Digital Commons Network^™

Uncovering Novel Regulators Of Memory Using C Elegans Genetic And Genomic Analysis, Katie L Brandel-Ankrapp, Rachel N Arey

Faculty, Staff and Students Publications

How organisms learn and encode memory is an outstanding question in neuroscience research. Specifically, how memories are acquired and consolidated at the level of molecular and gene pathways remains unclear. In addition, memory is disrupted in a wide variety of neurological disorders; therefore, discovering molecular regulators of memory may reveal therapeutic targets for these disorders. C. elegans are an excellent model to uncover molecular and genetic regulators of memory. Indeed, the nematode's invariant neuronal lineage, fully mapped genome, and conserved associative behaviors have allowed the development of a breadth of genetic and genomic tools to examine learning and memory. In …

Trpv1-Mediated Sonogenetic Neuromodulation Of Motor Cortex In Freely Moving Mice, Kevin Xu, Yaoheng Yang, Zhongtao Hu, Yimei Yue, Yan Gong, Jianmin Cui, Joseph P Culver, Michael R Bruchas, Hong Chen

2020-Current year OA Pubs

No abstract provided.

Mitochondrial Phosphatidylethanolamine Modulates Ucp1 To Promote Brown Adipose Thermogenesis, Jordan M Johnson, Irfan J Lodhi, Et Al.

2020-Current year OA Pubs

Thermogenesis by uncoupling protein 1 (UCP1) is one of the primary mechanisms by which brown adipose tissue (BAT) increases energy expenditure. UCP1 resides in the inner mitochondrial membrane (IMM), where it dissipates membrane potential independent of adenosine triphosphate (ATP) synthase. Here, we provide evidence that phosphatidylethanolamine (PE) modulates UCP1-dependent proton conductance across the IMM to modulate thermogenesis. Mitochondrial lipidomic analyses revealed PE as a signature molecule whose abundance bidirectionally responds to changes in thermogenic burden. Reduction in mitochondrial PE by deletion of phosphatidylserine decarboxylase (PSD) made mice cold intolerant and insensitive to β3 adrenergic receptor agonist-induced increase in whole-body oxygen …

Microrna Profiles In Intestinal Epithelial Cells In A Mouse Model Of Sepsis, Siqingaowa Caidengbate, Yuichi Akama, Anik Banerjee, Khwanchanok Mokmued, Eiji Kawamoto, Arong Gaowa, Louise D Mccullough, Motomu Shimaoka, Juneyoung Lee, Eun Jeong Park

Faculty, Staff and Student Publications

Sepsis is a systemic inflammatory disorder that leads to the dysfunction of multiple organs. In the intestine, the deregulation of the epithelial barrier contributes to the development of sepsis by triggering continuous exposure to harmful factors. However, sepsis-induced epigenetic changes in gene-regulation networks within intestinal epithelial cells (IECs) remain unexplored. In this study, we analyzed the expression profile of microRNAs (miRNAs) in IECs isolated from a mouse model of sepsis generated via cecal slurry injection. Among 239 miRNAs, 14 miRNAs were upregulated, and 9 miRNAs were downregulated in the IECs by sepsis. Upregulated miRNAs in IECs from septic mice, particularly …

Feasibility Of [18f]Fspg Pet For Early Response Assessment To Combined Blockade Of Egfr And Glutamine Metabolism In Wild-Type Kras Colorectal Cancer, Seong-Woo Bae, Jianbo Wang, Dimitra K Georgiou, Xiaoxia Wen, Allison S Cohen, Ling Geng, Mohammed Noor Tantawy, H Charles Manning

Faculty, Staff and Student Publications

Early response assessment is critical for personalizing cancer therapy. Emerging therapeutic regimens with encouraging results in the wild-type (WT) KRAS colorectal cancer (CRC) setting include inhibitors of epidermal growth factor receptor (EGFR) and glutaminolysis. Towards predicting clinical outcome, this preclinical study evaluated non-invasive positron emission tomography (PET) with (4S)-4-(3-[18F]fluoropropyl)-L-glutamic acid ([18F]FSPG) in treatment-sensitive and treatment-resistant WT KRAS CRC patient-derived xenografts (PDXs). Tumor-bearing mice were imaged with [18F]FSPG PET before and one week following the initiation of treatment with either EGFR-targeted monoclonal antibody (mAb) therapy, glutaminase inhibitor therapy, or the combination. Imaging was correlated with tumor volume and histology. In PDX …

Macroh2a Histone Variants Modulate Enhancer Activity To Repress Oncogenic Programs And Cellular Reprogramming, Wazim Mohammed Ismail, Amelia Mazzone, Flavia G Ghiraldini, Jagneet Kaur, Manvir Bains, Amik Munankarmy, Monique S Bagwell, Stephanie L Safgren, John Moore-Weiss, Marina Buciuc, Lynzie Shimp, Kelsey A Leach, Luis F Duarte, Chandandeep S Nagi, Saul Carcamo, Chi-Yeh Chung, Dan Hasson, Neda Dadgar, Jian Zhong, Jeong-Heon Lee, Fergus J Couch, Alexander Revzin, Tamas Ordog, Emily Bernstein, Alexandre Gaspar-Maia

Faculty, Staff and Students Publications

Considerable efforts have been made to characterize active enhancer elements, which can be annotated by accessible chromatin and H3 lysine 27 acetylation (H3K27ac). However, apart from poised enhancers that are observed in early stages of development and putative silencers, the functional significance of cis-regulatory elements lacking H3K27ac is poorly understood. Here we show that macroH2A histone variants mark a subset of enhancers in normal and cancer cells, which we coined 'macro-Bound Enhancers', that modulate enhancer activity. We find macroH2A variants localized at enhancer elements that are devoid of H3K27ac in a cell type-specific manner, indicating a role for macroH2A at …

Dpc29 Promotes Post-Initiation Mitochondrial Translation In Saccharomyces Cerevisiae, Kyle A. Hubble, Michael F. Henry

Rowan-Virtua School of Osteopathic Medicine Departmental Research

Mitochondrial ribosomes synthesize essential components of the oxidative phosphorylation (OXPHOS) system in a tightly regulated process. In the yeast Saccharomyces cerevisiae, mitochondrial mRNAs require specific translational activators, which orchestrate protein synthesis by recognition of their target gene's 5'-untranslated region (UTR). Most of these yeast genes lack orthologues in mammals, and only one such gene-specific translational activator has been proposed in humans-TACO1. The mechanism by which TACO1 acts is unclear because mammalian mitochondrial mRNAs do not have significant 5'-UTRs, and therefore must promote translation by alternative mechanisms. In this study, we examined the role of the TACO1 orthologue in yeast. We …

Tfeb-Mediated Lysosomal Exocytosis Alleviates High-Fat Diet-Induced Lipotoxicity In The Kidney, Jun Nakamura, Takeshi Yamamoto, Yoshitsugu Takabatake, Tomoko Namba-Hamano, Satoshi Minami, Atsushi Takahashi, Jun Matsuda, Shinsuke Sakai, Hiroaki Yonishi, Shihomi Maeda, Sho Matsui, Isao Matsui, Takayuki Hamano, Masatomo Takahashi, Maiko Goto, Yoshihiro Izumi, Takeshi Bamba, Miwa Sasai, Masahiro Yamamoto, Taiji Matsusaka, Fumio Niimura, Motoko Yanagita, Shuhei Nakamura, Tamotsu Yoshimori, Andrea Ballabio, Yoshitaka Isaka

Duncan NRI Faculty and Staff Publications

Obesity is a major risk factor for end-stage kidney disease. We previously found that lysosomal dysfunction and impaired autophagic flux contribute to lipotoxicity in obesity-related kidney disease, in both humans and experimental animal models. However, the regulatory factors involved in countering renal lipotoxicity are largely unknown. Here, we found that palmitic acid strongly promoted dephosphorylation and nuclear translocation of transcription factor EB (TFEB) by inhibiting the mechanistic target of rapamycin kinase complex 1 pathway in a Rag GTPase-dependent manner, though these effects gradually diminished after extended treatment. We then investigated the role of TFEB in the pathogenesis of obesity-related kidney …

Alternative Splicing Mediates The Compensatory Upregulation Of Mbnl2 Upon Mbnl1 Loss-Of-Function, Larissa Nitschke, Rong-Chi Hu, Andrew N Miller, Lathan Lucas, Thomas A Cooper

Faculty, Staff and Students Publications

Loss of gene function can be compensated by paralogs with redundant functions. An example of such compensation are the paralogs of the Muscleblind-Like (MBNL) family of RNA-binding proteins that are sequestered and lose their function in Myotonic Dystrophy Type 1 (DM1). Loss of MBNL1 increases the levels of its paralog MBNL2 in tissues where Mbnl2 expression is low, allowing MBNL2 to functionally compensate for MBNL1 loss. Here, we show that loss of MBNL1 increases the inclusion of Mbnl2 exon 6 and exon 9. We find that inclusion of Mbnl2 exon 6 increases the translocation of MBNL2 to the nucleus, while …

Setd2 Regulates Chromatin Accessibility And Transcription To Suppress Lung Tumorigenesis, Yuchen Xie, Merve Sahin, Toru Wakamatsu, Akane Inoue-Yamauchi, Wanming Zhao, Song Han, Amrita M. Nargund, Shaoyuan Yang, Yang Lyu, James J. Hsieh, Christina S. Leslie, Emily H. Cheng

2020-Current year OA Pubs

SETD2, a H3K36 trimethyltransferase, is the most frequently mutated epigenetic modifier in lung adenocarcinoma, with a mutation frequency of approximately 9%. However, how SETD2 loss of function promotes tumorigenesis remains unclear. Using conditional Setd2-KO mice, we demonstrated that Setd2 deficiency accelerated the initiation of KrasG12D-driven lung tumorigenesis, increased tumor burden, and significantly reduced mouse survival. An integrated chromatin accessibility and transcriptome analysis revealed a potentially novel tumor suppressor model of SETD2 in which SETD2 loss activates intronic enhancers to drive oncogenic transcriptional output, including the KRAS transcriptional signature and PRC2-repressed targets, through regulation of chromatin accessibility and histone chaperone recruitment. …

Ccl17 Protects Against Viral Myocarditis By Suppressing The Recruitment Of Regulatory T Cells, Guoshuai Feng, Cuige Zhu, Chieh-Yu Lin, Andrea Bredemeyer, Irmgard Förster, Daniel Kreisel, Kory J Lavine

2020-Current year OA Pubs

Background Viral myocarditis is characterized by leukocyte infiltration of the heart and cardiomyocyte death. We recently identified C-C chemokine ligand (CCL) 17 as a proinflammatory effector of C-C chemokine receptor 2-positive macrophages and dendritic cells that are recruited to the heart and contribute to adverse left ventricular remodeling following myocardial infarction and pressure overload. Methods and Results Mouse encephalomyocarditis virus was used to investigate the function of CCL17 in a viral myocarditis model.

Lacrimal Gland Epithelial Cells Shape Immune Responses Through The Modulation Of Inflammasomes And Lipid Metabolism, Vanessa Delcroix, Olivier Mauduit, Menglu Yang, Amrita Srivastava, Takeshi Umazume, Cintia S De Paiva, Valery I Shestopalov, Darlene A Dartt, Helen P Makarenkova

Faculty, Staff and Students Publications

Lacrimal gland inflammation triggers dry eye disease through impaired tear secretion by the epithelium. As aberrant inflammasome activation occurs in autoimmune disorders including Sjögren's syndrome, we analyzed the inflammasome pathway during acute and chronic inflammation and investigated its potential regulators. Bacterial infection was mimicked by the intraglandular injection of lipopolysaccharide (LPS) and nigericin, known to activate the NLRP3 inflammasome. Acute injury of the lacrimal gland was induced by interleukin (IL)-1α injection. Chronic inflammation was studied using two Sjögren's syndrome models: diseased

Tcr-Engineered Adoptive Cell Therapy Effectively Treats Intracranial Murine Glioblastoma, Maximilian O. Schaettler, Rupen Desai, Anthony Z. Wang, Alexandra J. Livingstone, Dale K. Kobayashi, Andrew T. Coxon, Jay A. Bowman-Kirigin, Connor J. Liu, Mao Li, Diane E. Bender, Michael J. White, David M. Kranz, Tanner M. Johanns, Gavin P. Dunn

2020-Current year OA Pubs

BACKGROUND: Adoptive cellular therapies with chimeric antigen receptor T cells have revolutionized the treatment of some malignancies but have shown limited efficacy in solid tumors such as glioblastoma and face a scarcity of safe therapeutic targets. As an alternative, T cell receptor (TCR)-engineered cellular therapy against tumor-specific neoantigens has generated significant excitement, but there exist no preclinical systems to rigorously model this approach in glioblastoma.

METHODS: We employed single-cell PCR to isolate a TCR specific for the Imp3

RESULTS: We isolated and characterized the 3×1.1C TCR that displayed a high affinity for mImp3 but no wild-type cross-reactivity. To provide a …

Alternative Polyadenylation Alters Protein Dosage By Switching Between Intronic And 3’Utr Sites, Nicola De Prisco, Caitlin Ford, Nathan D Elrod, Winston Lee, Lauren C Tang, Kai-Lieh Huang, Ai Lin, Ping Ji, Venkata S Jonnakuti, Lia Boyle, Maximilian Cabaj, Salvatore Botta, Katrin Õunap, Karit Reinson, Monica H Wojcik, Jill A Rosenfeld, Weimin Bi, Kristian Tveten, Trine Prescott, Thorsten Gerstner, Audrey Schroeder, Chin-To Fong, Jaya K George-Abraham, Catherine A Buchanan, Andrea Hanson-Khan, Jonathan A Bernstein, Aikaterini A Nella, Wendy K Chung, Vicky Brandt, Marko Jovanovic, Kimara L Targoff, Hari Krishna Yalamanchili, Eric J Wagner, Vincenzo A Gennarino

Faculty, Staff and Students Publications

Alternative polyadenylation (APA) creates distinct transcripts from the same gene by cleaving the pre-mRNA at poly(A) sites that can lie within the 3' untranslated region (3'UTR), introns, or exons. Most studies focus on APA within the 3'UTR; however, here, we show that CPSF6 insufficiency alters protein levels and causes a developmental syndrome by deregulating APA throughout the transcript. In neonatal humans and zebrafish larvae, CPSF6 insufficiency shifts poly(A) site usage between the 3'UTR and internal sites in a pathway-specific manner. Genes associated with neuronal function undergo mostly intronic APA, reducing their expression, while genes associated with heart and skeletal function …

Exploiting Prmt5 As A Target For Combination Therapy In Mantle Cell Lymphoma Characterized By Frequent Atm And Tp53 Mutations, Yuxuan Che, Yang Liu, Yixin Yao, Holly A Hill, Yijing Li, Qingsong Cai, Fangfang Yan, Preetesh Jain, Wei Wang, Lixin Rui, Michael Wang

Faculty, Staff and Student Publications

Constant challenges for the treatment of mantle cell lymphoma (MCL) remain to be recurrent relapses and therapy resistance, especially in patients harboring somatic mutations in the tumor suppressors ATM and TP53, which are accumulated as therapy resistance emerges and the disease progresses, consistent with our OncoPrint results that ATM and TP53 alterations were most frequent in relapsed/refractory (R/R) MCL. We demonstrated that protein arginine methyltransferase-5 (PRMT5) was upregulated in R/R MCL, which predicted a poor prognosis. PRMT5 inhibitors displayed profound antitumor effects in the mouse models of MCL with mutated ATM and/or TP53, or refractory to CD19-targeted CAR T-cell therapy. …

Emergent Dynamics Of Adult Stem Cell Lineages From Single Nucleus And Single Cell Rna-Seq Of Drosophila Testes, Amelie A Raz, Gabriela S Vida, Sarah R Stern, Sharvani Mahadevaraju, Jaclyn M Fingerhut, Jennifer M Viveiros, Soumitra Pal, Jasmine R Grey, Mara R Grace, Cameron W Berry, Hongjie Li, Jasper Janssens, Wouter Saelens, Zhantao Shao, Chun Hu, Yukiko M Yamashita, Teresa Przytycka, Brian Oliver, Julie A Brill, Henry Krause, Erika L Matunis, Helen White-Cooper, Stephen Dinardo, Margaret T Fuller

Faculty, Staff and Students Publications

Proper differentiation of sperm from germline stem cells, essential for production of the next generation, requires dramatic changes in gene expression that drive remodeling of almost all cellular components, from chromatin to organelles to cell shape itself. Here, we provide a single nucleus and single cell RNA-seq resource covering all of spermatogenesis in Drosophila starting from in-depth analysis of adult testis single nucleus RNA-seq (snRNA-seq) data from the Fly Cell Atlas (FCA) study. With over 44,000 nuclei and 6000 cells analyzed, the data provide identification of rare cell types, mapping of intermediate steps in differentiation, and the potential to identify …

Intestinal Neuropod Cell Gucy2c Regulates Visceral Pain, Joshua R. Barton, Annie K. Londregran, Tyler D. Alexander, Ariana A. Entezari, Shely Bar-Ad, Lan Cheng, Angelo C. Lepore, Adam E. Snook, Manuel Covarrubias, Scott A. Waldman

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Visceral pain (VP) is a global problem with complex etiologies and limited therapeutic options. Guanylyl cyclase C (GUCY2C), an intestinal receptor producing cyclic GMP(cGMP), which regulates luminal fluid secretion, has emerged as a therapeutic target for VP. Indeed, FDA-approved GUCY2C agonists ameliorate VP in patients with chronic constipation syndromes, although analgesic mechanisms remain obscure. Here, we revealed that intestinal GUCY2C was selectively enriched in neuropod cells, a type of enteroendocrine cell that synapses with submucosal neurons in mice and humans. GUCY2Chi neuropod cells associated with cocultured dorsal root ganglia neurons and induced hyperexcitability, reducing the rheobase and increasing the resulting …

Developmental Programming: Adverse Sexually Dimorphic Transcriptional Programming Of Gestational Testosterone Excess In Cardiac Left Ventricle Of Fetal Sheep, Venkateswaran Ramamoorthi Elangovan, Nadia Saadat, Adel Ghnenis, Vasantha Padmanabhan, Arpita K Vyas

2020-Current year OA Pubs

Adverse in-utero insults during fetal life alters offspring's developmental trajectory, including that of the cardiovascular system. Gestational hyperandrogenism is once such adverse in-utero insult. Gestational testosterone (T)-treatment, an environment of gestational hyperandrogenism, manifests as hypertension and pathological left ventricular (LV) remodeling in adult ovine offspring. Furthermore, sexual dimorphism is noted in cardiomyocyte number and morphology in fetal life and at birth. This study investigated transcriptional changes and potential biomarkers of prenatal T excess-induced adverse cardiac programming. Genome-wide coding and non-coding (nc) RNA expression were compared between prenatal T-treated (T propionate 100 mg intramuscular twice weekly from days 30 to 90 …

Decreasing Mutant Atxn1 Nuclear Localization Improves A Spectrum Of Sca1-Like Phenotypes And Brain Region Transcriptomic Profiles, Hillary P Handler, Lisa Duvick, Jason S Mitchell, Marija Cvetanovic, Molly Reighard, Alyssa Soles, Kathleen B Mather, Orion Rainwater, Shannah Serres, Tessa Nichols-Meade, Stephanie L Coffin, Yun You, Brian L Ruis, Brennon O'Callaghan, Christine Henzler, Huda Y Zoghbi, Harry T Orr

Duncan NRI Faculty and Staff Publications

Spinocerebellar ataxia type 1 (SCA1) is a dominant trinucleotide repeat neurodegenerative disease characterized by motor dysfunction, cognitive impairment, and premature death. Degeneration of cerebellar Purkinje cells is a frequent and prominent pathological feature of SCA1. We previously showed that transport of ATXN1 to Purkinje cell nuclei is required for pathology, where mutant ATXN1 alters transcription. To examine the role of ATXN1 nuclear localization broadly in SCA1-like disease pathogenesis, CRISPR-Cas9 was used to develop a mouse with an amino acid alteration (K772T) in the nuclear localization sequence of the expanded ATXN1 protein. Characterization of these mice indicates that proper nuclear localization …

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

2020-Current year OA Pubs

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

Fmr1 Mutation Alters The Early Development Of Sensory Coding And Hunting And Social Behaviors In Larval Zebrafish, Shuyu I Zhu, Michael H Mccullough, Zac Pujic, Jordan Sibberas, Biao Sun, Thomas Darveniza, Bianca Bucknall, Lilach Avitan, Geoffrey J Goodhill

2020-Current year OA Pubs

Autism spectrum disorders (ASDs) are developmental in origin; however, little is known about how they affect the early development of behavior and sensory coding. The most common inherited form of autism is Fragile X syndrome (FXS), caused by a mutation in

Disruption Of The Atxn1-Cic Complex Reveals The Role Of Additional Nuclear Atxn1 Interactors In Spinocerebellar Ataxia Type 1, Stephanie L Coffin, Mark A Durham, Larissa Nitschke, Eder Xhako, Amanda M Brown, Jean-Pierre Revelli, Esmeralda Villavicencio Gonzalez, Tao Lin, Hillary P Handler, Yanwan Dai, Alexander J Trostle, Ying-Wooi Wan, Zhandong Liu, Roy V Sillitoe, Harry T Orr, Huda Y Zoghbi

Faculty, Staff and Students Publications

Spinocerebellar ataxia type 1 (SCA1) is a paradigmatic neurodegenerative disease in that it is caused by a mutation in a broadly expressed protein, ATXN1; however, only select populations of cells degenerate. The interaction of polyglutamine-expanded ATXN1 with the transcriptional repressor CIC drives cerebellar Purkinje cell pathogenesis; however, the importance of this interaction in other vulnerable cells remains unknown. Here, we mutated the 154Q knockin allele of Atxn1154Q/2Q mice to prevent the ATXN1-CIC interaction globally. This normalized genome-wide CIC binding; however, it only partially corrected transcriptional and behavioral phenotypes, suggesting the involvement of additional factors in disease pathogenesis. Using unbiased …

Cxcr4 Expression Is Associated With Proneural-To-Mesenchymal Transition In Glioblastoma, A Basit Khan, Sungho Lee, Akdes Serin Harmanci, Rajan Patel, Khatri Latha, Yuhui Yang, Anantha Marisetty, Hyun-Kyoung Lee, Amy B Heimberger, Gregory N Fuller, Benjamin Deneen, Ganesh Rao

Faculty, Staff and Students Publications

Glioblastoma (GBM) is the most common primary intracranial malignant tumor and consists of three molecular subtypes: proneural (PN), mesenchymal (MES) and classical (CL). Transition between PN to MES subtypes (PMT) is the glioma analog of the epithelial-mesenchymal transition (EMT) in carcinomas and is associated with resistance to therapy. CXCR4 signaling increases the expression of MES genes in glioma cell lines and promotes EMT in other cancers. RNA sequencing (RNAseq) data of PN GBMs in The Cancer Genome Atlas (TCGA) and secondary high-grade gliomas (HGGs) from an internal cohort were examined for correlation between CXCR4 expression and survival as well as …

Combination Of Epha2- And Wee1-Targeted Therapies In Endometrial Cancer, Santosh K Dasari, Robiya Joseph, Sujanitha Umamaheswaran, Lingegowda S Mangala, Emine Bayraktar, Cristian Rodriguez-Aguayo, Yutuan Wu, Nghi Nguyen, Reid T Powell, Mary Sobieski, Yuan Liu, Mamur A Chowdhury, Paola Amero, Clifford Stephan, Gabriel Lopez-Berestein, Shannon N Westin, Anil K Sood

Faculty, Staff and Student Publications

EphA2 tyrosine kinase is upregulated in many cancers and correlated with poor survival of patients, including those with endometrial cancer. EphA2-targeted drugs have shown modest clinical benefit. To improve the therapeutic response to such drugs, we performed a high-throughput chemical screen to discover novel synergistic partners for EphA2-targeted therapeutics. Our screen identified the Wee1 kinase inhibitor, MK1775, as a synergistic partner to EphA2, and this finding was confirmed using both in vitro and in vivo experiments. We hypothesized that Wee1 inhibition would sensitize cells to EphA2-targeted therapy. Combination treatment decreased cell viability, induced apoptosis, and reduced clonogenic potential in endometrial …

Curq+, A Next-Generation Formulation Of Curcumin, Ameliorates Growth Plate Chondrocyte Stress And Increases Limb Growth In A Mouse Model Of Pseudoachondroplasia, Jacqueline T Hecht, Alka C Veerisetty, Mohammad G Hossain, Frankie Chiu, Karen L Posey

Faculty, Staff and Student Publications

Mutations in cartilage oligomeric matrix protein (COMP) causes protein misfolding and accumulation in chondrocytes that compromises skeletal growth and joint health in pseudoachondroplasia (PSACH), a severe dwarfing condition. Using the MT-COMP mice, a murine model of PSACH, we showed that pathological autophagy blockage was key to the intracellular accumulation of mutant-COMP. Autophagy is blocked by elevated mTORC1 signaling, preventing ER clearance and ensuring chondrocyte death. We demonstrated that resveratrol reduces the growth plate pathology by relieving the autophagy blockage allowing the ER clearance of mutant-COMP, which partially rescues limb length. To expand potential PSACH treatment options, CurQ+, a uniquely absorbable …

Curq+, A Next-Generation Formulation Of Curcumin, Ameliorates Growth Plate Chondrocyte Stress And Increases Limb Growth In A Mouse Model Of Pseudoachondroplasia, Jacqueline T Hecht, Alka C Veerisetty, Mohammad G Hossain, Frankie Chiu, Karen L Posey

Faculty, Staff and Student Publications

Mutations in cartilage oligomeric matrix protein (COMP) causes protein misfolding and accumulation in chondrocytes that compromises skeletal growth and joint health in pseudoachondroplasia (PSACH), a severe dwarfing condition. Using the MT-COMP mice, a murine model of PSACH, we showed that pathological autophagy blockage was key to the intracellular accumulation of mutant-COMP. Autophagy is blocked by elevated mTORC1 signaling, preventing ER clearance and ensuring chondrocyte death. We demonstrated that resveratrol reduces the growth plate pathology by relieving the autophagy blockage allowing the ER clearance of mutant-COMP, which partially rescues limb length. To expand potential PSACH treatment options, CurQ+, a uniquely absorbable …

Ambient Oxygen Levels Regulate Intestinal Dysbiosis And Gvhd Severity After Allogeneic Stem Cell Transplantation, Keisuke Seike, Anders Kiledal, Hideaki Fujiwara, Israel Henig, Marina Burgos Da Silva, Marcel R M Van Den Brink, Robert Hein, Matthew Hoostal, Chen Liu, Katherine Oravecz-Wilson, Emma Lauder, Lu Li, Yaping Sun, Thomas M Schmidt, Yatrik M Shah, Robert R Jenq, Gregory Dick, Pavan Reddy

Faculty, Staff and Student Publications

The severity of T cell-mediated gastrointestinal (GI) diseases such as graft-versus-host disease (GVHD) and inflammatory bowel diseases correlates with a decrease in the diversity of the host gut microbiome composition characterized by loss of obligate anaerobic commensals. The mechanisms underpinning these changes in the microbial structure remain unknown. Here, we show in multiple specific pathogen-free (SPF), gnotobiotic, and germ-free murine models of GI GVHD that the initiation of the intestinal damage by the pathogenic T cells altered ambient oxygen levels in the GI tract and caused dysbiosis. The change in oxygen levels contributed to the severity of intestinal pathology in …

Antileukemic Properties Of The Kinase Inhibitor Otssp167 In T-Cell Acute Lymphoblastic Leukemia, Cory Seth Bridges, Taylor J Chen, Monica Puppi, Karen R Rabin, H Daniel Lacorazza

Faculty, Staff and Students Publications

Novel drugs are needed to increase treatment response in children with high-risk T-cell acute lymphoblastic leukemia (T-ALL). Following up on our previous report on the activation of the MAP2K7-JNK pathway in pediatric T-ALL, here we demonstrate that OTSSP167, recently shown to inhibit MAP2K7, has antileukemic capacity in T-ALL. OTSSP167 exhibited dose-dependent cytotoxicity against a panel of T-ALL cell lines with IC50 in the nanomolar range (10-50 nM). OTSSP167 induces apoptosis and cell cycle arrest in T-ALL cell lines, associated at least partially with the inhibition of MAP2K7 kinase activity and lower activation of its downstream substrate, JNK. Other leukemic T-cell …

Staphylococcus Aureus Breast Implant Infection Isolates Display Recalcitrance To Antibiotic Pocket Irrigants, Jesus M. Duran Ramirez, Jana Gomez, Blake M. Hanson, Taha Isa, Terence M. Myckatyn, Jennifer N. Walker

2020-Current year OA Pubs

Breast implant-associated infections (BIAIs) are the primary complication following placement of breast prostheses in breast cancer reconstruction. Given the prevalence of breast cancer, reconstructive failure due to infection results in significant patient distress and health care expenditures. Thus, effective BIAI prevention strategies are urgently needed. This study tests the efficacy of one infection prevention strategy: the use of a triple antibiotic pocket irrigant (TAPI) against Staphylococcus aureus, the most common cause of BIAIs. TAPI, which consists of 50,000 U bacitracin, 1 g cefazolin, and 80 mg gentamicin diluted in 500 mL of saline, is used to irrigate the breast implant …

Mrna Vaccine Mitigates Sars-Cov-2 Infections And Covid-19, Christina M. Kackos, Sherri L. Surman, Bart G. Jones, Robert E. Sealy, Trushar Jeevan, Christopher J H Davitt, Sergei Pustylnikov, Tamarand L. Darling, Adrianus C M Boon, Julia L. Hurwitz, Marcelo M. Samsa, Richard J. Webby

2020-Current year OA Pubs

The novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was identified in December of 2019 and is responsible for millions of infections and deaths across the globe. Vaccination against SARS-CoV-2 has proven effective to contain the spread of the virus and reduce disease. The production and distribution of these vaccines occurred at a remarkable pace, largely through the employment of the novel mRNA platform. However, interruptions in supply chain and high demand for clinical grade reagents have impeded the manufacture and distribution of mRNA vaccines at a time when accelerated vaccine deployment is crucial. Furthermore, the emergence of SARS-CoV-2 …