Digital Commons Network^™

Alternative Polyadenylation Contributes To Fibroblast Senescence In Pulmonary Fibrosis, Jingjing Huang, Maria Jose Gacha-Garay, Yu Wang, Scott D Collum, Rene A Girard, Hydia Puente, Seung-Hee Yoo, Rahat Hussain, Jayeshkumar Patel, Manish Patel, Eric J Wagner, Hari Krishnayalamanchili, Harry Karmouty-Quintana, Zheng Chen, Tingting Mills

Faculty, Staff and Students Publications

Idiopathic pulmonary fibrosis (IPF) is a prevalent and deadly age-related disease characterized by chronic, progressive, and irreversible fibrosis. A key effector cell population in the fibroproliferative response is the fibroblasts. Fibroblast cell senescence gradually worsens during aging, and the acquisition of a senescence-associated secretory phenotype (SASP) turns senescent fibroblasts into pro-inflammatory cells. However, the mechanism promoting senescence in IPF, especially at the post-transcriptional level, is poorly understood. We recently discovered that Nudix Hydrolase 21 (NUDT21, also named CFIm25), an RNA-binding protein, plays a critical role in regulating the expression of SASP factors through alternative polyadenylation (APA). APA allows adding poly(A) …

Thermoneutrality Does Not Affect Angiotensin Ii–Induced Aortic Aneurysms In Hypercholesterolemic Mice, Liyuan Zhu, Bowen Li, Michael K. Franklin, Deborah A. Howatt, Yuriko Katsumata, Alan Daugherty, Hong S. Lu

Physiology Faculty Publications

No abstract provided.

Establishment Of A Reverse Genetics System For Studying Human Immune Functions In Mice, Priya Pal, Shuai Gao, Hongbo Gao, Xiwen Qin, Marina Cella, Qiankun Wang, Liang Shan

2020-Current year OA Pubs

Reverse genetics approaches in mice are widely used to understand gene functions and their aberrations in diseases. However, limitations exist in translating findings from animal models to human physiology. Humanized mice provide a powerful bridge to understanding human physiology and mechanisms of disease pathogenesis while maintaining the feasibility of working with small animals. Methods for generating humanized mouse models that allow scientists to probe contributions of particular genes have been rudimentary. Here, we established an efficient method for generating genetically modified human cord blood-derived CD34

Pi(4)P Recruits Cide Proteins To Promote The Formation Of Unilocular Lipid Droplets During Adipogenesis And Hepatic Steatosis, Jin Wu, Mingming Gao, Xiaoqin Wu, Yang Liu, Taiping Zhang, Yan Liang, Haixia Yang, Chengxin Ma, Youpi Ye, Chunmei Chang, Peng Li, Feng-Jung Chen, Hongyuan Yang

Faculty, Staff and Student Publications

Lipid droplets (LDs) are evolutionarily conserved organelles that play important roles in metabolism. Each LD is enclosed by a monolayer of phospholipids, distinct from bilayer membranes. The composition of LD surface phospholipids and their impact on LD growth and function remain to be defined. Phosphoinositides mark cellular organelles and regulate organellar function. Here, we demonstrate that PI(4)P decorates a subset of LDs to recruit and activate CIDE proteins. Enhanced expression of ORP2 and ORP5, LD-associated lipid transfer proteins that remove PI(4)P from LDs, abolished the localization and function of CIDE proteins. Blocking the synthesis of PI(4)P on the LD surface …

A Forward Genetic Screen Identifies Potassium Channel Essentiality In Shh Medulloblastoma Maintenance, Jerry J Fan, Anders W Erickson, Julia Carrillo-Garcia, Xin Wang, Patryk Skowron, Xian Wang, Xin Chen, Guanqiao Shan, Wenkun Dou, Shahrzad Bahrampour, Yi Xiong, Weifan Dong, Namal Abeysundara, Michelle A Francisco, Ronwell J Pusong, Wei Wang, Miranda Li, Elliot Ying, Raúl A Suárez, Hamza Farooq, Borja L Holgado, Xiaochong Wu, Craig Daniels, Adam J Dupuy, Juan Cadiñanos, Allan Bradley, Anindya Bagchi, Branden S Moriarity, David A Largaespada, A Sorana Morrissy, Vijay Ramaswamy, Stephen C Mack, Livia Garzia, Peter B Dirks, Xuejun Li, Siyi Wanggou, Sean Egan, Yu Sun, Michael D Taylor, Xi Huang

Faculty, Staff and Students Publications

Distinguishing tumor maintenance genes from initiation, progression, and passenger genes is critical for developing effective therapies. We employed a functional genomic approach using the Lazy Piggy transposon to identify tumor maintenance genes in vivo, and applied this to SHH medulloblastoma (MB). Combining Lazy Piggy screening in mice and transcriptomic profiling of human MB, we identified the voltage-gated potassium channel KCNB2 as a candidate maintenance driver. KCNB2 governs cell volume of MB-propagating cells, with KCNB2 depletion causing osmotic swelling, decreased plasma membrane tension, and elevated endocytic internalization of EGFR, thereby mitigating proliferation of MB-propagating cells to ultimately impair MB growth. …

Effects Of Prebiotic Phytocompound Administration In Gestational Diabetic Dams And Its Influence On Offspring Cognitive Outcomes, Gayathri Jagadeesan, Tushar K Das, Jennifer M Mendoza, Ghalya Alrousan, Maria P Blasco-Conesa, Parimelazhagan Thangaraj, Bhanu Priya Ganesh

Faculty, Staff and Student Publications

Gestational diabetes mellitus (GD)-induced gut dysbiosis in pregnant mothers may increase the risk of cognitive impairment and neurological disorders in both the mother and offspring as they age. Restoring gut balance could improve cognitive outcomes for both. Despite advancements in GD treatment, side effects have increased, and long-term neurocognitive impacts on offspring born to GD mothers remain underexplored. This study uses a GD mouse model, inducing pancreatic dysfunction in 3-month-old pregnant C57BL/6J mice with Streptozotocin. The efficacy and mechanism of the prebiotic phytocompound green leaf extract (

Non-Invasive Real-Time Pulsed Doppler Assessment Of Blood Flow In Mouse Ophthalmic Artery, Iraida Sharina, Radwa Awad, Soren Cobb, Emil Martin, Sean P Marrelli, Anilkumar K Reddy

Faculty, Staff and Student Publications

Non-invasive and high-temporal resolution methods for characterizing blood flow in mouse cranial arteries, such as the ophthalmic artery (OphA), are lacking. We present an application of pulsed Doppler ultrasound to provide real-time, non-invasive measurement of blood flow velocity in the OphA through an identified soft tissue window in the mouse head. We confirmed the identity of the artery and mapped its origin from the internal carotid artery by a combination of microcomputed tomography (microCT) vascular imaging and transient occlusion of the internal carotid artery. Application of our approach demonstrated sex differences in the OphA vasodilative response to agonists. We also …

A Natural Small Molecule Isoginkgetin Alleviates Hypercholesterolemia And Atherosclerosis By Targeting Acly, Zhidan Zhang, Meijie Chen, Yitong Xu, Zhihua Wang, Zhenghong Liu, Chenyang He, Fanshun Zhang, Xiaojun Feng, Xiayun Ni, Yuanli Chen, Jixia Wang, Xinmiao Liang, Zhifu Xie, Jingya Li, Maciej Banach, Jaroslav Pelisek, Yuqing Huo, Yunhui Hu, Paul C Evans, Li Wang, Xiao-Yu Tian, Jianbo Xiao, Yuhua Shang, Yijun Zheng, Xunde Xian, Jianping Weng, Suowen Xu

Faculty, Staff and Students Publications

Rationale: Atherosclerotic cardiovascular disease (ASCVD) represents the predominant cause of mortality and morbidity globally. Given the established role of hypercholesterolemia as a significant risk factor for ASCVD, the discovery of new lipid-lowering medications is of paramount importance. ATP citrate lyase (ACLY) is a crucial enzyme in cellular metabolism, providing acetyl-CoA as the building block for the biosynthesis of fatty acids and cholesterol. Consequently, it has emerged as a promising drug target for innovative treatments of lipid metabolic disorders.

Methods: Virtual screening of a natural product library was performed to identify small-molecule ACLY inhibitors, leading to the discovery of isoginkgetin (ISOGK). …

Cancer-Targeted Pro-Theranostic Bi-Metallic Organo-Coordination Nanoparticles, Hengbo Huang, Lei Fang, Janaka Wansapura, Julie L Prior, Brad Manion, Baogang Xu, Cody Hongsermeier, Nisha Gamadia, Nicole Blasi, Rui Tang, Christopher Egbulefu, Monica Shokeen, James D Quirk, Samuel Achilefu

2020-Current year OA Pubs

No abstract provided.

The Mutant Mouse Resource And Research Center (Mmrrc) Consortium: The Us-Based Public Mouse Repository System., Yuksel Agca, James Amos-Landgraf, Renee Araiza, Jennifer Brennan, Charisse Carlson, Dominic Ciavatta, Dave Clary, Craig Franklin, Ian Korf, Cathleen Lutz, Terry Magnuson, Fernando Pardo-Manuel De Villena, Oleg Mirochnitchenko, Samit Patel, Dan Port, Laura G Reinholdt, K C Kent Lloyd

Faculty Research 2024

Now in its 25th year, the Mutant Mouse Resource and Research Center (MMRRC) consortium continues to serve the United States and international biomedical scientific community as a public repository and distribution archive of laboratory mouse models of human disease for research. Supported by the National Institutes of Health (NIH), the MMRRC consists of 4 regionally distributed and dedicated vivaria, offices, and specialized laboratory facilities and an Informatics Coordination and Service Center (ICSC). The overarching purpose of the MMRRC is to facilitate groundbreaking biomedical research by offering an extensive repertoire of mutant mice that are essential for advancing the understanding of …

Mitochondrial Pyruvate Transport Regulates Presynaptic Metabolism And Neurotransmission, Anupama Tiwari, Jongyun Myeong, Arsalan Hashemiaghdam, Marion I Stunault, Hao Zhang, Xiangfeng Niu, Marissa A Laramie, Jasmin Sponagel, Leah P Shriver, Gary J Patti, Vitaly A Klyachko, Ghazaleh Ashrafi

2020-Current year OA Pubs

Glucose has long been considered the primary fuel source for the brain. However, glucose levels fluctuate in the brain during sleep or circuit activity, posing major metabolic stress. Here, we demonstrate that the mammalian brain uses pyruvate as a fuel source, and pyruvate can support neuronal viability in the absence of glucose. Nerve terminals are sites of metabolic vulnerability, and we show that mitochondrial pyruvate uptake is a critical step in oxidative ATP production in hippocampal terminals. We find that the mitochondrial pyruvate carrier is post-translationally modified by lysine acetylation, which, in turn, modulates mitochondrial pyruvate uptake. Our data reveal …

Loss Of Transient Receptor Potential Channel 5 Causes Obesity And Postpartum Depression, Yongxiang Li, Tessa M Cacciottolo, Na Yin, Yang He, Hesong Liu, Hailan Liu, Yuxue Yang, Elana Henning, Julia M Keogh, Katherine Lawler, Edson Mendes De Oliveira, Eugene J Gardner, Katherine A Kentistou, Panayiotis Laouris, Rebecca Bounds, Ken K Ong, John R B Perry, Inês Barroso, Longlong Tu, Jonathan C Bean, Meng Yu, Kristine M Conde, Mengjie Wang, Olivia Ginnard, Xing Fang, Lydia Tong, Junying Han, Tia Darwich, Kevin W Williams, Yongjie Yang, Chunmei Wang, Shelagh Joss, Helen V Firth, Yong Xu, I Sadaf Farooqi

Duncan NRI Faculty and Staff Publications

Hypothalamic neural circuits regulate instinctive behaviors such as food seeking, the fight/flight response, socialization, and maternal care. Here, we identified microdeletions on chromosome Xq23 disrupting the brain-expressed transient receptor potential (TRP) channel 5 (TRPC5). This family of channels detects sensory stimuli and converts them into electrical signals interpretable by the brain. Male TRPC5 deletion carriers exhibited food seeking, obesity, anxiety, and autism, which were recapitulated in knockin male mice harboring a human loss-of-function TRPC5 mutation. Women carrying TRPC5 deletions had severe postpartum depression. As mothers, female knockin mice exhibited anhedonia and depression-like behavior with impaired care of offspring. Deletion of …

Colorectal Cancer Murine Models: Initiation To Metastasis, Ramesh Pothuraju, Imran Khan, Maneesh Jain, Michael Bouvet, Mokenge Malafa, Hemant K Roy, Sushil Kumar, Surinder K Batra

Faculty, Staff and Students Publications

Despite significant advancements in prevention and treatment, colorectal cancer (CRC) remains the third leading cause of cancer-related deaths. Animal models, including xenografts, syngeneic, and genetically engineered, have emerged as indispensable tools in cancer research. These models offer a valuable platform to address critical questions regarding molecular pathogenesis and test therapeutic interventions before moving on to clinical trials. Advancements in CRC animal models have also facilitated the advent of personalized and precision medicine. Patient-derived xenografts and genetically engineered mice that mirror features of human tumors allow for tailoring treatments to specific CRC subtypes, improving treatment outcomes and quality of life. To …

Revolutionizing Psoriasis Topical Treatment: Enhanced Efficacy Through Ceramide/Phospholipid Composite Cerosomes Co-Delivery Of Cyclosporine And Dithranol: In-Vitro, Ex-Vivo, And In-Vivo Studies, Sammar Fathy Elhabal, Nashwa Abdelaal, Saeed A S Al-Zuhairy, Mohamed Fathi Mohamed Elrefai, Mohamed Mansour Khalifa, Mohammad Ahmad Khasawneh, Ahmed Mohsen Elsaid Hamdan, Passant M Mohie, Rania A Gad, Soad L Kabil, Mohamed Kandeel El-Ashery, Bhaskara R Jasti, Nahla A Elzohairy, Nehal Elfar, Tayseer Elnawawy, Fatma E Hassan, Mohamed Ahmed El-Nabarawi

Faculty, Staff and Students Publications

PURPOSE: Improving the treatment of psoriasis is a serious challenge today. Psoriasis is an immune-mediated skin condition affecting 125 million people worldwide. It is commonly treated with cyclosporine-A (CsA) and dithranol (DTH). CsA suppresses the activation of T-cells, immune cells involved in forming psoriatic lesions. Meanwhile, DTH is a potent anti-inflammatory and anti-proliferative drug that effectively reduces the severity of psoriasis symptoms such as redness, scaling, and skin thickness. CsA and DTH belong to BCS class II with limited oral bioavailability. We aim to develop a drug delivery system for topical co-delivery of CsA and DTH, exploring its therapeutic potential. …

Reduction Of Sparc Protects Mice Against Nlrp3 Inflammasome Activation And Obesity, Seungjin Ryu, Olga Spadaro, Sviatoslav Sidorov, Aileen H. Lee, Sonia Caprio, Christopher Morrison, Steven R. Smith, Eric Ravussin, Irina Shchukina, Maxim N. Artyomov, Yun-Hee Youm, Vishwa Deep Dixit

2020-Current year OA Pubs

The comprehensive assessment of long-term effects of reducing intake of energy (CALERIE-II; NCT00427193) clinical trial established that caloric restriction (CR) in humans lowers inflammation. The identity and mechanism of endogenous CR-mimetics that can be deployed to control obesity-associated inflammation and diseases are not well understood. Our studies have found that 2 years of 14% sustained CR in humans inhibits the expression of the matricellular protein, secreted protein acidic and rich in cysteine (SPARC), in adipose tissue. In mice, adipose tissue remodeling caused by weight loss through CR and low-protein diet feeding decreased, while high-fat diet-induced (HFD-induced) obesity increased SPARC expression …

Epicutaneous Sensitization To The Phytocannabinoid Β-Caryophyllene Induces Pruritic Inflammation, Saadet Inan, Sara J Ward, Citlalli T Baltazar, Gabrielle A. Peruggia, Elham Javed, Ajay P. Nayak

Center for Translational Medicine Faculty Papers

In recent years, there has been increased accessibility to cannabis for recreational and medicinal use. Incidentally, there has been an increase in reports describing allergic reactions to cannabis including exacerbation of underlying asthma. Recently, multiple protein allergens were discovered in cannabis, yet these fail to explain allergic sensitization in many patients, particularly urticaria and angioedema. Cannabis has a rich chemical profile including cannabinoids and terpenes that possess immunomodulatory potential. We examined whether major cannabinoids of cannabis such as cannabidiol (CBD) and the bicyclic sesquiterpene beta-caryophyllene (β-CP) act as contact sensitizers. The repeated topical application of mice skin with β-CP at …

Bicc1 Drives Pancreatic Cancer Progression By Inducing Vegf-Independent Angiogenesis, Chongbiao Huang, Hui Li, Yang Xu, Chao Xu, Huizhi Sun, Zengxun Li, Yi Ge, Hongwei Wang, Tiansuo Zhao, Song Gao, Xiuchao Wang, Shengyu Yang, Peiqing Sun, Zhe Liu, Jing Liu, Antao Chang, Jihui Hao

Faculty, Staff and Student Publications

VEGF inhibitors are one of the most successful antiangiogenic drugs in the treatment of many solid tumors. Nevertheless, pancreatic adenocarcinoma (PAAD) cells can reinstate tumor angiogenesis via activation of VEGF-independent pathways, thereby conferring resistance to VEGF inhibitors. Bioinformatic analysis showed that BICC1 was one of the top genes involved in the specific angiogenesis process of PAAD. The analysis of our own cohort confirmed that BICC1 was overexpressed in human PAAD tissues and was correlated to increased microvessel density and tumor growth, and worse prognosis. In cells and mice with xenograft tumors, BICC1 facilitated angiogenesis in pancreatic cancer in a VEGF-independent …

Chronic, Mild Hypothermic Environmental Temperature Does Not Ameliorate Cognitive Deficits In An Alzheimer's Disease Mouse., Samuel Mcfadden, Lindsey N Sime, Makayla F Cox, Caleigh A Findley, Mackenzie R Peck, Kathleen Quinn, Yimin Fang, Andrzej Bartke, Erin R Hascup, Kevin N Hascup

Articles

Metabolic dysfunction increases with age and is a contributing factor to Alzheimer's disease (AD) development. We have previously observed impaired insulin sensitivity and glucose homeostasis in the APP/PS1 model of AD. To improve these parameters, we chronically exposed male and female mice to mild hypothermic environmental temperature (eT), which positively modulates metabolism. Although a hypothermic eT normalized insulin sensitivity, glucose tolerance was still impaired in both sexes of AD mice. We observed increased plasma glucagon and B-cell activating factor in both sexes, but additional sexually dimorphic mechanisms may explain the impaired glucose homeostasis in AD mice. Hepatic Glut2 was decreased …

Influence Of Age And Gender On Alveolar Bone Healing Post Tooth Extraction In 129 Sv Mice: A Microtomographic, Histological, And Biochemical Characterization, Cláudia Cristina Biguetti, Bhuvana Lakkasetter Chandrashekar, Gustavo Baroni Simionato, Nataira Regina Momesso, Marco Antonio Hungaro Duarte, Danieli C. Rodrigues, Mariza Akemi Matsumoto

School of Podiatric Medicine Publications

Objectives

To analyze the effect of biological sex and aging on craniofacial bone features in 129 Sv mice and their influence on dental socket healing post tooth extraction.

Materials and methods

A total of 52 129 Sv mice were used, of which 28 were young (3–4 months) and 24 were aged (17–18 months), equally distributed according to biological sex. After an upper right incisor extraction, mice specimens were collected at 7, 14, and 21-days post-surgery for microtomographic (microCT) and comprehensive histological analysis. Mandible, skull bones, and maxillae at 21 days were analyzed by microCT, while blood plasma samples were collected …

Species Differences In Platelet Protease-Activated Receptors, Stephanie A Renna, Steven E. Mckenzie, James V. Michael

Cardeza Foundation for Hematologic Research

Protease-activated receptors (PARs) are a class of integral membrane proteins that are cleaved by a variety of proteases, most notably thrombin, to reveal a tethered ligand and promote activation. PARs are critical mediators of platelet function in hemostasis and thrombosis, and therefore are attractive targets for anti-platelet therapies. Animal models studying platelet PAR physiology have relied heavily on genetically modified mouse strains, which have provided ample insight but have some inherent limitations. The current review aims to summarize the notable PAR expression and functional differences between the mouse and human, in addition to highlighting some recently developed tools to further …

Effects Of Cannabichromene On Pain And Neuroinflammation In Hiv-1 Tat Transgenic Mice, Sydney Wheeler

Honors Theses

HIV-1 TransActivator of Transcription (Tat) is a vital regulatory protein involved in HIV replication and implicated in development of HIV-associated pain and neurocognitive deficits. Tat is thought to contribute to these pathologies through proinflammatory pathways. Developing mechanisms to curb Tat-mediated inflammation is a key step in improving the quality of life of those living with HIV. Both recreational and medicinal cannabis use is prevalent among many people living with HIV; given this prevalence and the perceived anti-inflammatory benefits of cannabis use, it is important to investigate how chemical constituents of cannabis may impact HIV. In the present study, the effects …

High Pulse Pressure Impairs Cerebral Artery Endothelial Function In Young, But Not Old, Mice, Nick R Winder, Emily H Reeve, Elise K Kronquist, Aleena Khurana, Byron Lee, Thuan Nguyen, Grant D Henson, Ashley E Walker

Faculty, Staff and Student Publications

One of the hallmarks of vascular aging is increased pulse pressure. This elevated pulse pressure is associated with deleterious effects on cerebral vascular function; however, it is unknown if age modulates the susceptibility to high pulse pressure. To examine the effects of age on the cerebral artery response to pulse pressure, we studied isolated cerebral arteries collected from young (6.1 ± 0.2 mo) and old (26.7 ± 0.5 mo) male C57BL/6 mice. Isolated cerebral arteries were exposed ex vivo to static pressure, low pulse pressure (25 mmHg), and high pulse pressure (50 mmHg). In cerebral arteries from young mice, endothelium-dependent …

Svep1 Is An Endogenous Ligand For The Orphan Receptor Pear1, Jared S Elenbaas, Upasana Pudupakkam, Katrina J Ashworth, Chul Joo Kang, Ved Patel, Katherine Santana, In-Hyuk Jung, Paul C Lee, Kendall H Burks, Junedh M Amrute, Robert P Mecham, Carmen M Halabi, Arturo Aliso, Jorge Di Paola, Nathan O Stitziel

2020-Current year OA Pubs

Sushi, von Willebrand factor type A, EGF and pentraxin domain containing 1 (SVEP1) is an extracellular matrix protein that causally promotes vascular disease and associates with platelet reactivity in humans. Here, using a human genomic and proteomic approach, we identify a high affinity, disease-relevant, and potentially targetable interaction between SVEP1 and the orphan receptor Platelet and Endothelial Aggregation Receptor 1 (PEAR1). This interaction promotes PEAR1 phosphorylation and disease associated AKT/mTOR signaling in vascular cells and platelets. Mice lacking SVEP1 have reduced platelet activation, and exogenous SVEP1 induces PEAR1-dependent activation of platelets. SVEP1 and PEAR1 causally and concordantly relate to platelet …

Myo/Nog Cells Give Rise To Myofibroblasts During Epiretinal Membrane Formation In A Mouse Model Of Proliferative Vitreoretinopathy., Mara Crispin, Jacquelyn Gerhart, Alison Heffer, Mark Martin, Fathma Abdalla, Arturo Bravo Nuevo, Nancy J Philp, Ajay E Kuriyan, Mindy George-Weinstein

PCOM Scholarly Works

PURPOSE: Myo/Nog cells are the source of myofibroblasts in the lens and synthesize muscle proteins in human epiretinal membranes (ERMs). In the current study, we examined the response of Myo/Nog cells during ERM formation in a mouse model of proliferative vitreoretinopathy (PVR).

METHODS: PVR was induced by intravitreal injections of gas and ARPE-19 cells. PVR grade was scored by fundus imaging, optical coherence tomography, and histology. Double label immunofluorescence localization was performed to quantify Myo/Nog cells, myofibroblasts, and leukocytes.

RESULTS: Myo/Nog cells, identified by co-labeling with antibodies to brain-specific angiogenesis inhibitor 1 (BAI1) and Noggin, increased throughout the eye with …

Pyridoxamine Treatment Ameliorates Large Artery Stiffening And Cerebral Artery Endothelial Dysfunction In Old Mice, Emily H Reeve, Elise K Kronquist, Julia R Wolf, Byron Lee, Aleena Khurana, Hanson Pham, Abigail E Cullen, Jessica A Peterson, Antonio Meza, R Colton Bramwell, Laura Villasana, Daniel R Machin, Grant D Henson, Ashley E Walker

Faculty, Staff and Student Publications

Age-related increases in large artery stiffness are associated with cerebrovascular dysfunction and cognitive impairment. Pyridoxamine treatment prevents large artery stiffening with advancing age, but the effects of pyridoxamine treatment on the cerebral vasculature or cognition is unknown. The purpose of this study was to investigate the effects of pyridoxamine on blood pressure, large artery stiffness, cerebral artery function, and cognitive function in old mice. Old male C57BL/6 mice consumed either pyridoxamine (2 g/L) or vehicle control in drinking water for ∼7.5 months and were compared with young male C57BL/6 mice. From pre- to post-treatment, systolic blood pressure increased in old …

Human Hematopoietic Stem Cell Engrafted Il-15 Transgenic Nsg Mice Support Robust Nk Cell Responses And Sustained Hiv-1 Infection., Shawn A Abeynaike, Tridu R Huynh, Abeera Mehmood, Teha Kim, Kayla Frank, Kefei Gao, Cristina Zalfa, Angel Gandarilla, Leonard D. Shultz, Silke Paust

Faculty Research 2023

Mice reconstituted with human immune systems are instrumental in the investigation of HIV-1 pathogenesis and therapeutics. Natural killer (NK) cells have long been recognized as a key mediator of innate anti-HIV responses. However, established humanized mouse models do not support robust human NK cell development from engrafted human hematopoietic stem cells (HSCs). A major obstacle to human NK cell reconstitution is the lack of human interleukin-15 (IL-15) signaling, as murine IL-15 is a poor stimulator of the human IL-15 receptor. Here, we demonstrate that immunodeficient NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice expressing a transgene encoding human IL-15 (NSG-Tg(IL-15)) have physiological levels of …

The Role Of Insulin-Like Growth Factor I In The Development Of The Cerebellum In Euthyroid And Hypothyroid Mice, Prathibha Mangedarage

All Graduate Theses, Dissertations, and Other Capstone Projects

Thyroid hormone deficiency during development is known to cause anatomical defects in the cerebellum that lead to neurological deficits. It has been observed that insufficient thyroid hormone levels also decrease the levels of brain derived Insulin-like growth factor 1 (Igf-1). Given that the deficits caused by low Igf-1 levels are similar to those caused by low thyroid hormone, we designed this study to investigate if the deficits caused in the development of the cerebellum by low thyroid hormone levels may be due to the lack of sufficient Igf-1. We also sought to determine if ectopic over expression of Igf-1 in …

Comorbidity Of Novel Crhr2 Gene Variants In Type 2 Diabetes And Depression, Mutaz Amin, Jurg Ott, Derek Gordon, Rongling Wu, Teodor T Postolache, Michael Vergare, Claudia Gragnoli

Department of Psychiatry and Human Behavior Faculty Papers

The corticotropin-releasing hormone receptor 2 (CRHR2) gene encodes CRHR2, contributing to the hypothalamic-pituitary-adrenal stress response and to hyperglycemia and insulin resistance. CRHR2-/- mice are hypersensitive to stress, and the CRHR2 locus has been linked to type 2 diabetes and depression. While CRHR2 variants confer risk for mood disorders, MDD, and type 2 diabetes, they have not been investigated in familial T2D and MDD. In 212 Italian families with type 2 diabetes and depression, we tested 17 CRHR2 single nucleotide polymorphisms (SNPs), using two-point parametric-linkage and linkage-disequilibrium (i.e., association) analysis (models: dominant-complete-penetrance-D1, dominant-incomplete-penetrance-D2, recessive-complete-penetrance-R1, recessive-incomplete-penetrance-R2). We detected novel linkage/linkage-disequilibrium/association …

Products Of Gut Microbial Toll/Interleukin-1 Receptor Domain Nadase Activities In Gnotobiotic Mice And Bangladeshi Children With Malnutrition, James S Weagley, Mark Zaydman, Siddarth Venkatesh, Yo Sasaki, Neha Damaraju, Alex Yenkin, William Buchser, Dmitry A Rodionov, Andrei Osterman, Tahmeed Ahmed, Michael J Barratt, Aaron Diantonio, Jeffrey Milbrandt, Jeffrey I Gordon

2020-Current year OA Pubs

Perturbed gut microbiome development has been linked to childhood malnutrition. Here, we characterize bacterial Toll/interleukin-1 receptor (TIR) protein domains that metabolize nicotinamide adenine dinucleotide (NAD), a co-enzyme with far-reaching effects on human physiology. A consortium of 26 human gut bacterial strains, representing the diversity of TIRs observed in the microbiome and the NAD hydrolase (NADase) activities of a subset of 152 bacterial TIRs assayed in vitro, was introduced into germ-free mice. Integrating mass spectrometry and microbial RNA sequencing (RNA-seq) with consortium membership manipulation disclosed that a variant of cyclic-ADPR (v-cADPR-x) is a specific product of TIR NADase activity and a …

Ces2 Sustains Hnf4Α Expression To Promote Pancreatic Adenocarcinoma Progression Through An Epoxide Hydrolase-Dependent Regulatory Loop, Yihui Chen, Michela Capello, Mayrim V Rios Perez, Jody V Vykoukal, David Roife, Ya'an Kang, Laura R Prakash, Hiroyuki Katayama, Ehsan Irajizad, Alia Fleury, Sammy Ferri-Borgogno, Dodge L Baluya, Jennifer B Dennison, Kim-Anh Do, Oliver Fiehn, Anirban Maitra, Huamin Wang, Paul J Chiao, Matthew H G Katz, Jason B Fleming, Samir M Hanash, Johannes F Fahrmann

Faculty, Staff and Student Publications

Objective: Intra-tumoral expression of the serine hydrolase carboxylesterase 2 (CES2) contributes to the activation of the pro-drug irinotecan in pancreatic ductal adenocarcinoma (PDAC). Given other potential roles of CES2, we assessed its regulation, downstream effects, and contribution to tumor development in PDAC.

Methods: Association between the mRNA expression of CES2 in pancreatic tumors and overall survival was assessed using The Cancer Genome Atlas. Cell viability, clonogenic, and anchorage-independent growth assays as well as an orthotopic mouse model of PDAC were used to evaluate the biological relevance of CES2 in pancreatic cancer. CES2-driven metabolic changes were determined by untargeted and targeted …