Digital Commons Network^™

Brain Injury Accelerates The Onset Of A Reversible Age-Related Microglial Phenotype Associated With Inflammatory Neurodegeneration, Rodney M Ritzel, Yun Li, Yun Jiao, Zhuofan Lei, Sarah J Doran, Junyun He, Rami A Shahror, Rebecca J Henry, Romeesa Khan, Chunfeng Tan, Shaolin Liu, Bogdan A Stoica, Alan I Faden, Gregory Szeto, David J Loane, Junfang Wu

Faculty, Staff and Student Publications

Lipofuscin is an autofluorescent (AF) pigment formed by lipids and misfolded proteins, which accumulates in postmitotic cells with advanced age. Here, we immunophenotyped microglia in the brain of old C57BL/6 mice (>18 months old) and demonstrate that in comparison to young mice, one-third of old microglia are AF, characterized by profound changes in lipid and iron content, phagocytic activity, and oxidative stress. Pharmacological depletion of microglia in old mice eliminated the AF microglia following repopulation and reversed microglial dysfunction. Age-related neurological deficits and neurodegeneration after traumatic brain injury (TBI) were attenuated in old mice lacking AF microglia. Furthermore, increased …

Mechanism Of Kmt5b Haploinsufficiency In Neurodevelopment In Humans And Mice, Sarah E Sheppard, Marisa Andrews, Dustin Baldridge, John Constantino, Et Al.

2020-Current year OA Pubs

Pathogenic variants in

Towards A Biomarker For Acute Arterial Thrombosis Using Complete Blood Count And White Blood Cell Differential Parameters In Mice, Hee Jeong Jang, Dawid Schellingerhout, Jiwon Kim, Jinyong Chung, Dong-Eog Kim

Faculty, Staff and Student Publications

There is no blood biomarker diagnostic of arterial thrombosis. We investigated if arterial thrombosis per se was associated with alterations in complete blood count (CBC) and white blood cell (WBC) differential count in mice. Twelve-week-old C57Bl/6 mice were used for FeCl3-mediated carotid thrombosis (n = 72), sham-operation (n = 79), or non-operation (n = 26). Monocyte count (/µL) at 30-min after thrombosis (median 160 [interquartile range 140-280]) was ~ 1.3-fold higher than at 30-min after sham-operation (120 [77.5-170]), and twofold higher than in non-operated mice (80 [47.5-92.5]). At day-1 and -4 post-thrombosis, compared with 30-min, monocyte count decreased by about …

Neurofibromatosis Type 1-Dependent Alterations In Mouse Microglia Function Are Not Cell-Intrinsic, Francesca Logiacco, Laura Cathleen Grzegorzek, Elizabeth C Cordell, Oliver Popp, Philipp Mertins, David H Gutmann, Helmut Kettenmann, Marcus Semtner

2020-Current year OA Pubs

We previously discovered a sex-by-genotype defect in microglia function using a heterozygous germline knockout mouse model of Neurofibromatosis type 1 (Nf1 ± mice), in which only microglia from male Nf1 ± mice exhibited defects in purinergic signaling. Herein, we leveraged an unbiased proteomic approach to demonstrate that male, but not female, heterozygous Nf1 ± microglia exhibit differences in protein expression, which largely reflect pathways involved in cytoskeletal organization. In keeping with these predicted defects in cytoskeletal function, only male Nf1 ± microglia had reduced process arborization and surveillance capacity. To determine whether these microglial defects were cell autonomous or reflected …

Role Of Klotho And Age/Rage-Wnt/Β-Catenin Signalling Pathway On The Development Of Cardiac And Renal Fibrosis In Diabetes, Beatriz Martín-Carro, Julia Martín-Vírgala, Sara Fernández-Villabrille, Alejandra Fernández-Fernández, Marcos Pérez-Basterrechea, Juan F Navarro-González, Javier Donate-Correa, Carmen Mora-Fernández, Adriana S Dusso, Natalia Carrillo-López, Sara Panizo, Manuel Naves-Díaz, José L Fernández-Martín, Jorge B Cannata-Andía, Cristina Alonso-Montes

2020-Current year OA Pubs

Fibrosis plays an important role in the pathogenesis of long-term diabetic complications and contributes to the development of cardiac and renal dysfunction. The aim of this experimental study, performed in a long-term rat model, which resembles type 1 diabetes mellitus, was to investigate the role of soluble Klotho (sKlotho), advanced glycation end products (AGEs)/receptor for AGEs (RAGE), fibrotic Wnt/β-catenin pathway, and pro-fibrotic pathways in kidney and heart. Diabetes was induced by streptozotocin. Glycaemia was maintained by insulin administration for 24 weeks. Serum and urine sKlotho, AGEs, soluble RAGE (sRAGE) and biochemical markers were studied. The levels of Klotho, RAGEs, ADAM10, …

Engineering T Cells To Suppress Acute Gvhd And Leukemia Relapse After Allogeneic Hematopoietic Stem Cell Transplantation, Feiyan Mo, Norihiro Watanabe, Kayleigh I Omdahl, Phillip M Burkhardt, Xiaoyun Ding, Eiko Hayase, Angela Panoskaltsis-Mortari, Robert R Jenq, Helen E Heslop, Leslie S Kean, Malcolm K Brenner, Victor Tkachev, Maksim Mamonkin

Faculty, Staff and Student Publications

Acute graft-versus-host disease (aGVHD) limits the therapeutic benefit of allogeneic hematopoietic stem cell transplantation (allo-HSCT) and requires immunosuppressive prophylaxis that compromises antitumor and antipathogen immunity. OX40 is a costimulatory receptor upregulated on circulating T cells in aGVHD and plays a central role in driving the expansion of alloreactive T cells. Here, we show that OX40 is also upregulated on T cells infiltrating GVHD target organs in a rhesus macaque model, supporting the hypothesis that targeted ablation of OX40+ T cells will mitigate GVHD pathogenesis. We thus created an OX40-specific cytotoxic receptor that, when expressed on human T cells, enables selective …

Young Astrocytic Mitochondria Attenuate The Elevated Level Of Ccl11 In The Aged Mice, Contributing To Cognitive Function Improvement, Ryosuke Tashiro, Dan Ozaki, Jesus Bautista-Garrido, Guanghua Sun, Lidiya Obertas, Alexis S Mobley, Gab Seok Kim, Jaroslaw Aronowski, Joo Eun Jung

Faculty, Staff and Student Publications

Aging drives cognitive decline, and mitochondrial dysfunction is a hallmark of age-induced neurodegeneration. Recently, we demonstrated that astrocytes secrete functional mitochondria (Mt), which help adjacent cells to resist damage and promote repair after neurological injuries. However, the relationship between age-dependent changes in astrocytic Mt function and cognitive decline remains poorly understood. Here, we established that aged astrocytes secret less functional Mt compared to young astrocytes. We found the aging factor C-C motif chemokine 11 (CCL11) is elevated in the hippocampus of aged mice, and that its level is reduced upon systemic administration of young Mt, in vivo. Aged mice receiving …

Adipose-Targeted Swell1 Deletion Exacerbates Obesity- And Age-Related Nonalcoholic Fatty Liver Disease, Susheel K. Gunasekar, John Heebink, Danielle H Carpenter, Ashutosh Kumar, Litao Xie, Haixia Zhang, Joel D. Schilling, Rajan Sah

2020-Current year OA Pubs

Healthy expansion of adipose tissue is critical for the maintenance of metabolic health, providing an optimized reservoir for energy storage in the form of triacylglycerol-rich lipoproteins. Dysfunctional adipocytes that are unable to efficiently store lipid can result in lipodystrophy and contribute to nonalcoholic fatty liver disease (NAFLD) and metabolic syndrome. Leucine-rich repeat containing protein 8a/SWELL1 functionally encodes the volume-regulated anion channel complex in adipocytes, is induced in early obesity, and is required for normal adipocyte expansion during high-fat feeding. Adipose-specific SWELL1 ablation (Adipo KO) leads to insulin resistance and hyperglycemia during caloric excess, both of which are associated with NAFLD. …

Neuronal Sirt3 Deletion Predisposes To Female-Specific Alterations In Cellular Metabolism, Memory, And Network Excitability, Jennifer N Pearson-Smith, Ruth Fulton, Christopher Q Huynh, Anna G Figueroa, Gia B Huynh, Li-Ping Liang, Lindsey B Gano, Cole R Michel, Nichole Reisdorph, Richard Reisdorph, Kristofer S Fritz, Eric Verdin, Manisha Patel

Faculty, Staff and Students Publications

Mitochondrial dysfunction is an early event in the pathogenesis of neurologic disorders and aging. Sirtuin 3 (SIRT3) regulates mitochondrial function in response to the cellular environment through the reversible deacetylation of proteins involved in metabolism and reactive oxygen species detoxification. As the primary mitochondrial deacetylase, germline, or peripheral tissue-specific deletion of SIRT3 produces mitochondrial hyperacetylation and the accelerated development of age-related diseases. Given the unique metabolic demands of neurons, the role of SIRT3 in the brain is only beginning to emerge. Using mass spectrometry-based acetylomics, high-resolution respirometry, video-EEG, and cognition testing, we report targeted deletion of SIRT3 from select neurons …

Multifaceted Role For P53 In Pancreatic Cancer Suppression, Stephano S Mello, Brittany M Flowers, Pawel K Mazur, James J Lee, Fabian Müller, Sarah K Denny, Sofia Ferreira, Kathryn Hanson, Seung K Kim, William J Greenleaf, Laura D Wood, Laura D Attardi

Faculty, Staff and Student Publications

The vast majority of human pancreatic ductal adenocarcinomas (PDACs) harbor TP53 mutations, underscoring p53's critical role in PDAC suppression. PDAC can arise when pancreatic acinar cells undergo acinar-to-ductal metaplasia (ADM), giving rise to premalignant pancreatic intraepithelial neoplasias (PanINs), which finally progress to PDAC. The occurrence of TP53 mutations in late-stage PanINs has led to the idea that p53 acts to suppress malignant transformation of PanINs to PDAC. However, the cellular basis for p53 action during PDAC development has not been explored in detail. Here, we leverage a hyperactive p53 variant-p5353,54-which we previously showed is a more robust PDAC suppressor than …

A Comprehensive And Integrative Approach To Mecp2 Disease Transcriptomics, Alexander J Trostle, Lucian Li, Seon-Young Kim, Jiasheng Wang, Rami Al-Ouran, Hari Krishna Yalamanchili, Zhandong Liu, Ying-Wooi Wan

Faculty, Staff and Students Publications

Mutations in MeCP2 result in a crippling neurological disease, but we lack a lucid picture of MeCP2's molecular role. Individual transcriptomic studies yield inconsistent differentially expressed genes. To overcome these issues, we demonstrate a methodology to analyze all modern public data. We obtained relevant raw public transcriptomic data from GEO and ENA, then homogeneously processed it (QC, alignment to reference, differential expression analysis). We present a web portal to interactively access the mouse data, and we discovered a commonly perturbed core set of genes that transcends the limitations of any individual study. We then found functionally distinct, consistently up- and …

A Genetic Locus Complements Resistance To Bordetella Pertussis-Induced Histamine Sensitization., Abbas Raza, Sean A Diehl, Dimitry N Krementsov, Laure K Case, Dawei Li, Jason Kost, Robyn L Ball, Elissa J Chesler, Vivek M. Philip, Rui Huang, Yan Chen, Runlin Ma, Anna L Tyler, J Matthew Mahoney, Elizabeth P Blankenhorn, Cory Teuscher

Faculty Research 2023

Histamine plays pivotal role in normal physiology and dysregulated production of histamine or signaling through histamine receptors (HRH) can promote pathology. Previously, we showed that Bordetella pertussis or pertussis toxin can induce histamine sensitization in laboratory inbred mice and is genetically controlled by Hrh1/HRH1. HRH1 allotypes differ at three amino acid residues with P

The Fly Homolog Of Supt16h, A Gene Associated With Neurodevelopmental Disorders, Is Required In A Cell-Autonomous Fashion For Cell Survival, Mengqi Ma, Xi Zhang, Yiming Zheng, Shenzhao Lu, Xueyang Pan, Xiao Mao, Hongling Pan, Hyung-Lok Chung, Hua Wang, Hong Guo, Hugo J Bellen

Faculty, Staff and Students Publications

SUPT16H encodes the large subunit of the FAcilitate Chromatin Transcription (FACT) complex, which functions as a nucleosome organizer during transcription. We identified two individuals from unrelated families carrying de novo missense variants in SUPT16H. The probands exhibit global developmental delay, intellectual disability, epilepsy, facial dysmorphism and brain structural abnormalities. We used Drosophila to characterize two variants: p.T171I and p.G808R. Loss of the fly ortholog, dre4, causes lethality at an early developmental stage. RNAi-mediated knockdown of dre4 in either glia or neurons causes severely reduced eclosion and longevity. Tissue-specific knockdown of dre4 in the eye or wing leads to the loss …

Heterochronic Parabiosis Causes Dacryoadenitis In Young Lacrimal Glands, Kaitlin K Scholand, Alexis F Mack, Gary U Guzman, Michael E Maniskas, Ritu Sampige, Gowthaman Govindarajan, Louise D Mccullough, Cintia S De Paiva

Faculty, Staff and Student Publications

Aging is associated with inflammation and oxidative stress in the lacrimal gland (LG). We investigated if heterochronic parabiosis of mice could modulate age-related LG alterations. In both males and females, there were significant increases in total immune infiltration in isochronic aged LGs compared to that in isochronic young LGs. Male heterochronic young LGs were significantly more infiltrated compared to male isochronic young LGs. While both females and males had significant increases in inflammatory and B-cell-related transcripts in isochronic and heterochronic aged LGs compared to levels isochronic and heterochronic young LGs, females had a greater fold expression of some of these …

Differences In Startle And Prepulse Inhibition In Contactin-Associated Protein-Like 2 Knock-Out Rats Are Associated With Sex-Specific Alterations In Brainstem Neural Activity, Alice Zheng, Kaela E Scott, Ashley L Schormans, Rajkamalpreet Mann, Brian L Allman, Susanne Schmid

Anatomy and Cell Biology Publications

The contactin-associated protein-like 2 (CNTNAP2) gene encodes for the CASPR2 protein, which plays an essential role in neurodevelopment. Mutations in CNTNAP2 are associated with neurodevelopmental disorders, including autism spectrum disorder and schizophrenia. Rats with a loss of function mutation in the Cntnap2 gene show increased acoustic startle response (ASR) and decreased prepulse inhibition (PPI). The neural basis of this altered auditory processing in Cntnap2 knock-out rats is currently unknown. Auditory brainstem recordings previously revealed no differences between the genotypes. The next step is to investigate brainstem structures outside of the primary auditory pathway that mediate ASR and PPI, which are …

Perivascular Cells Induce Microglial Phagocytic States And Synaptic Engulfment Via Spp1 In Mouse Models Of Alzheimer's Disease., Sebastiaan De Schepper, Judy Z Ge, Gerard Crowley, Laís S S Ferreira, Dylan Garceau, Christina E Toomey, Dimitra Sokolova, Javier Rueda-Carrasco, Sun-Hye Shin, Jung-Seok Kim, Thomas Childs, Tammaryn Lashley, Jemima J Burden, Michael Sasner, Carlo Sala Frigerio, Steffen Jung, Soyon Hong

Faculty Research 2023

Alzheimer's disease (AD) is characterized by synaptic loss, which can result from dysfunctional microglial phagocytosis and complement activation. However, what signals drive aberrant microglia-mediated engulfment of synapses in AD is unclear. Here we report that secreted phosphoprotein 1 (SPP1/osteopontin) is upregulated predominantly by perivascular macrophages and, to a lesser extent, by perivascular fibroblasts. Perivascular SPP1 is required for microglia to engulf synapses and upregulate phagocytic markers including C1qa, Grn and Ctsb in presence of amyloid-β oligomers. Absence of Spp1 expression in AD mouse models results in prevention of synaptic loss. Furthermore, single-cell RNA sequencing and putative cell-cell interaction analyses reveal …

High Sucrose Consumption Decouples Intrinsic And Synaptic Excitability Of Agrp Neurons Without Altering Body Weight., Austin C Korgan, Klausen Oliveira-Abreu, Wei Wei, Sophie L A Martin, Zoey J D Bridges, José Henrique Leal-Cardoso, Catherine Kaczorowski, Kristen M S O'Connell

Faculty Research 2023

BACKGROUND/OBJECTIVE: As the obesity epidemic continues, the understanding of macronutrient influence on central nervous system function is critical for understanding diet-induced obesity and potential therapeutics, particularly in light of the increased sugar content in processed foods. Previous research showed mixed effects of sucrose feeding on body weight gain but has yet to reveal insight into the impact of sucrose on hypothalamic functioning. Here, we explore the impact of liquid sucrose feeding for 12 weeks on body weight, body composition, caloric intake, and hypothalamic AgRP neuronal function and synaptic plasticity.

METHODS: Patch-clamp electrophysiology of hypothalamic AgRP neurons, metabolic phenotyping and food …

Genetic Mapping Of Microbial And Host Traits Reveals Production Of Immunomodulatory Lipids By Akkermansia Muciniphila In The Murine Gut., Qijun Zhang, Vanessa Linke, Katherine A Overmyer, Lindsay L Traeger, Kazuyuki Kasahara, Ian J Miller, Daniel E Manson, Thomas J Polaske, Robert L Kerby, Julia H Kemis, Edna A Trujillo, Thiru R Reddy, Jason D Russell, Kathryn L Schueler, Donald S Stapleton, Mary E Rabaglia, Marcus Seldin, Daniel M Gatti, Gregory R Keele, Duy T Pham, Joseph P Gerdt, Eugenio I Vivas, Aldons J Lusis, Mark P Keller, Gary Churchill, Helen E Blackwell, Karl W Broman, Alan D Attie, Joshua J Coon, Federico E Rey

Faculty Research 2023

The molecular bases of how host genetic variation impacts the gut microbiome remain largely unknown. Here we used a genetically diverse mouse population and applied systems genetics strategies to identify interactions between host and microbe phenotypes including microbial functions, using faecal metagenomics, small intestinal transcripts and caecal lipids that influence microbe-host dynamics. Quantitative trait locus (QTL) mapping identified murine genomic regions associated with variations in bacterial taxa; bacterial functions including motility, sporulation and lipopolysaccharide production and levels of bacterial- and host-derived lipids. We found overlapping QTL for the abundance of Akkermansia muciniphila and caecal levels of ornithine lipids. Follow-up in …

Macrophage-Derived Mlkl In Alcohol-Associated Liver Disease: Regulation Of Phagocytosis, Xiaoqin Wu, Xiude Fan, Megan R Mcmullen, Tatsunori Miyata, Adam Kim, Vai Pathak, Jianguo Wu, Le Z Day, Josiah E Hardesty, Nicole Welch, Jaividhya Dasarathy, Daniela S Allende, Arthur J Mccullough, Jon M Jacobs, Daniel M Rotroff, Srinivasan Dasarathy, Laura E Nagy

Faculty, Staff and Student Publications

BACKGROUND AND AIMS: Mixed lineage kinase domain-like pseudokinase (MLKL), a key terminal effector of necroptosis, also plays a role in intracellular vesicle trafficking that is critical for regulating liver inflammation and injury in alcohol-associated liver disease (ALD). Although receptor interacting protein kinase 3 (Rip3)-/- mice are completely protected from ethanol-induced liver injury, Mlkl-/- mice are only partially protected. Therefore, we hypothesized that cell-specific functions of MLKL may contribute to ethanol-induced injury.

APPROACH AND RESULTS: Bone marrow transplants between Mlkl-/- mice and littermates were conducted to distinguish the role of myeloid versus nonmyeloid Mlkl in the Gao-binge model of ALD. Ethanol-induced …

A Potent And Broad Neutralization Of Sars-Cov-2 Variants Of Concern By Darpins, Vikas Chonira, Young D Kwon, Jason Gorman, James Brett Case, Zhiqiang Ku, Rudo Simeon, Ryan G Casner, Darcy R Harris, Adam S Olia, Tyler Stephens, Lawrence Shapiro, Michael F Bender, Hannah Boyd, I-Ting Teng, Yaroslav Tsybovsky, Florian Krammer, Ningyan Zhang, Michael S Diamond, Peter D Kwong, Zhiqiang An, Zhilei Chen

Faculty, Staff and Student Publications

We report the engineering and selection of two synthetic proteins-FSR16m and FSR22-for the possible treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. FSR16m and FSR22 are trimeric proteins composed of DARPin SR16m or SR22 fused with a T4 foldon. Despite selection by a spike protein from a now historical SARS-CoV-2 strain, FSR16m and FSR22 exhibit broad-spectrum neutralization of SARS-CoV-2 strains, inhibiting authentic B.1.351, B.1.617.2 and BA.1.1 viruses, with respective IC

Endotrophin Neutralization Through Targeted Antibody Treatment Protects From Renal Fibrosis In A Podocyte Ablation Model, Yu A An, Wei Xiong, Shiuhwei Chen, Dawei Bu, Joseph M Rutkowski, Joel P Berger, Christine M Kusminski, Ningyan Zhang, Zhiqiang An, Philipp E Scherer

Faculty, Staff and Student Publications

OBJECTIVE: Renal fibrosis is a hallmark for chronic kidney disease (CKD), and often leads to end stage renal disease (ESRD). However, limited interventions are available clinically to ameliorate or reverse renal fibrosis.

METHODS: Herein, we evaluated whether blockade of endotrophin through neutralizing antibodies protects from renal fibrosis in the podocyte insult model (the "POD-ATTAC" mouse). We determined the therapeutic effects of endotrophin targeted antibody through assessing renal function, renal inflammation and fibrosis at histological and transcriptional levels, and podocyte regeneration.

RESULTS: We demonstrated that neutralizing endotrophin antibody treatment significantly ameliorates renal fibrosis at the transcriptional, morphological, and functional levels. In …

Persistent Nociceptor Hyperactivity As A Painful Evolutionary Adaptation, Edgar T Walters, Robyn J Crook, G Gregory Neely, Theodore J Price, Ewan St John Smith

Faculty, Staff and Student Publications

Chronic pain caused by injury or disease of the nervous system (neuropathic pain) has been linked to persistent electrical hyperactivity of the sensory neurons (nociceptors) specialized to detect damaging stimuli and/or inflammation. This pain and hyperactivity are considered maladaptive because both can persist long after injured tissues have healed and inflammation has resolved. While the assumption of maladaptiveness is appropriate in many diseases, accumulating evidence from diverse species, including humans, challenges the assumption that neuropathic pain and persistent nociceptor hyperactivity are always maladaptive. We review studies indicating that persistent nociceptor hyperactivity has undergone evolutionary selection in widespread, albeit selected, animal …

Dysregulated Amino Acid Sensing Drives Colorectal Cancer Growth And Metabolic Reprogramming Leading To Chemoresistance, Sumeet Solanki, Katherine Sanchez, Varun Ponnusamy, Vasudha Kota, Hannah N Bell, Chun-Seok Cho, Allison H Kowalsky, Michael Green, Jun Hee Lee, Yatrik M Shah

Faculty, Staff and Student Publications

BACKGROUND & AIMS: Colorectal cancer (CRC) is a devastating disease that is highly modulated by dietary nutrients. Mechanistic target of rapamycin complex 1 (mTORC1) contributes to tumor growth and limits therapy responses. Growth factor signaling is a major mechanism of mTORC1 activation. However, compensatory pathways exist to sustain mTORC1 activity after therapies that target oncogenic growth factor signaling. Amino acids potently activate mTORC1 via amino acid-sensing GTPase activity towards Rags (GATOR). The role of amino acid-sensing pathways in CRC is unclear.

METHODS: Human colon cancer cell lines, preclinical intestinal epithelial-specific GATOR1 and GATOR2 knockout mice subjected to colitis-induced or sporadic …

Highly Synchronized Cortical Circuit Dynamics Mediate Spontaneous Pain In Mice, Weihua Ding, Lukas Fischer, Qian Chen, Ziyi Li, Liuyue Yang, Zerong You, Kun Hu, Xinbo Wu, Xue Zhou, Wei Chao, Peter Hu, Tewodros Mulugeta Dagnew, Daniel M Dubreuil, Shiyu Wang, Suyun Xia, Caroline Bao, Shengmei Zhu, Lucy Chen, Changning Wang, Brian Wainger, Peng Jin, Jianren Mao, Guoping Feng, Mark T Harnett, Shiqian Shen

Faculty, Staff and Student Publications

Cortical neural dynamics mediate information processing for the cerebral cortex, which is implicated in fundamental biological processes such as vision and olfaction, in addition to neurological and psychiatric diseases. Spontaneous pain is a key feature of human neuropathic pain. Whether spontaneous pain pushes the cortical network into an aberrant state and, if so, whether it can be brought back to a "normal" operating range to ameliorate pain are unknown. Using a clinically relevant mouse model of neuropathic pain with spontaneous pain-like behavior, we report that orofacial spontaneous pain activated a specific area within the primary somatosensory cortex (S1), displaying synchronized …

Trpv4 Functional Status In Cystic Cells Regulates Cystogenesis In Autosomal Recessive Polycystic Kidney Disease During Variations In Dietary Potassium, Kyrylo Pyrshev, Anna Stavniichuk, Viktor N Tomilin, Naghmeh Hassanzadeh Khayyat, Guohui Ren, Mariya Kordysh, Oleg Zaika, Mykola Mamenko, Oleh Pochynyuk

Faculty, Staff and Student Publications

Mechanosensitive TRPV4 channel plays a dominant role in maintaining [Ca2+] i homeostasis and flow‐sensitive [Ca2+] i signaling in the renal tubule. Polycystic kidney disease (PKD) manifests as progressive cyst growth due to cAMP‐dependent fluid secretion along with deficient mechanosensitivity and impaired TRPV4 activity. Here, we tested how regulation of renal TRPV4 function by dietary K+ intake modulates the rate of cystogenesis and mechanosensitive [Ca2+] i signaling in cystic cells of PCK453 rats, a homologous model of human autosomal recessive PKD (ARPKD). One month treatment with both high KCl (5% K+) and KB/C (5% K+ with bicarbonate/citrate) diets significantly increased TRPV4 …

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 …

The Microbiome And Its Impact On Allogeneic Hematopoietic Cell Transplantation, Florent Malard, Robert R Jenq

Faculty, Staff and Student Publications

Allogeneic hematopoietic cell transplantation (alloHCT) is a standard curative therapy for a variety of benign and malignant hematological diseases. Previously, patients who underwent alloHCT were at high risk for complications with potentially life-threatening toxicities, including a variety of opportunistic infections as well as acute and chronic manifestations of graft-versus-host disease (GVHD), where the transplanted immune system can produce inflammatory damage to the patient. With recent advances, including newer conditioning regimens, advances in viral and fungal infection prophylaxis, and novel GVHD prophylactic and treatment strategies, improvements in clinical outcomes have steadily improved. One modality with great potential that has yet to …

Effect Of Sirolimus On Insulin Dynamics In Horses, Demia J De Tonnerre, Carlos E Medina Torres, Darko Stefanovski, Mary A Robinson, Kate L Kemp, François-René Bertin, Andrew W Van Eps

Faculty, Staff and Student Publications

BACKGROUND: Sirolimus, a mechanistic target of rapamycin inhibitor, suppresses insulin production in other species and has therapeutic potential for hyperinsulinemia in horses.

HYPOTHESIS/OBJECTIVE: Determine the pharmacokinetics (PKs) of sirolimus and evaluate its effect on insulin dynamics in healthy and insulin dysregulation (ID) horses.

ANIMALS: Eight Standardbred geldings.

METHODS: A PK study was performed followed by a placebo-controlled, randomized, crossover study. Blood sirolimus concentrations were measured by liquid chromatography-mass-spectrometry. PK indices were estimated by fitting a 2-compartment model using nonlinear least squares regression. An oral glucose test (OGT) was conducted before and 4, 24, 72, and 144 hours after administration of …

Linoleic Acid Improves Piezo2 Dysfunction In A Mouse Model Of Angelman Syndrome, Luis O Romero, Rebeca Caires, A Kaitlyn Victor, Juanma Ramirez, Francisco J Sierra-Valdez, Patrick Walsh, Vincent Truong, Jungsoo Lee, Ugo Mayor, Lawrence T Reiter, Valeria Vásquez, Julio F Cordero-Morales

Faculty, Staff and Student Publications

Angelman syndrome (AS) is a neurogenetic disorder characterized by intellectual disability and atypical behaviors. AS results from loss of expression of the E3 ubiquitin-protein ligase UBE3A from the maternal allele in neurons. Individuals with AS display impaired coordination, poor balance, and gait ataxia. PIEZO2 is a mechanosensitive ion channel essential for coordination and balance. Here, we report that PIEZO2 activity is reduced in Ube3a deficient male and female mouse sensory neurons, a human Merkel cell carcinoma cell line and female human iPSC-derived sensory neurons with UBE3A knock-down, and de-identified stem cell-derived neurons from individuals with AS. We find that loss …

Disruption Of Gcn2 Pathway Aggravates Vascular And Parenchymal Remodeling During Pulmonary Fibrosis, Diana Santos-Ribeiro, Marylène Lecocq, Michèle De Beukelaer, Stijn Verleden, Caroline Bouzin, Jérôme Ambroise, Peter Dorfmuller, Yousef Yakoub, François Huaux, Rozenn Quarck, Harry Karmouty-Quintana, Maria-Rosa Ghigna, Juliette Bignard, Sophie Nadaud, Florent Soubrier, Sandrine Horman, Frederic Perros, Laurent Godinas, Charles Pilette

Faculty, Staff and Student Publications

Pulmonary fibrosis (PF) and pulmonary hypertension (PH) are chronic diseases of the pulmonary parenchyma and circulation, respectively, which may coexist, but underlying mechanisms remain elusive. Mutations in the GCN2 (general control nonderepressible 2) gene (EIF2AK4 [eukaryotic translation initiation factor 2 alpha kinase 4]) were recently associated with pulmonary veno-occlusive disease. The aim of this study is to explore the involvement of the GCN2/eIF2α (eukaryotic initiation factor 2α) pathway in the development of PH during PF, in both human disease and in a laboratory animal model. Lung tissue from patients with PF with or without PH was collected at the …