Life Sciences Commons^™

Functional Redundancy Of Type I And Type Ii Receptors In The Regulation Of Skeletal Muscle Growth By Myostatin And Activin A., Se-Jin Lee, Adam Lehar, Yewei Liu, Chi Hai Ly, Quynh-Mai Pham, Michael Michaud, Renata Rydzik, Daniel W Youngstrom, Michael M Shen, Vesa Kaartinen, Emily L Germain-Lee, Thomas A Rando

Faculty Research 2020

Myostatin (MSTN) is a transforming growth factor-β (TGF-β) family member that normally acts to limit muscle growth. The function of MSTN is partially redundant with that of another TGF-β family member, activin A. MSTN and activin A are capable of signaling through a complex of type II and type I receptors. Here, we investigated the roles of two type II receptors (ACVR2 and ACVR2B) and two type I receptors (ALK4 and ALK5) in the regulation of muscle mass by these ligands by genetically targeting these receptors either alone or in combination specifically in myofibers in mice. We show that targeting …

The Impact Of Microbial Experience On The Murine Innate Immune Response, Cody Thomas Morrison

Masters Theses

The hygiene hypothesis predicts that certain environmental factors shape overall immune system function in animals and humans. While current specific pathogen free (SPF) mouse models are invaluable for studying the immune system, they have limitations for comparison with humans who have microbial exposures throughout their lifetimes. Several studies have shown that the composition of the immune system of SPF mice more closely resembles that of newborns, whereas the immune system from mice exposed to microbial pathogens more closely reflect adult immunity. In this study we have established a model using traditional SPF mice (“clean mice”) and SPF mice that were …

Ixodes Scapularis Src Kinase Is Required For Rickettsial Pathogen Survival In Ticks, Jeremy W. Turck

Biological Sciences Theses & Dissertations

Anaplasma phagocytophilum is an obligate intracellular bacterium that causes disease in humans and animals. It is the causative agent for human anaplasmosis. A. phagocytophilum uses certain strategies to infect both vertebrates and invertebrates. It uses Ixodes scapularis ticks as a vector for spreading infection to other mammal species. This bacterium has a specific path for infection through the salivary glands of its vector host. It also suppresses certain functions such as the inhibition of apoptosis and ROS production in order to increase its survival in ticks. Src kinase, a non-receptor protein-tyrosine kinase, is a major player in cell signaling. Src …

Lung Epithelial Trpa1 Mediates Lipopolysaccharide-Induced Lung Inflammation In Bronchial Epithelial Cells And Mice, Hsin-Kuo Ko, An-Hsuan Lin, Diahn-Warng Perng, Tzong-Shyuan Lee, Yu Ru Kou

Physiology Faculty Publications

Toll-like receptor (TLR) 4 was originally thought to be the sole pattern recognition receptor for lipopolysaccharide (LPS). Transient receptor potential ankyrin 1 (TRPA1), a Ca²⁺-permeant channel, has been suggested as a non-TLR receptor membrane-bound sensor of LPS. We recently reported that TRPA1 is expressed in lung epithelial cells (LECs) and mediates lung inflammation induced by cigarette smoke. However, the role of TRPA1 in LPS-induced lung inflammation has not been conclusively defined, and its underlying cellular mechanisms remain unclear. In this study, our in vitro results showed that LPS sequentially produced a cascade of events, including the elevation of …

Interleukin-17a Facilitates Chikungunya Virus Infection By Inhibiting Ifn-Α2 Expression, Biswas Neupane, Dhiraj Acharya, Farzana Nazneen, Gabriel Gonzalez-Fernandez, Alex Sutton Flynt, Fengwei Bai

Faculty Publications

Interferons (IFNs) are the key components of innate immunity and are crucial for host defense against viral infections. Here, we report a novel role of interleukin-17A (IL-17A) in inhibiting IFN-α2 expression thus promoting chikungunya virus (CHIKV) infection. CHIKV infected IL-17A deficient (Il17a^−/−) mice expressed a higher level of IFN-α2 and developed diminished viremia and milder footpad swelling in comparison to wild-type (WT) control mice, which was also recapitulated in IL-17A receptor-deficient (Il17ra^−/−) mice. Interestingly, IL-17A selectively blocked IFN-α2 production during CHIKV, but not West Nile virus (WNV) or Zika virus (ZIKV), infections. Recombinant IL-17A …

Genetic Variant Effects On Gene Expression In Human Pancreatic Islets And Their Implications For T2d., Ana Viñuela, Arushi Varshney, Martijn Van De Bunt, Rashmi B Prasad, Olof Asplund, Amanda Bennett, Michael Boehnke, Andrew A Brown, Michael R Erdos, João Fadista, Ola Hansson, Gad Hatem, Cédric Howald, Apoorva K Iyengar, Paul Johnson, Ulrika Krus, Patrick E Macdonald, Anubha Mahajan, Jocelyn E Manning Fox, Narisu Narisu, Vibe Nylander, Peter Orchard, Nikolay Oskolkov, Nikolaos I Panousis, Anthony Payne, Michael L. Stitzel, Swarooparani Vadlamudi, Ryan Welch, Francis S Collins, Karen L Mohlke, Anna L Gloyn, Laura J Scott, Emmanouil T Dermitzakis, Leif Groop, Stephen C J Parker, Mark I Mccarthy

Faculty Research 2020

Most signals detected by genome-wide association studies map to non-coding sequence and their tissue-specific effects influence transcriptional regulation. However, key tissues and cell-types required for functional inference are absent from large-scale resources. Here we explore the relationship between genetic variants influencing predisposition to type 2 diabetes (T2D) and related glycemic traits, and human pancreatic islet transcription using data from 420 donors. We find: (a) 7741 cis-eQTLs in islets with a replication rate across 44 GTEx tissues between 40% and 73%; (b) marked overlap between islet cis-eQTL signals and active regulatory sequences in islets, with reduced eQTL effect size observed in …

Obesity Worsens Gulf War Illness Symptom Persistence Pathology By Linking Altered Gut Microbiome Species To Long-Term Gastrointestinal, Hepatic, And Neuronal Inflammation In A Mouse Model, Dipro Bose, Punnag Saha, Ayan Mondal, Brian Fanelli, Ratanesh K. Seth, Patricia Janulewicz, Kimberly Sullivan, Stephen Lasley, Ronnie Horner, Rita R. Colwell, Ashok K. Shetty, Nancy Klimas, Saurabh Chatterjee

Faculty Publications

Persistence of Gulf War illness (GWI) pathology among deployed veterans is a clinical challenge even after almost three decades. Recent studies show a higher prevalence of obesity and metabolic disturbances among Gulf War veterans primarily due to the existence of post-traumatic stress disorder (PTSD), chronic fatigue, sedentary lifestyle, and consumption of a high-carbohydrate/high-fat diet. We test the hypothesis that obesity from a Western-style diet alters host gut microbial species and worsens gastrointestinal and neuroinflammatory symptom persistence. We used a 5 month Western diet feeding in mice that received prior Gulf War (GW) chemical exposure to mimic the home phase obese …

Dual Roles Of Neutrophils In Metastatic Colonization Are Governed By The Host Nk Cell Status., Peishan Li, Mingyang Lu, Jiayuan Shi, Li Hua, Zheng Gong, Qing Li, Leonard D. Shultz, Guangwen Ren

Faculty Research 2020

The role of neutrophils in solid tumor metastasis remains largely controversial. In preclinical models of solid tumors, both pro-metastatic and anti-metastatic effects of neutrophils have been reported. In this study, using mouse models of breast cancer, we demonstrate that the metastasis-modulating effects of neutrophils are dictated by the status of host natural killer (NK) cells. In NK cell-deficient mice, granulocyte colony-stimulating factor-expanded neutrophils show an inhibitory effect on the metastatic colonization of breast tumor cells in the lung. In contrast, in NK cell-competent mice, neutrophils facilitate metastatic colonization in the same tumor models. In an ex vivo neutrophil-NK cell-tumor cell …

Aluminum Reproductive Toxicity: A Summary And Interpretation Of Scientific Reports, Robert A. Yokel

Pharmaceutical Sciences Faculty Publications

Publications addressing aluminum (Al)-induced reproductive toxicity were reviewed. Key details were compiled in summary tables. Approximate systemic Al exposure, a measure of bioavailability, was calculated for each exposure, based on the Al percentage in the dosed Al species, Al bioavailability, and absorption time course reports for the exposure route. This was limited to laboratory animal studies because no controlled-exposure human studies were found. Intended Al exposure was compared to unintended dietary Al exposure. The considerable and variable Al content of laboratory animal diets creates uncertainty about reproductive function in the absence of Al. Aluminum-induced reproductive toxicity in female mice and …

Npc1 Deficiency Impairs Cerebellar Postnatal Development Of Microglia And Climbing Fiber Refinement In A Mouse Model Of Niemann-Pick Disease Type C., Bridget R Boyle, Sierra E Melli, Ruth S Altreche, Zachary M Padron, Fawad A K Yousufzai, Sarah Kim, Mariella D Vasquez, Dawn M Carone, Benjamin Carone, Ileana Soto Reyes

Faculty Scholarship for the College of Science & Mathematics

Little is known about the effects of NPC1 deficiency in brain development and whether these effects contribute to neurodegeneration in Niemann-Pick disease type C (NPC). Degeneration of cerebellar Purkinje cells occurs at an earlier stage and to a greater extent in NPC; therefore, we analyzed the effect of NPC1 deficiency on microglia and on climbing fiber synaptic refinement during cerebellar postnatal development using the

Opioids Disrupt Sleep And Wakefulness In C57bl/6j Mice, Clarence E. Locklear

Masters Theses

Opioid use disorder (OUD) is a major public health burden. According to the National Institutes of Health (NIH), studies helping to understand the mechanisms of OUD will help improve prevention and treatment. Opioids long have been shown to disrupt sleep and sleep disruption enhances the likelihood of addiction relapse in humans. The NIH refers to the mouse as one of the most powerful animal systems to study because of the genetic homologies between human and mouse. Prior to the present research, no studies have quantified the effect of opioids on states of sleep and wakefulness in mice. The current study …

Lipocalin 2 Induces Neuroinflammation And Blood-Brain Barrier Dysfunction Through Liver-Brain Axis In Murine Model Of Nonalcoholic Steatohepatitis, Ayan Mondal, Dipro Bose, Punnag Saha, Sutapa Sarkar, Ratanesh K. Seth, Diana Kimono, Muayad Albadrani, Mitzi Nagarkatti, Prakash Nagarkatti, Saurabh Chatterjee

Faculty Publications

BACKGROUND:

Recent clinical and basic research implicated a strong correlation between NAFLD/NASH phenotypes with ectopic manifestations including neuroinflammation and neurodegeneration, but the mediators and critical pathways involved are not well understood. Lipocalin 2 (Lcn2) is one of the important mediators exclusively produced in the liver and circulation during NASH pathology.

METHODS:

Using murine model of NASH, we studied the role of Lcn2 as a potent mediator of neuroinflammation and neurodegeneration in NASH pathology via the liver-brain axis. RESULTS: Results showed that high circulatory Lcn2 activated 24p3R (Lipocalin2 receptor) in the brain and induced the release of high mobility group box …

Facial Shape And Allometry Quantitative Trait Locus Intervals In The Diversity Outbred Mouse Are Enriched For Known Skeletal And Facial Development Genes., David C Katz, J David Aponte, Wei Liu, Rebecca M Green, Jessica M Mayeux, K Michael Pollard, Daniel Pomp, Steven C. Munger, Stephen A Murray, Charles C Roseman, Christopher J Percival, James Cheverud, Ralph S Marcucio, Benedikt Hallgrímsson

Faculty Research 2020

The biology of how faces are built and come to differ from one another is complex. Discovering normal variants that contribute to differences in facial morphology is one key to untangling this complexity, with important implications for medicine and evolutionary biology. This study maps quantitative trait loci (QTL) for skeletal facial shape using Diversity Outbred (DO) mice. The DO is a randomly outcrossed population with high heterozygosity that captures the allelic diversity of eight inbred mouse lines from three subspecies. The study uses a sample of 1147 DO animals (the largest sample yet employed for a shape QTL study in …

Covid-19 Preclinical Models: Human Angiotensin-Converting Enzyme 2 Transgenic Mice., Cathleen Lutz, Leigh Maher, Charles Lee, Wonyoung Kang

Faculty Research 2020

Coronavirus disease 2019 (COVID-19) is a declared pandemic that is spreading all over the world at a dreadfully fast rate. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the pathogen of COVID-19, infects the human body using angiotensin-converting enzyme 2 (ACE2) as a receptor identical to the severe acute respiratory syndrome (SARS) pandemic that occurred in 2002-2003. SARS-CoV-2 has a higher binding affinity to human ACE2 than to that of other species. Animal models that mimic the human disease are highly essential to develop therapeutics and vaccines against COVID-19. Here, we review transgenic mice that express human ACE2 in the airway and …

Recurring Circadian Disruption Alters Circadian Clock Sensitivity To Resetting, Tanya L. Leise, Ariella Goldberg, John Michael, Grace Montoya, Sabrina Solow, Penny Molyneux, Ramalingam Vetrivelan, Mary E. Harrington

Psychology: Faculty Publications

A single phase advance of the light:dark (LD) cycle can temporarily disrupt synchrony of neural circadian rhythms within the suprachiasmatic nucleus (SCN) and between the SCN and peripheral tissues. Compounding this, modern life can involve repeated disruptive light conditions. To model chronic disruption to the circadian system, we exposed male mice to more than a month of a 20-hr light cycle (LD10:10), which mice typically cannot entrain to. Control animals were housed under LD12:12. We measured locomotor activity and body temperature rhythms in vivo, and rhythms of PER2::LUC bioluminescence in SCN and peripheral tissues ex vivo. Unexpectedly, we discovered strong …

The Effects Of Insulin-Like Growth Factor-1 (Igf-1) And Insulin-Like Growth Factor Receptor (Igfr) Regulation On Cognition And Structure Of Astrocytes, Sariya Khan

Honors Theses

Insulin-like growth factor-1 (IGF-1) is a neuroendocrine signaling hormone that plays an integral role in bone and tissue growth and development. Inhibition of this hormone is known to disrupt the chemistry of the brain, resulting in cognitive impairments such as those seen in many common neurodegenerative diseases. While much research has been conducted on neurons and their relation with IGF-1, the role of astrocytes still needs to be explored. Our research investigates how astrocytes are affected as a result of IGF-1 regulation. Preliminary studies in our laboratory established a connection between IGF-1 and glial fibrillary acidic protein (GFAP), and in …

Tobacco Enhances Bacterial-Induced Periodontal Bone Loss In Mice., Mina Iskander

Electronic Theses and Dissertations

Background: Tobacco smoking is the leading environmental risk factor for periodontal diseases. Delineation of the mechanisms underlying tobacco-induced or exacerbated periodontitis is hampered by the lack of an appropriate and reliable animal model. Hypothesis: We hypothesized that Porphyromonas-gingivalis-infected, cigarette smoke-exposed mice would represent reproducible models of acute (ligature model) and chronic (oral gavage model) tobacco-enhanced periodontitis that reflect multiple aspects of the disease noted in human smokers. Methods: In a chronic oral gavage disease model, Balb/c mice (6-8 weeks, 4 groups of n = 6 per group) were exposed to smoke produced by a Teague-10 smoking machine from 1R6F research …

Characterizing The Range Shifts Of Two Peromyscus Species In Maine, Molly Bennett

Honors College

In a changing climate, two species of mice in Maine (Peromyscus maniculatus and Peromyscus leucopus) are currently undergoing range shifts. The objective of my thesis is to determine the historical and current range of each species within the state of Maine. I used two approaches. I assembled ear biopsies collected this summer in Acadia National Park and throughout the state by the Gardner and Levesque labs to genotype the mice as either P. maniculatus or P. leucopus. Additionally, I summarized research that denotes where the two species were historically present around the state. These species are functionally impossible to tell …

The Effects Of Total Body Proton Irradiation On Mouse Myometrium, Lillith Bulawa

Undergraduate Honors Theses

The boundaries of human space exploration continue to expand with new technology and discoveries making it even more important to investigate the effects of space on biological systems. Although humans have explored space in small increments, reproductive studies must be conducted to determine if stable short- or long-term residences for humans can exist in space. This study explored the effects of whole-body proton radiation on uterine smooth muscle known as the myometrium. Two types of mice utilized in this study were C57BL/6 and B6.129S6Cybbtm1Din/J NOX2 knockout mice. C57BL/6 mice are standard laboratory mice that were used to represent the wildtype …

What We Can Learn From A Genetic Rodent Model About Autism., Dorit Möhrle, Marta Fernández, Olga Peñagarikano, Andreas Frick, Brian Allman, Susanne Schmid

Anatomy and Cell Biology Publications

Autism spectrum disorders (ASD) are complex neurodevelopmental disorders that are caused by genetic and/or environmental impacts, often probably by the interaction of both. They are characterised by deficits in social communication and interaction and by restricted and repetitive behaviours and interests from early childhood on, causing significant impairment. While it is clear that no animal model captures the full complexity of ASD in humans, genetic models are extremely useful for studying specific symptoms associated with ASD and the underlying cellular and molecular mechanisms. In this review we summarize the behavioral paradigms used in rodents to model ASD symptoms as they …

Validation Of Ninein As An Ethanol-Related Quantitative Trait Gene: Reassessment, Design, And Functional Validation Of Reference Genes For Qpcr Analysis Of Brain Tissue In Mice, Jessica L. Jurmain

Theses and Dissertations

The increasing use of quantitative real-time polymerase chain reaction (qPCR) as a method for quantifying gene expression has led to an increased demand for standardization of data analysis methods to ensure accurate reporting and robust, reproducible results. The exponential nature of qPCR amplification results in the potential magnification of what are usually very small sources of error. Relative gene expression calculations circumvent this issue by normalizing target gene expression data to within-sample expression of a previously validated, stably expressed reference gene or genes. Multiple studies discussed herein have found that qPCR data are more reliable and reproducible when multiple reference …

Assessment Of In Vivo Muscle Force In The R6/2 Mouse Model Of Huntington's Disease Using Newly Designed Force Rig, Steven Russell Alan Burke

Browse all Theses and Dissertations

In this thesis, we develop a system to study in vivo muscle function in a mouse model of Huntington’s disease that allows for the recording of muscle force by stimulating the motor nerves or the muscles directly after a nerve block. This allows us to distinguish between defects in the nerve, such as problems with vesicle release, and primary muscle defects, such as altered intracellular calcium homeostasis. We hypothesize that there are primary defects in R6/2 skeletal muscle that are separate from neurodegeneration or defects in the CNS. In this case, we should see defects in muscle force generation during …

Granulosa Cell Proliferation Is Inhibited By Pge2 In The Primate Ovulatory Follicle, Patric S. Lundberg, Gil J. Moskowitz, Carmel Bellacose, Esra Demirel, Heidi A. Trau, Diane M. Duffy

Computer Science Faculty Publications

Prostaglandin E2 (PGE2) is a key paracrine mediator of ovulation. Few specific PGE2-regulated gene products have been identified, so we hypothesized that PGE2 may regulate the expression and/or activity of a network of proteins to promote ovulation. To test this concept, Ingenuity Pathway Analysis (IPA) was used to predict PGE2-regulated functionalities in the primate ovulatory follicle. Cynomolgus macaques underwent ovarian stimulation. Follicular granulosa cells were obtained before (0 h) or 36 h after an ovulatory dose of human chorionic gonadotropin (hCG), with ovulation anticipated 37-40 h after hCG. Granulosa cells were obtained from additional monkeys 36 h after treatment with …