. Consistent with there …

Gene Diversification Of An Emerging Pathogen: A Decade Of Mutation In A Novel Fish Viral Hemorrhagic Septicemia (Vhs) Substrain Since Its First Appearance In The Laurentian Great Lakes, Carol A. Stepien, Lindsey R. Pierce, Douglas W. Leaman, Megan D. Niner, Brian S. Shepherd

Biological Sciences Faculty Publications

Viral Hemorrhagic Septicemia virus (VHSv) is an RNA rhabdovirus, which causes one of the world's most serious fish diseases, infecting >80 freshwater and marine species across the Northern Hemisphere. A new, novel, and especially virulent substrain—VHSv-IVb—first appeared in the Laurentian Great Lakes about a decade ago, resulting in massive fish kills. It rapidly spread and has genetically diversified. This study analyzes temporal and spatial mutational patterns of VHSv-IVb across the Great Lakes for the novel non-virion (Nv) gene that is unique to this group of novirhabdoviruses, in relation to its glycoprotein (G), phosphoprotein (P), …

Role Of The Dna Sensor Sting In Protection From Lethal Infection Following Corneal And Intracerebral Challenge With Herpes Simplex Virus 1, Zachary M. Parker, Aisling A. Murphy, David. A. Leib

Dartmouth Scholarship

STING is a protein in the cytosolic DNA and cyclic dinucleotide sensor pathway that is critical for the initiation of innate responses to infection by various pathogens. Consistent with this, herpes simplex virus 1 (HSV-1) causes invariable and rapid lethality in STING-deficient (STING(-/-)) mice following intravenous (i.v.) infection. In this study, using real-time bioluminescence imaging and virological assays, as expected, we demonstrated that STING(-/-) mice support greater replication and spread in ocular tissues and the nervous system. In contrast, they did not succumb to challenge via the corneal route even with high titers of a virus that was routinely lethal …

Staphylococcus Aureus Biofilms Induce Macrophage Dysfunction Through Leukocidin Ab And Alpha-Toxin., Tyler D. Scherr, Mark L. Hanke, Ouwen Huang, David B.A. James, Alexander R. Horswill, Kenneth W. Bayles, Paul D. Fey, Victor J. Torres, Tammy Kielian

Journal Articles: Pathology and Microbiology

UNLABELLED: The macrophage response to planktonic Staphylococcus aureus involves the induction of proinflammatory microbicidal activity. However, S. aureus biofilms can interfere with these responses in part by polarizing macrophages toward an anti-inflammatory profibrotic phenotype. Here we demonstrate that conditioned medium from mature S. aureus biofilms inhibited macrophage phagocytosis and induced cytotoxicity, suggesting the involvement of a secreted factor(s). Iterative testing found the active factor(s) to be proteinaceous and partially agr-dependent. Quantitative mass spectrometry identified alpha-toxin (Hla) and leukocidin AB (LukAB) as critical molecules secreted by S. aureus biofilms that inhibit murine macrophage phagocytosis and promote cytotoxicity. A role for Hla …

Macroecology Of North American Suckers (Catostomidae): Tests Of Bergmann's And Rapoport's Rules, Stephen J. Jacquemin, Jason C. Doll

Biological Sciences Faculty Publications

Discerning spatial macroecological patterns in freshwater fishes has broad implications for community assembly, ecosystem dynamics, management, and conservation. This study explores the potential interspecific covariation of geographic range (Rapoport's rule) and body size (Bergmann's rule) with latitude in North American sucker fishes (Cypriniformes: Catostomidae). While numerous tests of Rapoport's and Bergmann's rules are documented in the literature, comparatively few of these studies have specifically tested for these patterns, and none have incorporated information reflecting shared ancestry into analyses of North American freshwater fish through a hierarchical model. This study utilized a hierarchical modeling approach with Bayesian inference to evaluate the …

Atomic Structure Of Grk5 Reveals Distinct Structural Features Novel For G Protein-Coupled Receptor Kinases, Konstantin E. Komolov, Anshul Bhardwaj, Jeffrey L. Benovic

Department of Biochemistry and Molecular Biology Faculty Papers

G protein-coupled receptor kinases (GRKs) are members of the protein kinase A, G, and C families (AGC) and play a central role in mediating G protein-coupled receptor phosphorylation and desensitization. One member of the family, GRK5, has been implicated in several human pathologies, including heart failure, hypertension, cancer, diabetes, and Alzheimer disease. To gain mechanistic insight into GRK5 function, we determined a crystal structure of full-length human GRK5 at 1.8 Å resolution. GRK5 in complex with the ATP analog 5'-adenylyl β,γ-imidodiphosphate or the nucleoside sangivamycin crystallized as a monomer. The C-terminal tail (C-tail) of AGC kinase domains is a highly …

The Role Of Glutaminase 1 In Hiv-1 Associated Neurocognitive Disorders And In Brain Development, Yi Wang

Theses & Dissertations

Glutaminase is the enzyme that converts glutamine into glutamate, which serves as a key excitatory neurotransmitter and one of the energy providers for cellular metabolism. Glutamate is essential for proper brain functioning but at excess levels, it is neurotoxic and has a key role in the pathogenesis of various neurodegenerative diseases, including HIV-1 associated neurocognitive disorders (HAND). However, the detailed mechanism of glutamate-mediated neurotoxicity remains unclear. In part I, we identified the regulation of glutaminase 1 (GLS1) in the central nervous system (CNS) of HAND animal models including HIV-Tat transgenic (Tg) mouse and HIVE-SCID mouse, since GLS1 is the dominant …

Investigation Of Behavioral And Cellular Changes In The Maternal Immune Activation Model Of Autism Spectrum Disorders, Shreya Roy

Theses & Dissertations

Maternal infection during pregnancy, which leads to maternal immune activation (MIA), is an environmental risk factor for autism spectrum disorders (ASD). MIA can be induced in mice and their offspring exhibit behaviors that model the core symptoms of ASD. One of the core behavioral symptoms in ASD patients is presence of increased repetitive behavior, which is modeled by an increase in marble burying in MIA mice. It has been shown that the deficits seen in MIA mice are associated with the dysregulation of cytokine levels in the developing brain, specifically an increase in pro-inflammatory cytokines. In this thesis, I tested …

Roles Of Serum Lycopene In The Prevalence And Mortality Of Metabolic Syndrome In The Adult Population, Guang-Ming Han

Theses & Dissertations

Metabolic syndrome (MetS) is a cluster of metabolic disorders, including increased fasting glucose, blood pressure, plasma triglyceride, reduced high-density lipoprotein cholesterol and abdominal obesity. It leads to an increased risk of cardiovascular disease and diabetes. The growing prevalence of MetS is strongly related to the increasing prevalence of overweight/obesity. As an antioxidant, lycopene can reduce the risk of MetS. However, it is unclear whether lycopene has similar effects among overweight/obese individuals and whether lycopene can reduce the risk of mortality among individuals with MetS. The purpose of this study was to explore the roles of lycopene in the prevalence and …

Application Of Β-Lactamase Reporter Fusions As An Indicator Of Effector Protein Secretion During Infections With The Obligate Intracellular Pathogen Chlamydia Trachomatis , Konrad E. Mueller, Kenneth A. Fields

Microbiology, Immunology, and Molecular Genetics Faculty Publications

Chlamydia spp. utilize multiple secretion systems, including the type III secretion system (T3SS), to deploy host-interactive effector proteins into infected host cells. Elucidation of secreted proteins has traditionally required ectopic expression in a surrogate T3SS followed by immunolocalization of endogenous candidate effectors to confirm secretion by chlamydiae. The ability to transform Chlamydia and achieve stable expression of recombinant gene products has enabled a more direct assessment of secretion. We adapted TEM-1 β-lactamase as a reporter system for assessment of chlamydial protein secretion. We provide evidence that this system facilitates visualization of secretion in the context of infection. Specifically, our findings …

Does The Microbiota Play A Role In The Pathogenesis Of Autoimmune Diseases?, Mairi H. Mclean, Dario Dieguez, Lindsey M. Miller, Howard A. Young

United States Public Health Resources

The microbiota of the human metaorganism is not a mere bystander. These microbes have coevolved with us and are pivotal to normal development and homoeostasis. Dysbiosis of the GI microbiota is associated with many disease susceptibilities, including obesity, malignancy, liver disease and GI pathology such as IBD. It is clear that there is direct and indirect crosstalk between this microbial community and host immune response. However, the precise mechanism of this microbial influence in disease pathogenesis remains elusive and is now a major research focus. There is emerging literature on the role of the microbiota in the pathogenesis of autoimmune …

Viewing The Extracellular Matrix: An Imaging Method For Tissue Engineering, Michael Drakopoulos, Sarah Calve

The Summer Undergraduate Research Fellowship (SURF) Symposium

The field of regenerative medicine seeks to create replacement tissues and organs, both to repair deficiencies in biological function and to treat structural damage caused by injury. Scaffoldings mimicking extracellular matrix (ECM), the structure to which cells attach to form tissues, have been developed from synthetic polymers and also been prepared by decellularizing adult tissue. However, the structure of ECM undergoes significant remodeling during natural tissue repair, suggesting that ECM-replacement constructs that mirror developing tissues may promote better regeneration than those modeled on adult tissues. This work investigated the effectiveness of a method of viewing the extracellular matrix of developing …

Behavioral Outputs Of Fragile-X Autistic Mice Exposed To Open-Field, Randomized, Short-Term Visual Stimuli, Nicholas M. Dicola, Alexander A. Chubykin

The Summer Undergraduate Research Fellowship (SURF) Symposium

Animal models of different neurological disorders are required for studying the pathophysiology of these diseases, and for potential development of pharmacological and behavioral treatments. The scientific community often uses mouse models for behavior studies due to their powerful genetic tools and low cost. However, subjective measurement techniques are often used when analyzing mice for behavioral traits which often results in discrepancies in results. An automated tracking software would aim to eliminate these discrepancies and subjective analysis. This lab has developed a software program which offered an ability to automatically collect open-field behavioral data with simultaneous on-line analysis. Python, an open …

The Right Tool For The Job: Detection Of Soil-Transmitted Helminths In Areas Co-Endemic For Other Helminths, Maria V. Periago, Renata C. Diniz, Simone A. Pinto, Anna Yakovleva, Rodrigo Correa-Oliveira, David J. Diemert, Jeffrey M. Bethony

Microbiology, Immunology, and Tropical Medicine Faculty Publications

Due to the recent increased use of the McMaster (MM) fecal egg counting method for assessing benzimidazole drug efficacy for treating soil-transmitted helminth (STH) infections, the aim of the current study was to determine the operational value of including the MM method alongside the Kato-Katz (KK) fecal thick smear to increase the diagnostic sensitivity when STHs are co-endemic with trematode helminths (e.g., Schistosoma mansoni).

Methods

A cross-sectional study was conducted in school-aged children aged 4-18 years in the northeastern region of the State of Minas Gerais (Brazil), where Necator americanus, Ascaris lumbricoides, Trichuris trichiura, and S …

Truncating Mutation In The Autophagy Gene Uvrag Confers Oncogenic Properties And Chemosensitivity In Colorectal Cancers, Shanshan He, Zhen Zhao, Yongfei Yang, Douglas O'Connell, Xiaowei Zhang, Soohwan Oh, Binyun Ma, Joo-Hyung Lee, Tian Zhang, Bino Varghese, Janae Yip, Sara Dolatshahi Pirooz, Ming Li, Yong Zhang, Guo-Min Li, Sue Ellen Martin, Keigo Machida, Chengyu Liang

Toxicology and Cancer Biology Faculty Publications

Autophagy-related factors are implicated in metabolic adaptation and cancer metastasis. However, the role of autophagy factors in cancer progression and their effect in treatment response remain largely elusive. Recent studies have shown that UVRAG, a key autophagic tumour suppressor, is mutated in common human cancers. Here we demonstrate that the cancer-related UVRAG frameshift (FS), which does not result in a null mutation, is expressed as a truncated UVRAG^FS in colorectal cancer (CRC) with microsatellite instability (MSI), and promotes tumorigenesis. UVRAG^FS abrogates the normal functions of UVRAG, including autophagy, in a dominant-negative manner. Furthermore, expression of UVRAG^FS can …

Standardization Of The Experimental Autoimmune Myasthenia Gravis (Eamg) Model By Immunization Of Rats With Torpedo Californica Acetylcholine Receptors- Recommendations For Methods And Experimental Designs., Mario Losen, Pilar Martinez-Martinez, Peter C. Molenaar, Konstantinos Lazaridis, Socrates Tzartos, Talma Brenner, Rui-Sheng Duan, Jie Luo, Jon Lindstrom, Linda Kusner

Pharmacology and Physiology Faculty Publications

Myasthenia gravis (MG) with antibodies against the acetylcholine receptor (AChR) is characterized by a chronic, fatigable weakness of voluntary muscles. The production of autoantibodies involves the dysregulation of T cells which provide the environment for the development of autoreactive B cells. The symptoms are caused by destruction of the postsynaptic membrane and degradation of the AChR by IgG autoantibodies, predominantly of the G1 and G3 subclasses. Active immunization of animals with AChR from mammalian muscles, AChR from Torpedo or Electrophorus electric organs, and recombinant or synthetic AChR fragments generates a chronic model of MG, termed experimental autoimmune myasthenia gravis (EAMG). …

Temporal And Spatial Changes In The Pattern Of Iba1 And Cd68 Staining In The Rat Brain Following Severe Traumatic Brain Injury, Debbie Smith, Diane Brooks, Eric Wohlgehagen, Thomas Rau, David Poulsen

Biomedical and Pharmaceutical Sciences Faculty Publications

We have previously demonstrated that acute treatment with low dose methamphetamine is neuroprotectivein a rat model of severe traumatic brain injury (TBI). Using gene expression analysis, we further showed that methamphetamine treatment significantly reduced the expression of proinflammatory genes after severe TBI. Therefore, to further investigate the potential effects of methamphetamine treatment on the neuroinflammatory response, we examined immunofluorescent staining of Iba1 and CD68, two marker of neuroinflammation, in the rat lateral fluid percussion injury model of severe TBI. In this study, we observed temporal and spatial alterations in the pattern of Iba1 and CD68 labeling within two weeks after …

Pharmacodynamics Of Folic Acid Receptor Targeted Antiretroviral Nanotherapy In Hiv-1-Infected Humanized Mice., Pavan Puligujja, Mariluz Araínga, Prasanta Dash, Diana L. Palandri, R. Lee Mosley, Santhi Gorantla, Larisa Y Poluektova, Joellyn Mcmillan, Howard Gendelman

Journal Articles: Pharmacology & Experimental Neuroscience

Long-acting nanoformulated antiretroviral therapy (nanoART) can sustain plasma drug levels and improve its biodistribution. Cell targeted-nanoART can achieve this and bring drug efficiently to viral reservoirs. However, whether such improvements affect antiretroviral responses remains unknown. To these ends, we tested folic acid (FA)-linked poloxamer407-coated ritonavir-boosted atazanavir (FA-nanoATV/r) nanoparticles for their ability to affect chronic HIV-1 infection in humanized mice. Following three, 100mg/kg FA-nanoATV/r intramuscular injections administered every other week to infected animals, viral RNA was at or below the detection limit, cell-associated HIV-1p24 reduced and CD4+ T cell counts protected. The dosing regimen improved treatment outcomes more than two fold …

Intracellular Listeria Monocytogenes Comprises A Minimal But Vital Fraction Of The Intestinal Burden Following Foodborne Infection, Grant S. Jones, Kate M. Bussell, Tanya Myers-Morales, Abigail M. Fieldhouse, Elsa N. Bou Ghanem, Sarah E. F. D'Orazio

Microbiology, Immunology, and Molecular Genetics Faculty Publications

Listeria monocytogenes is a highly adaptive bacterium that replicates as a free-living saprophyte in the environment as well as a facultative intracellular pathogen that causes invasive foodborne infections. The intracellular life cycle of L. monocytogenes is considered to be its primary virulence determinant during mammalian infection; however, the proportion of L. monocytogenes that is intracellular in vivo has not been studied extensively. In this report, we demonstrate that the majority of wild-type (strain EGDe) and mouse-adapted (InlA^m-expressing) L. monocytogenes recovered from the mesenteric lymph nodes (MLN) was extracellular within the first few days after foodborne infection. In addition, …

Optical Tracking System To Monitor Laparoscopic Training, William D. Rytlewski

Masters Theses

Laparoscopic Surgery, also known as Minimally Invasive Surgery, is a surgical technique where surgeons perform surgery through small incisions in the patient’s abdomen using a camera to monitor the movements of the instruments inside the patient. In order for the surgery to be performed, the surgeon must possess a unique set of skills obtained through training using a variety of techniques. Simulators are the preferred method of training for laparoscopic surgery since they provide medical residents with real world scenarios as well as a tremendous amount of feedback on what he/she did wrong or right. However, due to the high …

Mechanisms Of Immunological Tolerance In Central Nervous System Inflammatory Demyelination., Elisabeth R. Mari, Jason N. Moore, Guang-Xian Zhang, A. M. Rostami

Department of Neurology Faculty Papers

Multiple sclerosis is a complex autoimmune disease of the central nervous system that results in a disruption of the balance between pro-inflammatory and anti-inflammatory signals in the immune system. Given that central nervous system inflammation can be suppressed by various immunological tolerance mechanisms, immune tolerance has become a focus of research in the attempt to induce long-lasting immune suppression of pathogenic T cells. Mechanisms underlying this tolerance induction include induction of regulatory T cell populations, anergy and the induction of tolerogenic antigen-presenting cells. The intravenous administration of encephalitogenic peptides has been shown to suppress experimental autoimmune encephalomyelitis and induce tolerance …

Methylation Of Egfr By Arginine Methyltransferase Prmt1 Enhances Egfr Signaling And Cetuximab Resistance, Hsin-Wei Liao

Dissertations and Theses (Open Access)

Protein modifications of epidermal growth factor receptor (EGFR) intracellular domain are well known regulators of EGFR functions whereas those of its extracellular domain remain relatively unexplored. Here, we report that methylation at R198 and R200 of EGFR extracellular domain by protein arginine methyltransferase 1 (PRMT1) upregulates its binding to EGF and subsequent receptor dimerization and signaling activation. Methylation-defective EGFR mutant reduced tumor growth in mouse orthotopic xenograft model. Importantly, increased EGFR methylation sustains its signaling activation and cell proliferation in the presence of therapeutic EGFR monoclonal antibody, cetuximab. EGFR methylation level also correlates with higher recurrence rate after cetuximab treatment …

Prophylactic Cranial Irradiation Reduces The Incidence Of Brain Metastasis In A Mouse Model Of Metastatic Breast Cancer, Daniel L. Smith

Dissertations and Theses (Open Access)

Prophylactic cranial irradiation (PCI) is a preventative whole-brain irradiation technique used to reduce the incidence of brain metastasis and improve overall survival in select patients with small cell lung cancer and acute lymphoblastic leukemia. A population of breast cancer patients – stage IV, HER2+ or triple-negative – has emerged as having a high risk of developing brain metastases. Because only 10-20% of breast cancer patients diagnosed with brain metastases survive longer than one year, in this high-risk population the benefit of PCI – potential for reduced incidence of brain metastasis and improved overall survival – may outweigh the risks – …

Metabolic Profiling Of Prions In The Gastro-Intestinal Tract, Uffaf Khan

Dissertations and Theses (Open Access)

Metabolic profiling of prions in the gastro-intestinal tract

Uffaf Khan, B.S.

Thesis Advisor: Claudio Soto, Ph.D.

Abstract

Prion diseases, also known as transmissible spongiform encephalopathies (TSEs), are a group of debilitating neurodegenerative disorders that affect both humans and animals. They can be spread by horizontal transmission as seen in chronic wasting disease in deer and elk population. In addition, transmission to humans has also been documented which includes bovine spongiform encephalopathy in cattle to variant Creutzfeldt-Jakob disease in humans due to consumption of contaminated meat. The most probable natural route of transmission is by oral consumption of infectious material. Even …

Ankyrin-B And Mtor Complex 1 In The Regulation Of Electrical Activities In The Heart, Henry C. Wu, Henry C. Wu

Dissertations and Theses (Open Access)

The mammalian target of rapamycin complex 1 (mTORC1) activity is paramount in the regulation of electrical activities in the brain and the heart. In the brain, the tumor suppressor gene TSC2 encodes the protein product tuberin that interacts with hamartin to form a heterodimer Tuberous Sclerosis Complex (TSC) that regulates mTORC1. When TSC2 is disrupted, mTORC1 activity becomes dysregulated resulting in abnormal electrical activities in the brain manifesting in the form of epileptic seizures. In the heart, mTORC1 activity is triggered by a sustained increase in hemodynamic pressure causing the heart to electrically remodel. A likely candidate serving as the …