Digital Commons Network^™

A Bayesian Model Selection Approach To Mediation Analysis., Wesley L Crouse, Gregory R Keele, Madeleine S Gastonguay, Gary Churchill, William Valdar

Faculty Research 2022

Genetic studies often seek to establish a causal chain of events originating from genetic variation through to molecular and clinical phenotypes. When multiple phenotypes share a common genetic association, one phenotype may act as an intermediate for the genetic effects on the other. Alternatively, the phenotypes may be causally unrelated but share genetic loci. Mediation analysis represents a class of causal inference approaches used to determine which of these scenarios is most plausible. We have developed a general approach to mediation analysis based on Bayesian model selection and have implemented it in an R package, bmediatR. Bayesian model selection provides …

Genome-Wide Transcript And Protein Analysis Highlights The Role Of Protein Homeostasis In The Aging Mouse Heart., Isabela Gerdes Gyuricza, Joel M Chick, Gregory R Keele, Andrew Deighan, Steven C. Munger, Ron Korstanje, Steven P Gygi, Gary Churchill

Faculty Research 2022

Investigation of the molecular mechanisms of aging in the human heart is challenging because of confounding factors, such as diet and medications, as well as limited access to tissues from healthy aging individuals. The laboratory mouse provides an ideal model to study aging in healthy individuals in a controlled environment. However, previous mouse studies have examined only a narrow range of the genetic variation that shapes individual differences during aging. Here, we analyze transcriptome and proteome data from 185 genetically diverse male and female mice at ages 6, 12, and 18 mo to characterize molecular changes that occur in the …

Suppression Of Microrna 124–3p And Microrna 340–5p Ameliorates Retinoic Acid-Induced Cleft Palate In Mice, Hiroki Yoshioka, Akiko Suzuki, Chihiro Iwaya, Junichi Iwata

Faculty, Staff and Student Publications

The etiology of cleft lip with or without cleft palate (CL/P), a common congenital birth defect, is complex, with genetic and epigenetic, as well as environmental, contributing factors. Recent studies suggest that fetal development is affected by maternal conditions through microRNAs (miRNAs), a group of short noncoding RNAs. Here, we show that miR-129-5p and miR-340-5p suppress cell proliferation in both primary mouse embryonic palatal mesenchymal cells and O9-1 cells, a neural crest cell line, through the regulation of Sox5 and Trp53 by miR-129-5p, and the regulation of Chd7, Fign and Tgfbr1 by miR-340-5p. Notably, miR-340-5p, but not miR-129-5p, was upregulated …

Extracellular Vesicles Released After Cranial Radiation: An Insight Into An Early Mechanism Of Brain Injury., Suriyan Sukati, Jenni Ho, Luksana Chaiswing, Pradoldej Sompol, Harshul Pandit, Wendy Wei, Tadahide Izumi, Quan Chen, Heidi Weiss, Teresa Noel, Subbarao Bondada, D Allan Butterfield, Daret K St Clair

Microbiology, Immunology, and Molecular Genetics Faculty Publications

Cranial radiation is important for treating both primary brain tumors and brain metastases. A potential delayed side effect of cranial radiation is neurocognitive function decline. Early detection of CNS injury might prevent further neuronal damage. Extracellular vesicles (EVs) have emerged as a potential diagnostic tool because of their unique membranous characteristics and cargos. We investigated whether EVs can be an early indicator of CNS injury by giving C57BJ/6 mice 10 Gy cranial IR. EVs were isolated from sera to quantify: 1) number of EVs using nanoparticle tracking analysis (NTA); 2) Glial fibrillary acidic protein (GFAP), an astrocyte marker; and 3) …

The Disordered N-Terminal Domain Of Dnmt3a Recognizes H2ak119ub And Is Required For Postnatal Development, Tianpeng Gu, Dapeng Hao, Junsung Woo, Teng-Wei Huang, Lei Guo, Xueqiu Lin, Anna G Guzman, Ayala Tovy, Carina Rosas, Mira Jeong, Yubin Zhou, Benjamin Deneen, Yun Huang, Wei Li, Margaret A Goodell

Faculty, Staff and Students Publications

DNA methyltransferase 3a (DNMT3A) plays a crucial role during mammalian development. Two isoforms of DNMT3A are differentially expressed from stem cells to somatic tissues, but their individual functions remain largely uncharacterized. Here we report that the long isoform DNMT3A1, but not the short DNMT3A2, is essential for mouse postnatal development. DNMT3A1 binds to and regulates bivalent neurodevelopmental genes in the brain. Strikingly, Dnmt3a1 knockout perinatal lethality could be partially rescued by DNMT3A1 restoration in the nervous system. We further show that the intrinsically disordered N terminus of DNMT3A1 is required for normal development and DNA methylation at DNMT3A1-enriched regions. Mechanistically, …

Mitochondrial Sirtuin-3 (Sirt3) Prevents Doxorubicin-Induced Dilated Cardiomyopathy By Modulating Protein Acetylation And Oxidative Stress, Mateusz M Tomczyk, Kyle G Cheung, Bo Xiang, Nahid Tamanna, Ana L Fonseca Teixeira, Prasoon Agarwal, Stephanie M Kereliuk, Victor Spicer, Ligen Lin, Jason Treberg, Qiang Tong, Vernon W Dolinsky

Faculty, Staff and Students Publications

BACKGROUND: High doses of doxorubicin put cancer patients at risk for developing dilated cardiomyopathy. Previously, we showed that doxorubicin treatment decreases SIRT3 (sirtuin 3), the main mitochondrial deacetylase and increases protein acetylation in rat cardiomyocytes. Here, we hypothesize that SIRT3 expression can attenuate doxorubicin induced dilated cardiomyopathy in vivo by preventing the acetylation of mitochondrial proteins.

METHODS: Nontransgenic, M3-SIRT3 (truncated SIRT3; short isoform), and M1-SIRT3 (full-length SIRT3; mitochondrial localized) transgenic mice were treated with doxorubicin for 4 weeks (8 mg/kg body weight per week). Echocardiography was performed to assess cardiac structure and function and validated by immunohistochemistry and immunofluorescence (n=4-10). …

A D2 To D1 Shift In Dopaminergic Inputs To Midbrain 5-Ht Neurons Causes Anorexia In Mice, Xing Cai, Hailan Liu, Bing Feng, Meng Yu, Yang He, Hesong Liu, Chen Liang, Yongjie Yang, Longlong Tu, Nan Zhang, Lina Wang, Na Yin, Junying Han, Zili Yan, Chunmei Wang, Pingwen Xu, Qi Wu, Qingchun Tong, Yanlin He, Yong Xu

Faculty, Staff and Students Publications

Midbrain dopamine (DA) and serotonin (5-HT) neurons regulate motivated behaviors, including feeding, but less is known about how these circuits may interact. In this study, we found that DA neurons in the mouse ventral tegmental area bidirectionally regulate the activity of 5-HT neurons in the dorsal raphe nucleus (DRN), with weaker stimulation causing DRD2-dependent inhibition and overeating, while stronger stimulation causing DRD1-dependent activation and anorexia. Furthermore, in the activity-based anorexia (ABA) paradigm, which is a mouse model mimicking some clinical features of human anorexia nervosa (AN), we observed a DRD2 to DRD1 shift of DA neurotransmission on 5-HT

Whole Exome Sequencing Identifies Potential Candidate Genes For Spina Bifida Derived From Mouse Models, Chunyan Wang, Steve Seltzsam, Bixia Zheng, Chen-Han Wilfred Wu, Camille Nicolas-Frank, Kirollos Yousef, Kit Sing Au, Nina Mann, Dalia Pantel, Sophia Schneider, Luca Schierbaum, Thomas M Kitzler, Dervla M Connaughton, Youying Mao, Rufeng Dai, Makiko Nakayama, Jameela A Kari, Sherif El Desoky, Mohammed Shalaby, Loai A Eid, Hazem S Awad, Velibor Tasic, Shrikant M Mane, Richard P Lifton, Michelle A Baum, Shirlee Shril, Carlos R Estrada, Friedhelm Hildebrandt

Faculty, Staff and Student Publications

Spina bifida (SB) is the second most common nonlethal congenital malformation. The existence of monogenic SB mouse models and human monogenic syndromes with SB features indicate that human SB may be caused by monogenic genes. We hypothesized that whole exome sequencing (WES) allows identification of potential candidate genes by (i) generating a list of 136 candidate genes for SB, and (ii) by unbiased exome-wide analysis. We generated a list of 136 potential candidate genes from three categories and evaluated WES data of 50 unrelated SB cases for likely deleterious variants in 136 potential candidate genes, and for potential SB candidate …

Targeting The Notch1-Myc-Cd44 Axis In Leukemia-Initiating Cells In T-All, Sujan Piya, Yaling Yang, Seemana Bhattacharya, Priyanka Sharma, Huaxian Ma, Hong Mu, Hua He, Vivian Ruvolo, Natalia Baran, R Eric Davis, Abhinav K Jain, Marina Konopleava, Hagop Kantarjian, Michael Andreeff, M James You, Gautam Borthakur

Faculty, Staff and Student Publications

The NOTCH1-MYC-CD44 axis integrates cell-intrinsic and extrinsic signaling to ensure the persistence of leukemia-initiating cells (LICs) in T-cell acute lymphoblastic leukemia (T-ALL) but a common pathway to target this circuit is poorly defined. Bromodomain-containing protein 4 (BRD4) is implicated to have a role in the transcriptional regulation of oncogenes MYC and targets downstream of NOTCH1, and here we demonstrate its role in transcriptional regulation of CD44. Hence, targeting BRD4 will dismantle the NOTCH1-MYC-CD44 axis. As a proof of concept, degrading BRD4 with proteolysis targeting chimera (PROTAC) ARV-825, prolonged the survival of mice in Notch1 mutated patient-derived xenograft (PDX) and genetic …

Free Cholesterol Bioavailability And Atherosclerosis, Rei J Abe, Jun-Ichi Abe, Minh T H Nguyen, Elizabeth A Olmsted-Davis, Abrar Mamun, Priyanka Banerjee, John P Cooke, Longhou Fang, Henry Pownall, Nhat-Tu Le

Faculty, Staff and Student Publications

Purpose of review: As both a cholesterol acceptor and carrier in the reverse cholesterol transport (RCT) pathway, high-density lipoprotein (HDL) is putatively atheroprotective. However, current pharmacological therapies to increase plasma HDL cholesterol (HDL-c) concentration have paradoxically failed to prevent or reduce atherosclerosis and cardiovascular disease (CVD). Given that free cholesterol (FC) transfer between surfaces of lipoproteins and cells is reversible, excess plasma FC can be transferred to the cells of peripheral tissue sites resulting in atherosclerosis. Here, we summarize potential mechanisms contributing to this paradox and highlight the role of excess free cholesterol (FC) bioavailability in atherosclerosis vs. atheroprotection.

Recent …

The Microrna-183/96/182 Cluster Inhibits Lung Cancer Progression And Metastasis By Inducing An Interleukin-2-Mediated Antitumor Cd8+ Cytotoxic T-Cell Response, Samrat T Kundu, B Leticia Rodriguez, Laura A Gibson, Amanda N Warner, Mabel G Perez, Rakhee Bajaj, Jared J Fradette, Caleb A Class, Luisa M Solis, Frank R Rojas Alvarez, Ignacio I Wistuba, Lixia Diao, Fengju Chen, Mohit Sachdeva, Jing Wang, David G Kirsch, Chad J Creighton, Don L Gibbons

Faculty, Staff and Student Publications

Here, Kundu et al. investigated the role of the microRNA-183/96/182 cluster (m96cl) in lung cancer and used a novel conditional m96cl mouse to establish that loss of m96cl accelerated the growth of K-Ras mutant autochthonous lung adenocarcinomas. Overall, the authors identified a novel mechanistic role of the m96cl in the suppression of lung cancer growth and metastasis by inducing an IL2-mediated systemic CD8+ CTL immune response.

Berberine Remodels Adipose Tissue To Attenuate Metabolic Disorders By Activating Sirtuin 3, Dan Li, Chao Yang, Jian-Zhong Zhu, Eduardo Lopez, Tian Zhang, Qiang Tong, Cheng Peng, Li-Gen Lin

Faculty, Staff and Students Publications

Adipose tissue remodelling is considered a critical pathophysiological hallmark of obesity and related metabolic diseases. Berberine (BBR), a natural isoquinoline alkaloid, has potent anti-hyperlipidaemic and anti-hyperglycaemic effects. This study aimed to explore the role of BBR in modulating adipose tissue remodelling and the underlying mechanisms. BBR protected high fat diet (HFD)-fed mice against adiposity, insulin resistance and hyperlipidemia. BBR alleviated adipose tissue inflammation and fibrosis by inhibiting macrophage infiltration, pro-inflammatory macrophage polarization and the abnormal deposition of extracellular matrix, and the effect was mediated by BBR directly binding and activating the deacetylase Sirtuin 3 (SIRT3) and suppressing the activation of …

Phgdh Heterogeneity Potentiates Cancer Cell Dissemination And Metastasis, Matteo Rossi, Patricia Altea-Manzano, Margherita Demicco, Ginevra Doglioni, Laura Bornes, Marina Fukano, Anke Vandekeere, Alejandro M Cuadros, Juan Fernández-García, Carla Riera-Domingo, Cristina Jauset, Mélanie Planque, H Furkan Alkan, David Nittner, Dongmei Zuo, Lindsay A Broadfield, Sweta Parik, Antonino Alejandro Pane, Francesca Rizzollo, Gianmarco Rinaldi, Tao Zhang, Shao Thing Teoh, Arin B Aurora, Panagiotis Karras, Ines Vermeire, Dorien Broekaert, Joke Van Elsen, Maximilian M L Knott, Martin F Orth, Sofie Demeyer, Guy Eelen, Lacey E Dobrolecki, Ayse Bassez, Thomas Van Brussel, Karl Sotlar, Michael T Lewis, Harald Bartsch, Manfred Wuhrer, Peter Van Veelen, Peter Carmeliet, Jan Cools, Sean J Morrison, Jean-Christophe Marine, Diether Lambrechts, Massimiliano Mazzone, Gregory J Hannon, Sophia Y Lunt, Thomas G P Grünewald, Morag Park, Jacco Van Rheenen, Sarah-Maria Fendt

Faculty, Staff and Students Publications

Cancer metastasis requires the transient activation of cellular programs enabling dissemination and seeding in distant organs1. Genetic, transcriptional and translational heterogeneity contributes to this dynamic process2,3. Metabolic heterogeneity has also been observed4, yet its role in cancer progression is less explored. Here, we discover that loss of phosphoglycerate dehydrogenase (PHGDH) potentiates metastatic dissemination. Specifically, we find that heterogeneous or low PHGDH expression in primary tumors of breast cancer patients is associated with decreased metastasis free survival time. In mice, circulating tumor cells and early metastatic lesions are enriched with PHGDH low cancer …

Evaluation Of Biochemical And Pathological Parameters At Different Doses Of Cisplatin In Experimental Animal Model: Toxicological Study On An Antineoplastic Drug, Farhana Sultana, Muhammed Mohibul Islam, Mohammad Nurul Amin, Nusrat Jahan, Asma Kabir, Talha Bin Emran, Bibek Chandra Sutradhar, Sujan Banik

Makara Journal of Health Research

Background: This study aimed to assess the effect of cisplatin-induced toxicities on biochemical and pathological parameters such as body, liver, and kidney weights, blood urea nitrogen (BUN), creatinine, alanine aminotransferase (ALT), and blood cells (RBCs and WBCs) in white Swiss albino mice.

Methods: Cisplatin’s potential toxic effects on body, liver, and kidney weights were evaluated using standard laboratory methods. Blood biochemical levels such as BUN, creatinine, and ALT levels were determined by an auto-hemolyzer using commercial diagnostic kits. Blood cells (RBCs and WBCs) were counted under a microscope by a hemocytometer.

Results: Cisplatin’s potential toxic effects on …

Targeting Cd123 In Blastic Plasmacytoid Dendritic Cell Neoplasm Using Allogeneic Anti-Cd123 Car T Cells, Tianyu Cai, Agnès Gouble, Kathryn L Black, Anna Skwarska, Ammar S Naqvi, Deanne Taylor, Ming Zhao, Qi Yuan, Mayumi Sugita, Qi Zhang, Roman Galetto, Stéphanie Filipe, Antonio Cavazos, Lina Han, Vinitha Kuruvilla, Helen Ma, Connie Weng, Chang-Gong Liu, Xiuping Liu, Sergej Konoplev, Jun Gu, Guilin Tang, Xiaoping Su, Gheath Al-Atrash, Stefan Ciurea, Sattva S Neelapu, Andrew A Lane, Hagop Kantarjian, Monica L Guzman, Naveen Pemmaraju, Julianne Smith, Andrei Thomas-Tikhonenko, Marina Konopleva

Faculty, Staff and Student Publications

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy with poor outcomes with conventional therapy. Nearly 100% of BPDCNs overexpress interleukin 3 receptor subunit alpha (CD123). Given that CD123 is differentially expressed on the surface of BPDCN cells, it has emerged as an attractive therapeutic target. UCART123 is an investigational product consisting of allogeneic T cells expressing an anti-CD123 chimeric antigen receptor (CAR), edited with TALEN

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 …

A Periplasmic Cinched Protein Is Required For Siderophore Secretion And Virulence Of Mycobacterium Tuberculosis., Lei Zhang, James E Kent, Meredith Whitaker, David C Young, Dominik Herrmann, Alexander E Aleshin, Ying-Hui Ko, Gino Cingolani, Jamil S Saad, D Branch Moody, Francesca M Marassi, Sabine Ehrt, Michael Niederweis

Department of Biochemistry and Molecular Biology Faculty Papers

Iron is essential for growth of Mycobacterium tuberculosis, the causative agent of tuberculosis. To acquire iron from the host, M. tuberculosis uses the siderophores called mycobactins and carboxymycobactins. Here, we show that the rv0455c gene is essential for M. tuberculosis to grow in low-iron medium and that secretion of both mycobactins and carboxymycobactins is drastically reduced in the rv0455c deletion mutant. Both water-soluble and membrane-anchored Rv0455c are functional in siderophore secretion, supporting an intracellular role. Lack of Rv0455c results in siderophore toxicity, a phenotype observed for other siderophore secretion mutants, and severely impairs replication of M. tuberculosis in mice, demonstrating …

Silencing Alanine Transaminase 2 In Diabetic Liver Attenuates Hyperglycemia By Reducing Gluconeogenesis From Amino Acids, Michael R. Martino, Manuel Gutiérrez-Aguilar, Nicole K. H. Yiew, Andrew J. Lutkewitte, Jason M. Singer, Kyle S. Mccommis, Daniel Ferguson, Kim H. H. Liss, Jun Yoshino, M. Katie Renkemeyer, Gordon I. Smith, Kevin Cho, Justin A. Fletcher, Samuel Klein, Gary J. Patti, Shawn C. Burgess, Brian N. Finck

2020-Current year OA Pubs

Hepatic gluconeogenesis from amino acids contributes significantly to diabetic hyperglycemia, but the molecular mechanisms involved are incompletely understood. Alanine transaminases (ALT1 and ALT2) catalyze the interconversion of alanine and pyruvate, which is required for gluconeogenesis from alanine. We find that ALT2 is overexpressed in the liver of diet-induced obese and db/db mice and that the expression of the gene encoding ALT2 (GPT2) is downregulated following bariatric surgery in people with obesity. The increased hepatic expression of Gpt2 in db/db liver is mediated by activating transcription factor 4, an endoplasmic reticulum stress-activated transcription factor. Hepatocyte-specific knockout of Gpt2 attenuates incorporation of

The Girl Who Wouldn't Brush Her Hair, Karen Abbott

Children's Book and Media Review

A young girl washes her hair but refuses to brush it, because that's just how she is. A mouse sets up a roost in her tangles and she enjoys his company. Then there are two mice, then three, then one hundred. Living with so many mice is getting complex, but she makes it work. When teacher finally tells her she has broken the rule of one companion at nap time and must leave her beloved doll at home, our heroine is inspired. Kindly evicting the furry inhabitants, she finally washes her hair again. This time she brushes it out, because …

A Somatic Mutation In Moesin Drives Progression Into Acute Myeloid Leukemia, Ouyang Yuan, Jeffrey A Magee, Et Al.

Open Access Publications

Acute myeloid leukemia (AML) arises when leukemia-initiating cells, defined by a primary genetic lesion, acquire subsequent molecular changes whose cumulative effects bypass tumor suppression. The changes that underlie AML pathogenesis not only provide insights into the biology of transformation but also reveal novel therapeutic opportunities. However, backtracking these events in transformed human AML samples is challenging, if at all possible. Here, we approached this question using a murine in vivo model with an MLL-ENL fusion protein as a primary molecular event. Upon clonal transformation, we identified and extensively verified a recurrent codon-changing mutation (Arg

Reduction Of Mutant Atxn1 Rescues Premature Death In A Conditional Sca1 Mouse Model, James P Orengo, Larissa Nitschke, Meike E Van Der Heijden, Nicholas A Ciaburri, Harry T Orr, Huda Y Zoghbi

Duncan NRI Faculty and Staff Publications

Spinocerebellar ataxia type 1 (SCA1) is an adult-onset neurodegenerative disorder. As disease progresses, motor neurons are affected, and their dysfunction contributes toward the inability to maintain proper respiratory function, a major driving force for premature death in SCA1. To investigate the isolated role of motor neurons in SCA1, we created a conditional SCA1 (cSCA1) mouse model. This model suppresses expression of the pathogenic SCA1 allele with a floxed stop cassette. cSCA1 mice crossed to a ubiquitous Cre line recapitulate all the major features of the original SCA1 mouse model; however, they took twice as long to develop. We found that …

Murine Respiratory Tract Infection With Classical Klebsiella Pneumoniae Induces Bronchus-Associated Lymphoid Tissue, Rachel K Wasbotten, Aubree A Dahler, Joseph J Mackel, Catherine Morffy Smith, David A Rosen

Open Access Publications

Klebsiella pneumoniae is a Gram-negative, opportunistic pathogen that commonly causes nosocomial pneumonia, urinary tract infection, and septicemia. Our recent work utilizing a murine model of respiratory tract infection with classical K. pneumoniae demonstrated leukocyte aggregates in the lungs of mice at 28 days postinfection. Here, we sought to characterize the composition and development of these structures. Histopathological analyses of murine lungs revealed immune cell clusters surrounding the pulmonary vasculature and airways by 14 days postinfection, resembling inducible bronchus-associated lymphoid tissue (iBALT). Further investigation of these structures demonstrated central B cell aggregates with concomitant dispersed T cells. At day 28 postinfection, …

Preclinical Characterization And Target Validation Of The Antimalarial Pantothenamide Mmv693183., Laura E. De Vries, Patrick A. M. Jansen, Catalina Barcelo, Justin Munro, Julie M. J. Verhoef, Charisse Flerida A. Pasaje, Kelly Rubiano, Josefine Striepen, Nada Abla, Luuk Berning, Judith M. Bolscher, Claudia Demarta-Gatsi, Rob W. M. Henderson, Tonnie Huijs, Karin M J Koolen, Patrick K. Tumwebaze, Tomas Yeo, Anna C. C. Aguiar, Iñigo Angulo-Barturen, Alisje Churchyard, Jake Baum, Benigno Crespo Fernández, Aline Fuchs, Francisco-Javier Gamo, Rafael V. C. Guido, María Belén Jiménez-Diaz, Dhelio B. Pereira, Rosemary Rochford, Camille Roesch, Laura M. Sanz, Graham Trevitt, Benoit Witkowski, Sergio Wittlin, Roland A. Cooper, Philip J. Rosenthal, Robert W. Sauerwein, Joost Schalkwijk, Pedro H. H. Hermkens, Roger V. Bonnert, Brice Campo, David A. Fidock, Manuel Llinás, Jacquin C. Niles, Taco W. A. Kooij, Koen J. Dechering

Natural Sciences and Mathematics | Faculty Scholarship

Drug resistance and a dire lack of transmission-blocking antimalarials hamper malaria elimination. Here, we present the pantothenamide MMV693183 as a first-in-class acetyl-CoA synthetase (AcAS) inhibitor to enter preclinical development. Our studies demonstrate attractive drug-like properties and in vivo efficacy in a humanized mouse model of Plasmodium falciparum infection. The compound shows single digit nanomolar in vitro activity against P. falciparum and P. vivax clinical isolates, and potently blocks P. falciparum transmission to Anopheles mosquitoes. Genetic and biochemical studies identify AcAS as the target of the MMV693183-derived antimetabolite, CoA-MMV693183. Pharmacokinetic-pharmacodynamic modelling predict that a single 30 mg oral dose is sufficient …

Cross-Reactive Antibodies Elicited To Conserved Epitopes On Sars-Cov-2 Spike Protein After Infection And Vaccination., Eric S. Geanes, Cas Lemaster, Elizabeth Fraley, Santosh Khanal, Rebecca Mclennan, Elin Grundberg, Rangaraj Selvarangan, Todd Bradley

Manuscripts, Articles, Book Chapters and Other Papers

SARS-CoV-2 is a novel betacoronavirus that caused coronavirus disease 2019 and has resulted in millions of deaths worldwide. Novel coronavirus infections in humans have steadily become more common. Understanding antibody responses to SARS-CoV-2, and identifying conserved, cross-reactive epitopes among coronavirus strains could inform the design of vaccines and therapeutics with broad application. Here, we determined that individuals with previous SARS-CoV-2 infection or vaccinated with the Pfizer-BioNTech BNT162b2 vaccine produced antibody responses that cross-reacted with related betacoronaviruses. Moreover, we designed a peptide-conjugate vaccine with a conserved SARS-CoV-2 S2 spike epitope, immunized mice and determined cross-reactive antibody binding to SARS-CoV-2 and other …

Dynamics Of Huntingtin Protein Interactions In The Striatum Identifies Candidate Modifiers Of Huntington Disease, Todd M Greco, Christopher Secker, Eduardo Silva Ramos, Joel D Federspiel, Jeh-Ping Liu, Alma M Perez, Ismael Al-Ramahi, Jeffrey P Cantle, Jeffrey B Carroll, Juan Botas, Scott O Zeitlin, Erich E Wanker, Ileana M Cristea

Duncan NRI Faculty and Staff Publications

Huntington’s disease (HD) is a monogenic neurodegenerative disorder with one causative gene, huntingtin (HTT). Yet, HD pathobiology is multifactorial, suggesting that cellular factors influence disease progression. Here, we define HTT protein-protein interactions (PPIs) perturbed by the mutant protein with expanded polyglutamine in the mouse striatum, a brain region with selective HD vulnerability. Using metabolically labeled tissues and immunoaffinity purification-mass spectrometry, we establish that polyglutamine-dependent modulation of HTT PPI abundances and relative stability starts at an early stage of pathogenesis in a Q140 HD mouse model. We identify direct and indirect PPIs that are also genetic disease modifiers using in-cell two-hybrid …

Safety And Efficacy Of Systemic Anti-Scg3 Therapy To Treat Oxygen-Induced Retinopathy, Chang Dai, Hong Tian, Amit Bhatt, Guanfang Su, Keith A Webster, Wei Li

Faculty, Staff and Students Publications

BACKGROUND: To circumvent possible systemic side effects, anti-angiogenic drugs targeting vascular endothelial growth factor (VEGF) for ocular neovascular diseases in adults are approved only for intravitreal administration. However, intravitreal injection itself can elicit injection-related adverse effects, and premature eyes of infants with retinopathy of prematurity (ROP) may be particularly susceptible to intravitreal injection. Therefore, an unmet clinical need is to develop safe systemic anti-angiogenic therapies for ROP. We recently reported that secretogranin III (Scg3) is a disease-restricted angiogenic factor and that systemic anti-Scg3 mAb alleviates ROP in animal models with minimal side effects on developing eyes and organs. The aim …

Ror Activation By Nobiletin Enhances Antitumor Efficacy Via Suppression Of Iκb/Nf-Κb Signaling In Triple-Negative Breast Cancer, Eunju Kim, Yoon-Jin Kim, Zhiwei Ji, Jin Muk Kang, Marvin Wirianto, Keshav Raj Paudel, Joshua A Smith, Kaori Ono, Jin-Ah Kim, Kristin Eckel-Mahan, Xiaobo Zhou, Hyun Kyoung Lee, Ji Young Yoo, Seung-Hee Yoo, Zheng Chen

Faculty, Staff and Student Publications

Triple-negative breast cancer (TNBC) is a heterogeneous disease characterized by poor response to standard therapies and therefore unfavorable clinical outcomes. Better understanding of TNBC and new therapeutic strategies are urgently needed. ROR nuclear receptors are multifunctional transcription factors with important roles in circadian pathways and other processes including immunity and tumorigenesis. Nobiletin (NOB) is a natural compound known to display anticancer effects, and our previous studies showed that NOB activates RORs to enhance circadian rhythms and promote physiological fitness in mice. Here, we identified several TNBC cell lines being sensitive to NOB, by itself or in combination. Cell and xenograft …

Safety And Efficacy Of Systemic Anti-Scg3 Therapy To Treat Oxygen-Induced Retinopathy, Chang Dai, Hong Tian, Amit Bhatt, Guanfang Su, Keith A Webster, Wei Li

Faculty, Staff and Students Publications

BACKGROUND: To circumvent possible systemic side effects, anti-angiogenic drugs targeting vascular endothelial growth factor (VEGF) for ocular neovascular diseases in adults are approved only for intravitreal administration. However, intravitreal injection itself can elicit injection-related adverse effects, and premature eyes of infants with retinopathy of prematurity (ROP) may be particularly susceptible to intravitreal injection. Therefore, an unmet clinical need is to develop safe systemic anti-angiogenic therapies for ROP. We recently reported that secretogranin III (Scg3) is a disease-restricted angiogenic factor and that systemic anti-Scg3 mAb alleviates ROP in animal models with minimal side effects on developing eyes and organs. The aim …

Time Dependent Analysis Of Rat Microglial Surface Markers In Traumatic Brain Injury Reveals Dynamics Of Distinct Cell Subpopulations, Assaf Gottlieb, Naama Toledano-Furman, Karthik S Prabhakara, Akshita Kumar, Henry W Caplan, Supinder Bedi, Charles S Cox, Scott D Olson

Faculty, Staff and Student Publications

Traumatic brain injury (TBI) results in a cascade of cellular responses, which produce neuroinflammation, partly due to the activation of microglia. Accurate identification of microglial populations is key to understanding therapeutic approaches that modify microglial responses to TBI and improve long-term outcome measures. Notably, previous studies often utilized an outdated convention to describe microglial phenotypes. We conducted a temporal analysis of the response to controlled cortical impact (CCI) in rat microglia between ipsilateral and contralateral hemispheres across seven time points, identified microglia through expression of activation markers including CD45, CD11b/c, and p2y12 receptor and evaluated their activation state using additional …

Cs1 Car-T Targeting The Distal Domain Of Cs1 (Slamf7) Shows Efficacy In High Tumor Burden Myeloma Model Despite Fratricide Of Cd8+Cs1 Expressing Car-T Cells, Julie O'Neal, Julie K Ritchey, Matthew L Cooper, Jessica Niswonger, L Sofía González, Emily Street, Michael P Rettig, Susan W Gladney, Leah Gehrs, Ramzi Abboud, Julie L Prior, Gabriel J Haas, Reyka G Jayasinghe, Li Ding, Armin Ghobadi, Ravi Vij, John F Dipersio

2020-Current year OA Pubs

Despite improvement in treatment options for myeloma patients, including targeted immunotherapies, multiple myeloma remains a mostly incurable malignancy. High CS1 (SLAMF7) expression on myeloma cells and limited expression on normal cells makes it a promising target for CAR-T therapy. The CS1 protein has two extracellular domains - the distal Variable (V) domain and the proximal Constant 2 (C2) domain. We generated and tested CS1-CAR-T targeting the V domain of CS1 (Luc90-CS1-CAR-T) and demonstrated anti-myeloma killing in vitro and in vivo using two mouse models. Since fratricide of CD8 + cells occurred during production, we generated fratricide resistant CS1 deficient Luc90- …