Digital Commons Network^™

Probiotic Limosilactobacillus Reuteri Dsm 17938 Changes Foxp3 Deficiency-Induced Dyslipidemia And Chronic Hepatitis In Mice, Erini Nessim Kostandy, Ji Ho Suh, Xiangjun Tian, Beanna Okeugo, Erin Rubin, Sara Shirai, Meng Luo, Christopher M Taylor, Kang Ho Kim, J Marc Rhoads, Yuying Liu

Faculty, Staff and Student Publications

The probiotic Limosilactobacillus reuteri DSM 17938 produces anti-inflammatory effects in scurfy (SF) mice, a model characterized by immune dysregulation, polyendocrinopathy, enteropathy, and X-linked inheritance (called IPEX syndrome in humans), caused by regulatory T cell (Treg) deficiency and is due to a Foxp3 gene mutation. Considering the pivotal role of lipids in autoimmune inflammatory processes, we investigated alterations in the relative abundance of lipid profiles in SF mice (± treatment with DSM 17938) compared to normal WT mice. We also examined the correlation between plasma lipids and gut microbiota and circulating inflammatory markers. We noted a significant upregulation of plasma lipids …

Circuit-Based Intervention Corrects Excessive Dentate Gyrus Output In The Fragile X Mouse Model, Pan-Yue Deng, Ajeet Kumar, Valeria Cavalli, Vitaly A Klyachko

2020-Current year OA Pubs

Abnormal cellular and circuit excitability is believed to drive many core phenotypes in fragile X syndrome (FXS). The dentate gyrus is a brain area performing critical computations essential for learning and memory. However, little is known about dentate circuit defects and their mechanisms in FXS. Understanding dentate circuit dysfunction in FXS has been complicated by the presence of two types of excitatory neurons, the granule cells and mossy cells. Here we report that loss of FMRP markedly decreased excitability of dentate mossy cells, a change opposite to all other known excitability defects in excitatory neurons in FXS. This mossy cell …

In Vivo Dynamic Volumetric Imaging Of Mouse Testis And Epididymis With Optical Coherence Tomography†, Kohei Umezu, Guzel R Musina, Irina V Larina

Faculty, Staff and Students Publications

The implementation of live imaging in reproductive research is crucial for studying the physiological dynamics. Sperm transport is a highly dynamic process regulated by tubular contractions and luminal flows within the male reproductive tract. However, due to the lack of imaging techniques to capture these dynamics in vivo, there is little information on the physiological and biomechanical regulation of sperm transport through the male reproductive tract. Here, we present a functional in vivo imaging approach using optical coherence tomography, enabling live, label-free, depth-resolved, three-dimensional, high-resolution visualization of the mouse testis and epididymis. With this approach, we spatiotemporally captured tubular contractility …

Srf-Deficient Astrocytes Provide Neuroprotection In Mouse Models Of Excitotoxicity And Neurodegeneration, Surya Chandra Rao Thumu, Monika Jain, Sumitha Soman, Soumen Das, Vijaya Verma, Arnab Nandi, David H Gutmann, Balaji Jayaprakash, Deepak Nair, James P Clement, Swananda Marathe, Narendrakumar Ramanan

2020-Current year OA Pubs

Reactive astrogliosis is a common pathological hallmark of CNS injury, infection, and neurodegeneration, where reactive astrocytes can be protective or detrimental to normal brain functions. Currently, the mechanisms regulating neuroprotective astrocytes and the extent of neuroprotection are poorly understood. Here, we report that conditional deletion of serum response factor (SRF) in adult astrocytes causes reactive-like hypertrophic astrocytes throughout the mouse brain. These

Scaffold Protein Sh3bp2 Signalosome Is Pivotal For Immune Activation In Nephrotic Syndrome., Tarak Srivastava, Robert E. Garola, Jianping Zhou, Varun C. Boinpelly, Mohammad Rezaiekhaligh, Trupti Joshi, Yuexu Jiang, Diba Ebadi, Siddarth Sharma, Christine Sethna, Vincent S. Staggs, Ram Sharma, Debbie S. Gipson, Wei Hao, Yujie Wang, Laura H. Mariani, Jeffrey B. Hodgin, Robert Rottapel, Teruhito Yoshitaka, Yasuyoshi Ueki, Mukut Sharma

Manuscripts, Articles, Book Chapters and Other Papers

Despite clinical use of immunosuppressive agents, the immunopathogenesis of minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) remains unclear. Src homology 3-binding protein 2 (SH3BP2), a scaffold protein, forms an immune signaling complex (signalosome) with 17 other proteins, including phospholipase Cγ2 (PLCγ2) and Rho-guanine nucleotide exchange factor VAV2 (VAV2). Bioinformatic analysis of human glomerular transcriptome (Nephrotic Syndrome Study Network cohort) revealed upregulated SH3BP2 in MCD and FSGS. The SH3BP2 signalosome score and downstream MyD88, TRIF, and NFATc1 were significantly upregulated in MCD and FSGS. Immune pathway activation scores for Toll-like receptors, cytokine-cytokine receptor, and NOD-like receptors were increased in …

Immunoglobulin Replacement Products Protect Against Sars-Cov-2 Infection In Vivo Despite Poor Neutralizing Activity, Ofer Zimmerman, Alexa Michelle Altman Doss, Baoling Ying, Chieh-Yu Liang, Samantha R. Mackin, Hannah G. Davis-Adams, Lucas J. Adams, Laura A. Vanblargan, Rita E. Chen, Suzanne M. Scheaffer, Pritesh Desai, Saravanan Raju, Tarisa L. Mantia, Caitlin C. O'Shaughnessy, Jennifer Marie Monroy, H. James Wedner, Christopher J. Rigell, Andrew L. Kau, Tiffany Biason Dy, Zhen Ren, Jackson S. Turner, Jane A. O'Halloran, Rachel M. Presti, Peggy L. Kendall, Daved H. Fremont, Ali H. Ellebedy, Michael S Diamond

2020-Current year OA Pubs

Immunoglobulin (IG) replacement products are used routinely in patients with immune deficiency and other immune dysregulation disorders who have poor responses to vaccination and require passive immunity conferred by commercial antibody products. The binding, neutralizing, and protective activity of intravenously administered IG against SARS-CoV-2 emerging variants remains unknown. Here, we tested 198 different IG products manufactured from December 2019 to August 2022. We show that prepandemic IG had no appreciable cross-reactivity or neutralizing activity against SARS-CoV-2. Anti-spike antibody titers and neutralizing activity against SARS-CoV-2 WA1/2020 D614G increased gradually after the pandemic started and reached levels comparable to vaccinated healthy donors …

Genomemuster Mouse Genetic Variation Service Enables Multitrait, Multipopulation Data Integration And Analysis., Robyn L Ball, Molly A. Bogue, Hongping Liang, Anuj Srivastava, David G Ashbrook, Anna Lamoureux, Matthew Gerring, Alexander S Hatoum, Matthew J Kim, Hao He, Jake Emerson, Alexander Berger, David O Walton, Keith Sheppard, Baha El Kassaby, Francisco Castellanos, Govindarajan Kunde-Ramamoorthy, Lu Lu, John Bluis, Sejal Desai, Beth A. Sundberg, Gary Peltz, Zhuoqing Fang, Gary Churchill, Robert W Williams, Arpana Agrawal, Carol J Bult, Vivek M. Philip, Elissa J Chesler

Faculty Research 2024

Hundreds of inbred mouse strains and intercross populations have been used to characterize the function of genetic variants that contribute to disease. Thousands of disease-relevant traits have been characterized in mice and made publicly available. New strains and populations including consomics, the collaborative cross, expanded BXD, and inbred wild-derived strains add to existing complex disease mouse models, mapping populations, and sensitized backgrounds for engineered mutations. The genome sequences of inbred strains, along with dense genotypes from others, enable integrated analysis of trait-variant associations across populations, but these analyses are hampered by the sparsity of genotypes available. Moreover, the data are …

Aspscr1-Tfe3 Reprograms Transcription By Organizing Enhancer Loops Around Hexameric Vcp/P97, Amir Pozner, Li Li, Shiv Prakash Verma, Shuxin Wang, Jared J Barrott, Mary L Nelson, Jamie S E Yu, Gian Luca Negri, Shane Colborne, Christopher S Hughes, Ju-Fen Zhu, Sydney L Lambert, Lara S Carroll, Kyllie Smith-Fry, Michael G Stewart, Sarmishta Kannan, Bodrie Jensen, Cini M John, Saif Sikdar, Hongrui Liu, Ngoc Ha Dang, Jennifer Bourdage, Jinxiu Li, Jeffery M Vahrenkamp, Katelyn L Mortenson, John S Groundland, Rosanna Wustrack, Donna L Senger, Franz J Zemp, Douglas J Mahoney, Jason Gertz, Xiaoyang Zhang, Alexander J Lazar, Martin Hirst, Gregg B Morin, Torsten O Nielsen, Peter S Shen, Kevin B Jones

Faculty, Staff and Student Publications

The t(X,17) chromosomal translocation, generating the ASPSCR1::TFE3 fusion oncoprotein, is the singular genetic driver of alveolar soft part sarcoma (ASPS) and some Xp11-rearranged renal cell carcinomas (RCCs), frustrating efforts to identify therapeutic targets for these rare cancers. Here, proteomic analysis identifies VCP/p97, an AAA+ ATPase with known segregase function, as strongly enriched in co-immunoprecipitated nuclear complexes with ASPSCR1::TFE3. We demonstrate that VCP is a likely obligate co-factor of ASPSCR1::TFE3, one of the only such fusion oncoprotein co-factors identified in cancer biology. Specifically, VCP co-distributes with ASPSCR1::TFE3 across chromatin in association with enhancers genome-wide. VCP presence, its hexameric assembly, and its …

Genomemuster Mouse Genetic Variation Service Enables Multitrait, Multipopulation Data Integration And Analysis, Robyn L Ball, Alexander S Hatoum, Arpana Agrawal, Et Al.

2020-Current year OA Pubs

Hundreds of inbred mouse strains and intercross populations have been used to characterize the function of genetic variants that contribute to disease. Thousands of disease-relevant traits have been characterized in mice and made publicly available. New strains and populations including consomics, the collaborative cross, expanded BXD, and inbred wild-derived strains add to existing complex disease mouse models, mapping populations, and sensitized backgrounds for engineered mutations. The genome sequences of inbred strains, along with dense genotypes from others, enable integrated analysis of trait-variant associations across populations, but these analyses are hampered by the sparsity of genotypes available. Moreover, the data are …

An Excitatory Projection From The Basal Forebrain To The Ventral Tegmental Area That Underlies Anorexia-Like Phenotypes, Jing Cai, Yanyan Jiang, Yuanzhong Xu, Zhiying Jiang, Claire Young, Hongli Li, Joshua Ortiz-Guzman, Yizhou Zhuo, Yulong Li, Yong Xu, Benjamin R Arenkiel, Qingchun Tong

Faculty, Staff and Students Publications

Maladaptation in balancing internal energy needs and external threat cues may result in eating disorders. However, brain mechanisms underlying such maladaptations remain elusive. Here, we identified that the basal forebrain (BF) sends glutamatergic projections to glutamatergic neurons in the ventral tegmental area (VTA) in mice. Glutamatergic neurons in both regions displayed correlated responses to various stressors. Notably, in vivo manipulation of BF terminals in the VTA revealed that the glutamatergic BF → VTA circuit reduces appetite, increases locomotion, and elicits avoidance. Consistently, activation of VTA glutamatergic neurons reduced body weight, blunted food motivation, and caused hyperactivity with behavioral signs of …

Longitudinal Single-Cell Transcriptional Dynamics Throughout Neurodegeneration In Sca1, Leon Tejwani, Neal G Ravindra, Changwoo Lee, Yubao Cheng, Billy Nguyen, Kimberly Luttik, Luhan Ni, Shupei Zhang, Logan M Morrison, John Gionco, Yangfei Xiang, Jennifer Yoon, Hannah Ro, Fatema Haidery, Rosalie M Grijalva, Eunwoo Bae, Kristen Kim, Regina T Martuscello, Harry T Orr, Huda Y Zoghbi, Hayley S Mcloughlin, Laura P W Ranum, Vikram G Shakkottai, Phyllis L Faust, Siyuan Wang, David Van Dijk, Janghoo Lim

Duncan NRI Faculty and Staff Publications

Neurodegeneration is a protracted process involving progressive changes in myriad cell types that ultimately results in the death of vulnerable neuronal populations. To dissect how individual cell types within a heterogeneous tissue contribute to the pathogenesis and progression of a neurodegenerative disorder, we performed longitudinal single-nucleus RNA sequencing of mouse and human spinocerebellar ataxia type 1 (SCA1) cerebellar tissue, establishing continuous dynamic trajectories of each cell population. Importantly, we defined the precise transcriptional changes that precede loss of Purkinje cells and, for the first time, identified robust early transcriptional dysregulation in unipolar brush cells and oligodendroglia. Finally, we applied a …

A Cre-Dependent Reporter Mouse For Quantitative Real-Time Imaging Of Protein Kinase A Activity Dynamics, Elizabeth I Tilden, Aditi Maduskar, Anna Oldenborg, Bernardo L Sabatini, Yao Chen

2020-Current year OA Pubs

Intracellular signaling dynamics play a crucial role in cell function. Protein kinase A (PKA) is a key signaling molecule that has diverse functions, from regulating metabolism and brain activity to guiding development and cancer progression. We previously developed an optical reporter, FLIM-AKAR, that allows for quantitative imaging of PKA activity via fluorescence lifetime imaging microscopy and photometry. However, using viral infection or electroporation for the delivery of FLIM-AKAR is invasive and results in variable expression. Here, we developed a reporter mouse, FL-AK, which expresses FLIM-AKAR in a Cre-dependent manner from the ROSA26 locus. FL-AK provides robust and consistent expression of …

A Mouse Model To Distinguish Nlrp6-Mediated Inflammasome-Dependent And -Independent Functions, Runzhi Li, Yang Zan, Decai Wang, Xuequn Chen, Anmin Wang, Haoyuan Tan, Guorong Zhang, Siyuan Ding, Chen Shen, Hao Wu, Shu Zhu

2020-Current year OA Pubs

The NOD-like receptor (NLR) family pyrin domain containing 6 (NLRP6) serves as a sensor for microbial dsRNA or lipoteichoic acid (LTA) in intestinal epithelial cells (IECs), and initiating multiple pathways including inflammasome pathway and type I interferon (IFN) pathway, or regulating nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) pathways. NLRP6 can exert its function in both inflammasome-dependent and inflammasome-independent manners. However, there is no tool to distinguish the contribution of individual NLRP6-mediated pathway to the physiology and pathology in vivo. Here, we validated that Arg39 and Trp50 residues in the pyrin domain (PYD) of murine NLRP6 are required for …

Dmhppp1r17 Neurons Regulate Aging And Lifespan In Mice Through Hypothalamic-Adipose Inter-Tissue Communication, Kyohei Tokizane, Cynthia S Brace, Shin-Ichiro Imai

2020-Current year OA Pubs

Recent studies have shown that the hypothalamus functions as a control center of aging in mammals that counteracts age-associated physiological decline through inter-tissue communications. We have identified a key neuronal subpopulation in the dorsomedial hypothalamus (DMH), marked by Ppp1r17 expression (DMH

Chimeric Antigen Receptor Macrophages Target And Resorb Amyloid Plaques, Alexander B. Kim, Qingli Xiao, Ping Yan, Qiuyun Pan, Gaurav Pandey, Susie Grathwohl, Ernesto Gonzales, Isabella Xu, Yoonho Cho, Hans Haecker, Slava Epelman, Abhinav Diwan, Jin-Moo Lee, Carl J Deselm

2020-Current year OA Pubs

Substantial evidence suggests a role for immunotherapy in treating Alzheimer's disease (AD). While the precise pathophysiology of AD is incompletely understood, clinical trials of antibodies targeting aggregated forms of β amyloid (Aβ) have shown that reducing amyloid plaques can mitigate cognitive decline in patients with early-stage AD. Here, we describe what we believe to be a novel approach to target and degrade amyloid plaques by genetically engineering macrophages to express an Aβ-targeting chimeric antigen receptor (CAR-Ms). When injected intrahippocampally, first-generation CAR-Ms have limited persistence and fail to significantly reduce plaque load, which led us to engineer next-generation CAR-Ms that secrete …

Fluvoxamine Inhibits Th1 And Th17 Polarization And Function By Repressing Glycolysis To Attenuate Autoimmune Progression In Type 1 Diabetes, Yuan Zou, Jing Zhang, Fei Sun, Qianqian Xu, Longmin Chen, Xi Luo, Ting Wang, Qing Zhou, Shu Zhang, Fei Xiong, Wen Kong, Ping Yang, Qilin Yu, Shiwei Liu, Cong-Yi Wang

Faculty, Staff and Student Publications

BACKGROUND: Fluvoxamine is one of the selective serotonin reuptake inhibitors (SSRIs) that are regarded as the first-line drugs to manage mental disorders. It has been also recognized with the potential to treat inflammatory diseases and viral infection. However, the effect of fluvoxamine on autoimmune diseases, particularly type 1 diabetes (T1D) and the related cellular and molecular mechanisms, are yet to be addressed.

METHOD: Herein in this report, we treated NOD mice with fluvoxamine for 2 weeks starting from 10-week of age to dissect the impact of fluvoxamine on the prevention of type 1 diabetes. We compared the differences of immune …

Efficacy Of Novel Agents Against Cellular Models Of Familial Platelet Disorder With Myeloid Malignancy (Fpd-Mm), Christopher P Mill, Warren C Fiskus, Courtney D Dinardo, Patrick Reville, John A Davis, Christine E Birdwell, Kaberi Das, Hanxi Hou, Koichi Takahashi, Lauren Flores, Xinjia Ruan, Xiaoping Su, Sanam Loghavi, Joseph D Khoury, Kapil N Bhalla

Faculty, Staff and Student Publications

Germline, mono-allelic mutations in RUNX1 cause familial platelet disorder (RUNX1-FPD) that evolves into myeloid malignancy (FPD-MM): MDS or AML. FPD-MM commonly harbors co-mutations in the second RUNX1 allele and/or other epigenetic regulators. Here we utilized patient-derived (PD) FPD-MM cells and established the first FPD-MM AML cell line (GMR-AML1). GMR-AML1 cells exhibited active super-enhancers of MYB, MYC, BCL2 and CDK6, augmented expressions of c-Myc, c-Myb, EVI1 and PLK1 and surface markers of AML stem cells. In longitudinally studied bone marrow cells from a patient at FPD-MM vs RUNX1-FPD state, we confirmed increased chromatin accessibility and mRNA expressions of MYB, MECOM and …

Aneuploid Embryonic Stem Cells Drive Teratoma Metastasis, Rong Xiao, Deshu Xu, Meili Zhang, Zhanghua Chen, Li Cheng, Songjie Du, Mingfei Lu, Tonghai Zhou, Ruoyan Li, Fan Bai, Yue Huang

Faculty, Staff and Student Publications

Aneuploidy, a deviation of the chromosome number from euploidy, is one of the hallmarks of cancer. High levels of aneuploidy are generally correlated with metastasis and poor prognosis in cancer patients. However, the causality of aneuploidy in cancer metastasis remains to be explored. Here we demonstrate that teratomas derived from aneuploid murine embryonic stem cells (ESCs), but not from isogenic diploid ESCs, disseminated to multiple organs, for which no additional copy number variations were required. Notably, no cancer driver gene mutations were identified in any metastases. Aneuploid circulating teratoma cells were successfully isolated from peripheral blood and showed high capacities …

Aducanumab Anti-Amyloid Immunotherapy Induces Sustained Microglial And Immune Alterations, Mika P Cadiz, Katelin A Gibson, Kennedi T Todd, David G Nascari, Nashali Massa, Meredith T Lilley, Kimberly C Olney, Md Mamun Al-Amin, Hong Jiang, David M Holtzman, John D Fryer

2020-Current year OA Pubs

Aducanumab, an anti-amyloid immunotherapy for Alzheimer's disease, efficiently reduces Aβ, though its plaque clearance mechanisms, long-term effects, and effects of discontinuation are not fully understood. We assessed the effect of aducanumab treatment and withdrawal on Aβ, neuritic dystrophy, astrocytes, and microglia in the APP/PS1 amyloid mouse model. We found that reductions in amyloid and neuritic dystrophy during acute treatment were accompanied by microglial and astrocytic activation, and microglial recruitment to plaques and adoption of an aducanumab-specific pro-phagocytic and pro-degradation transcriptomic signature, indicating a role for microglia in aducanumab-mediated Aβ clearance. Reductions in Aβ and dystrophy were sustained 15 but not …

Gestational Diabetes Augments Group B Streptococcus Infection By Disrupting Maternal Immunity And The Vaginal Microbiota, Vicki Mercado-Evans, Marlyd E Mejia, Jacob J Zulk, Samantha Ottinger, Zainab A Hameed, Camille Serchejian, Madelynn G Marunde, Clare M Robertson, Mallory B Ballard, Simone H Ruano, Natalia Korotkova, Anthony R Flores, Kathleen A Pennington, Kathryn A Patras

Faculty, Staff and Student Publications

Group B Streptococcus (GBS) is a pervasive perinatal pathogen, yet factors driving GBS dissemination in utero are poorly defined. Gestational diabetes mellitus (GDM), a complication marked by dysregulated immunity and maternal microbial dysbiosis, increases risk for GBS perinatal disease. Using a murine GDM model of GBS colonization and perinatal transmission, we find that GDM mice display greater GBS in utero dissemination and subsequently worse neonatal outcomes. Dual-RNA sequencing reveals differential GBS adaptation to the GDM reproductive tract, including a putative glycosyltransferase (yfhO), and altered host responses. GDM immune disruptions include reduced uterine natural killer cell activation, impaired recruitment to placentae, …

Nlgn4x Tcr Transgenic T Cells To Treat Gliomas., Christoper Krämer, Michael Kilian, Yu-Chan Chih, Alexandros Kourtesakis, Dirk C Hoffmann, Tamara Boschert, Philipp Koopmann, Khwab Sanghvi, Alice De Roia, Stefanie Jung, Kristine Jähne, Bryan Day, Leonard D. Shultz, Miriam Ratliff, Richard Harbottle, Edward W Green, Rainer Will, Wolfgang Wick, Michael Platten, Lukas Bunse

Faculty Research 2024

BACKGROUND: Neuroligin 4 X-linked (NLGN4X) harbors a human leukocyte antigen (HLA)-A*02-restricted tumor-associated antigen, overexpressed in human gliomas, that was found to induce specific cytotoxic T cell responses following multi-peptide vaccination in patients with newly diagnosed glioblastoma.

METHODS: T cell receptor (TCR) discovery was performed using droplet-based single-cell TCR sequencing of NLGN4X-tetramer-sorted T cells postvaccination. The identified TCR was delivered to Jurkat T cells and primary human T cells (NLGN4X-TCR-T). Functional profiling of NLGN4X-TCR-T was performed by flow cytometry and cytotoxicity assays. Therapeutic efficacy of intracerebroventricular NLGN4X-TCR-T was assessed in NOD scid gamma (NSG) major histocompatibility complex (MHC) I/II knockout (KO) …

Targeting Alk Averts Ribonuclease 1-Induced Immunosuppression And Enhances Antitumor Immunity In Hepatocellular Carcinoma, Chunxiao Liu, Chenhao Zhou, Weiya Xia, Yifan Zhou, Yufan Qiu, Jialei Weng, Qiang Zhou, Wanyong Chen, Ying-Nai Wang, Heng-Huan Lee, Shao-Chun Wang, Ming Kuang, Dihua Yu, Ning Ren, Mien-Chie Hung

Faculty, Staff and Student Publications

Tumor-secreted factors contribute to the development of a microenvironment that facilitates the escape of cancer cells from immunotherapy. In this study, we conduct a retrospective comparison of the proteins secreted by hepatocellular carcinoma (HCC) cells in responders and non-responders among a cohort of ten patients who received Nivolumab (anti-PD-1 antibody). Our findings indicate that non-responders have a high abundance of secreted RNase1, which is associated with a poor prognosis in various cancer types. Furthermore, mice implanted with HCC cells that overexpress RNase1 exhibit immunosuppressive tumor microenvironments and diminished response to anti-PD-1 therapy. RNase1 induces the polarization of macrophages towards a …

Tumor-Specific Polycistronic Mirna Delivered By Engineered Exosomes For The Treatment Of Glioblastoma, Malcolm F Mcdonald, Anwar Hossain, Eric N Momin, Irtiza Hasan, Sanjay Singh, Satoshi Adachi, Joy Gumin, Daniel Ledbetter, Jing Yang, Lihong Long, Marc Daou, Sricharan Gopakumar, Lynette M Phillips, Brittany Parker Kerrigan, Frederick F Lang

Faculty, Staff and Student Publications

Background: Glioblastoma (GBM) has poor prognosis due to ineffective agents and poor delivery methods. MicroRNAs (miRs) have been explored as novel therapeutics for GBM, but the optimal miRs and the ideal delivery strategy remain unresolved. In this study, we sought to identify the most effective pan-subtype anti-GBM miRs and to develop an improved delivery system for these miRs.

Methods: We conducted an unbiased screen of over 600 miRs against 7 glioma stem cell (GSC) lines representing all GBM subtypes to identify a set of pan-subtype-specific anti-GBM miRs and then used available TCGA GBM patient outcomes and miR expression data to …

Targeting Prostate Tumor Low-Molecular Weight Tyrosine Phosphatase For Oxidation-Sensitizing Therapy, Stephanie M Stanford, Tiffany P Nguyen, Joseph Chang, Zixuan Zhao, G Lavender Hackman, Eugenio Santelli, Colton M Sanders, Madhusudhanarao Katiki, Eleonora Dondossola, Brooke L Brauer, Michael A Diaz, Yuan Zhan, Sterling H Ramsey, Philip A Watson, Banumathi Sankaran, Claudia Paindelli, Vanessa Parietti, Antonios G Mikos, Alessia Lodi, Aditya Bagrodia, Andrew Elliott, Rana R Mckay, Ramachandran Murali, Stefano Tiziani, Arminja N Kettenbach, Nunzio Bottini

Faculty, Staff and Student Publications

Protein tyrosine phosphatases (PTPs) play major roles in cancer and are emerging as therapeutic targets. Recent reports suggest low-molecular weight PTP (LMPTP)-encoded by the ACP1 gene-is overexpressed in prostate tumors. We found ACP1 up-regulated in human prostate tumors and ACP1 expression inversely correlated with overall survival. Using CRISPR-Cas9-generated LMPTP knockout C4-2B and MyC-CaP cells, we identified LMPTP as a critical promoter of prostate cancer (PCa) growth and bone metastasis. Through metabolomics, we found that LMPTP promotes PCa cell glutathione synthesis by dephosphorylating glutathione synthetase on inhibitory Tyr270. PCa cells lacking LMPTP showed reduced glutathione, enhanced activation of eukaryotic initiation factor …

Rapid And Accurate Remethylation Of Dna In Dnmt3a- Deficient Hematopoietic Cells With Restoration Of Dnmt3a Activity, Yang Li, Haley J Abel, Michelle Cai, Taylor A Lavalle, Tiankai Yin, Nichole M Helton, Amanda M Smith, Christopher A Miller, Timothy J Ley

2020-Current year OA Pubs

Here, we characterize the DNA methylation phenotypes of bone marrow cells from mice with hematopoietic deficiency of

Brain Injury Drives Optic Glioma Formation Through Neuron-Glia Signaling, Jit Chatterjee, Joshua P Koleske, Astoria Chao, Andrew D Sauerbeck, Ji-Kang Chen, Xuanhe Qi, Megan Ouyang, Lucy G Boggs, Rujuta Idate, Lara Isabel Marco Y Marquez, Terrence T Kummer, David H Gutmann

2020-Current year OA Pubs

Tissue injury and tumorigenesis share many cellular and molecular features, including immune cell (T cells, monocytes) infiltration and inflammatory factor (cytokines, chemokines) elaboration. Their common pathobiology raises the intriguing possibility that brain injury could create a tissue microenvironment permissive for tumor formation. Leveraging several murine models of the Neurofibromatosis type 1 (NF1) cancer predisposition syndrome and two experimental methods of brain injury, we demonstrate that both optic nerve crush and diffuse traumatic brain injury induce optic glioma (OPG) formation in mice harboring Nf1-deficient preneoplastic progenitors. We further elucidate the underlying molecular and cellular mechanisms, whereby glutamate released from damaged neurons …

A Comparative Biochemical And Pathological Evaluation Of Brain Samples From Knock-In Murine Models Of Gaucher Disease, Makaila L Furderer, Bahafta Berhe, Tiffany C Chen, Stephen Wincovitch, Xuntian Jiang, Nahid Tayebi, Ellen Sidransky, Tae-Un Han

2020-Current year OA Pubs

Gaucher disease (GD) is a lysosomal storage disorder stemming from biallelic mutations in

A Single-Cell Time-Lapse Of Mouse Prenatal Development From Gastrula To Birth., Chengxiang Qiu, Beth K Martin, Ian C Welsh, Riza M Daza, Truc-Mai Le, Xingfan Huang, Eva K Nichols, Megan L Taylor, Olivia Fulton, Diana R O'Day, Anne Roshella Gomes, Saskia Ilcisin, Sanjay Srivatsan, Xinxian Deng, Christine M Disteche, William Stafford Noble, Nobuhiko Hamazaki, Cecilia B Moens, David Kimelman, Junyue Cao, Alexander F Schier, Malte Spielmann, Stephen A Murray, Cole Trapnell, Jay Shendure

Faculty Research 2024

The house mouse (Mus musculus) is an exceptional model system, combining genetic tractability with close evolutionary affinity to humans1,2 . Mouse gestation lasts only 3 weeks, during which the genome orchestrates the astonishing transformation of a single-cell zygote into a free-living pup composed of more than 500 million cells. Here, to establish a global framework for exploring mammalian development, we applied optimized single-cell combinatorial indexing3 to profile the transcriptional states of 12.4 million nuclei from 83 embryos, precisely staged at 2- to 6-hour intervals spanning late gastrulation (embryonic day 8) to birth (postnatal day 0). From these data, we annotate …

Astaxanthin And Meclizine Extend Lifespan In Um-Het3 Male Mice; Fisetin, Sg1002 (Hydrogen Sulfide Donor), Dimethyl Fumarate, Mycophenolic Acid, And 4-Phenylbutyrate Do Not Significantly Affect Lifespan In Either Sex At The Doses And Schedules Used., David E Harrison, Randy Strong, Peter C. Reifsnyder, Nadia Rosenthal, Ron Korstanje, Elizabeth Fernandez, Kevin Flurkey, Brett C Ginsburg, Meredith D Murrell, Martin A Javors, Marisa Lopez-Cruzan, James F Nelson, Bradley J Willcox, Richard Allsopp, David M Watumull, David G Watumull, Gino Cortopassi, James L Kirkland, Tamar Tchkonia, Young Geun Choi, Matthew J Yousefzadeh, Paul D Robbins, James R Mitchell, Murat Acar, Ethan A Sarnoski, Michael R Bene, Adam Salmon, Navasuja Kumar, Richard A Miller

Faculty Research 2024

In genetically heterogeneous (UM-HET3) mice produced by the CByB6F1 × C3D2F1 cross, the Nrf2 activator astaxanthin (Asta) extended the median male lifespan by 12% (p = 0.003, log-rank test), while meclizine (Mec), an mTORC1 inhibitor, extended the male lifespan by 8% (p = 0.03). Asta was fed at 1840 ± 520 (9) ppm and Mec at 544 ± 48 (9) ppm, stated as mean ± SE (n) of independent diet preparations. Both were started at 12 months of age. The 90th percentile lifespan for both treatments was extended in absolute value by 6% in males, but neither was significant by …

Transcriptional And Functional Consequences Of Oncostatin M Signaling On Young Dnmt3a-Mutant Hematopoietic Stem Cells., Logan S Schwartz, Kira Young, Timothy M Stearns, Nathan Boyer, Kristina D Mujica, Jennifer J. Trowbridge

Faculty Research 2024

Age-associated clonal hematopoiesis (CH) occurs due to somatic mutations accrued in hematopoietic stem cells (HSCs) that confer a selective growth advantage in the context of aging. The mechanisms by which CH-mutant HSCs gain this advantage with aging are not comprehensively understood. Using unbiased transcriptomic approaches, we identified Oncostatin M (OSM) signaling as a candidate contributor to age-related Dnmt3a-mutant CH. We found that Dnmt3a-mutant HSCs from young adult mice (3-6 months old) subjected to acute OSM stimulation do not demonstrate altered proliferation, apoptosis, hematopoietic engraftment, or myeloid differentiation. Dnmt3a-mutant HSCs from young mice do transcriptionally upregulate an inflammatory cytokine network in …