Digital Commons Network^™

Mbnl Overexpression Rescues Cardiac Phenotypes In A Myotonic Dystrophy Type 1 Heart Mouse Model, Rong-Chi Hu, Yi Zhang, Larissa Nitschke, Sara J Johnson, Ayrea E Hurley, William R Lagor, Zheng Xia, Thomas A Cooper

Faculty, Staff and Students Publications

Myotonic dystrophy type 1 (DM1) is an autosomal dominant disease caused by a CTG repeat expansion in the dystrophia myotonica protein kinase (DMPK) gene. The expanded CUG repeat RNA (CUGexp RNA) transcribed from the mutant allele sequesters the muscleblind-like (MBNL) family of RNA-binding proteins, causing their loss of function and disrupting regulated pre-mRNA processing. We used a DM1 heart mouse model that inducibly expresses CUGexp RNA to test the contribution of MBNL loss to DM1 cardiac abnormalities and explored MBNL restoration as a potential therapy. AAV9-mediated overexpression of MBNL1 and/or MBNL2 significantly rescued DM1 cardiac phenotypes including conduction delays, contractile …

The Tie2 Antagonist Rebastinib Reduces Ovarian Cancer Growth In A Syngeneic Murine Model, Vijayalaxmi G Gupta, Katherine F Roby, Harsh B Pathak, Andrew K Godwin, Sumedha Gunewardena, Dineo Khabele

2020-Current year OA Pubs

BACKGROUND: The receptor tyrosine kinase TIE2 and its ligands, angiopoietins (ANGPTs), promote angiogenesis. In addition to expression on vascular endothelial cells, TIE2 is expressed on M2-like pro-tumorigenic macrophages. Thus, the TIE2 inhibitor rebastinib was developed as a potential therapy to address multiple cancers. The objective of this study was to determine the effects of rebastinib alone and combined with chemotherapy in a syngeneic murine model of ovarian cancer.

METHODS: Female C57Bl6J mice were intraperitoneally injected with syngeneic ID8 ovarian cancer cells. Once tumors were established, mice were untreated (control) or treated with rebastinib, carboplatin plus paclitaxel (chemotherapy), or rebastinib plus …

Lifespan In Rodents With Myt1l Heterozygous Mutation, Allyson Schreiber, Raylynn G Swift, Leslie Wilson, Kristen L Kroll, Joseph D Dougherty, Susan E Maloney

2020-Current year OA Pubs

MYT1L syndrome is a newly recognized disorder characterized by intellectual disability, speech and motor delay, neuroendocrine disruptions, ADHD, and autism. In order to study this gene and its association with these phenotypes, our lab recently created a Myt1l heterozygous mutant mouse inspired by a clinically relevant mutation. This model recapitulates several of the physical and neurologic abnormalities seen in humans with MYT1L syndrome, such as weight gain, microcephaly, and behavioral disruptions. The majority of patients with this syndrome are young, and little is known about the impact of age on health and mortality in these patients. Using a Myt1l mutant …

Long-Read Sequencing Of 945 Han Individuals Identifies Structural Variants Associated With Phenotypic Diversity And Disease Susceptibility, Jiao Gong, Huiru Sun, Kaiyuan Wang, Yanhui Zhao, Yechao Huang, Qinsheng Chen, Hui Qiao, Yang Gao, Jialin Zhao, Yunchao Ling, Ruifang Cao, Jingze Tan, Qi Wang, Yanyun Ma, Jing Li, Jingchun Luo, Sijia Wang, Jiucun Wang, Guoqing Zhang, Shuhua Xu, Feng Qian, Fang Zhou, Huiru Tang, Dali Li, Chinese Pangenome Consortium (Cpc), Fritz J Sedlazeck, Li Jin, Yuting Guan, Shaohua Fan

Faculty, Staff and Students Publications

Genomic structural variants (SVs) are a major source of genetic diversity in humans. Here, through long-read sequencing of 945 Han Chinese genomes, we identify 111,288 SVs, including 24.56% unreported variants, many with predicted functional importance. By integrating human population-level phenotypic and multi-omics data as well as two humanized mouse models, we demonstrate the causal roles of two SVs: one SV that emerges at the common ancestor of modern humans, Neanderthals, and Denisovans in GSDMD for bone mineral density and one modern-human-specific SV in WWP2 impacting height, weight, fat, craniofacial phenotypes and immunity. Our results suggest that the GSDMD SV could …

Neuronal Network Activation Induced By Forniceal Deep Brain Stimulation In Mice, Bin Tang, Zhenyu Wu, Qi Wang, Jianrong Tang

Faculty, Staff and Students Publications

Background: The fimbria-fornix is a nerve fiber bundle that connects various structures of the limbic system in the brain and plays a key role in cognition. It has become a major target of deep brain stimulation (DBS) to treat memory impairment in both dementia patients and animal models of neurological diseases. Previously, we have reported the beneficial memory effects of chronic forniceal DBS in mouse models of intellectual disability disorders. In Rett syndrome and CDKL5 deficiency disorder models, DBS strengthens hippocampal synaptic plasticity, reduces dentate inhibitory transmission or increases adult hippocampal neurogenesis that aids memory. However, the underlying neuronal circuitry …

Motor Pool Selectivity Of Neuromuscular Degeneration In Type I Spinal Muscular Atrophy Is Conserved Between Human And Mouse, Justin C Lee, Wendy K Chung, David J Pisapia, Christopher E Henderson

Faculty, Staff and Students Publications

Spinal muscular atrophy (SMA) is caused by low levels of the survival motor neuron (SMN) protein. Even though SMN is ubiquitously expressed, the disease selectively affects motor neurons, leading to progressive muscle weakness. Even among motor neurons, certain motor units appear more clinically resistant to SMA. To quantitatively survey selective resistance, we studied extensive neuromuscular autopsies of Type I SMA patients and age-matched controls. We found highly divergent degrees of degeneration of neighboring motor units, even within individual cranial nerves or a single anatomical area such as the neck. Examination of a Type I SMA patient maintained on life support …

Bacterial Community Assembly Of Specific Pathogen-Free Neonatal Mice, Elizabeth A Kennedy, James S Weagley, Andrew H Kim, Avan Antia, Anna L Deveaux, Megan T Baldridge

2020-Current year OA Pubs

BACKGROUND: Neonatal mice are frequently used to model diseases that affect human infants. Microbial community composition has been shown to impact disease progression in these models. Despite this, the maturation of the early-life murine microbiome has not been well-characterized. We address this gap by characterizing the assembly of the bacterial microbiota of C57BL/6 and BALB/c litters from birth to adulthood across multiple independent litters.

RESULTS: The fecal microbiome of young pups is dominated by only a few pioneering bacterial taxa. These taxa are present at low levels in the microbiota of multiple maternal body sites, precluding a clear identification of …

A Synthetic Chronogenetic Gene Circuit For Programmed Circadian Drug Delivery, Lara Pferdehirt, Anna R Damato, Kristin L Lenz, Maria F Gonzalez-Aponte, Daniel Palmer, Qing-Jun Meng, Erik D Herzog, Farshid Guilak

2020-Current year OA Pubs

Circadian medicine, the delivery of therapeutic interventions based on an individual's daily rhythms, has shown improved efficacy and reduced side-effects for various treatments. Rheumatoid arthritis and other inflammatory diseases are characterized by diurnal changes in cytokines, leading to inflammatory flares, with peak disease activity in the early morning. Using a combination of synthetic biology and tissue engineering, we developed circadian-based gene circuits, termed "chronogenetics", that express a prescribed transgene downstream of the core clock gene promoter, Period2 (Per2). Gene circuits were transduced into induced pluripotent stem cells that were tissue-engineered into cartilage constructs. Our anti-inflammatory chronogenetic constructs produced therapeutic concentrations …

Oncogenic Kras Mutations Confer A Unique Mechanotransduction Response To Peristalsis In Colorectal Cancer Cells, Abigail J Clevenger, Claudia A Collier, John Paul M Gorley, Sarah Colijn, Maygan K Mcfarlin, Spencer C Solberg, Scott Kopetz, Amber N Stratman, Shreya A Raghavan

Faculty, Staff and Student Publications

Colorectal cancer tumors start as polyps on the inner lining of the colorectum, in which they are exposed to the mechanics of peristalsis. Our previous work leveraged a custom-built peristalsis bioreactor to demonstrate that colonic peristalsis led to cancer stem cell enrichment in colorectal cancer cells. However, this malignant mechanotransductive response was confined to select colorectal cancer lines that harbored an oncogenic mutation in the Kirsten rat sarcoma virus (KRAS) gene. In this study, we explored the involvement of activating KRAS mutations on peristalsis-associated mechanotransduction in colorectal cancer. Peristalsis enriched cancer stem cell marker Leucine-rich repeat-containing G protein-coupled receptor 5 …

Preclinical Efficacy Of Cdk7 Inhibitor-Based Combinations Against Myeloproliferative Neoplasms Transformed To Aml, Warren Fiskus, Christopher P Mill, Prithviraj Bose, Lucia Masarova, Naveen Pemmaraju, Andrew Dunbar, Christine E Birdwell, John A Davis, Kaberi Das, Hanxi Hou, Taghi Manshouri, Antrix Jain, Anna Malovannaya, Kevin Philip, Noor Alhamadani, Alicia Matthews, Katie Lin, Lauren B Flores, Sanam Loghavi, Courtney Dinardo, Xiaoping Su, Raajit K Rampal, Kapil N Bhalla

Faculty, Staff and Student Publications

Rising blast percentage or secondary acute myeloid leukemia (sAML) transformation in myeloproliferative neoplasms (MPNs) leads to JAK1/2 inhibitor (JAKi) therapy resistance and poor survival. Here, we demonstrate that treatment with the CDK7 inhibitor (CDK7i) SY-5609 depletes phenotypically characterized post-MPN sAML stem/progenitor cells. In cultured post-MPN sAML SET2, HEL and patient-derived (PD) post-MPN sAML cells, SY-5609 treatment inhibited growth and induced lethality while sparing normal cells. RNA-sequencing analysis after SY-5609 treatment reduced mRNA expression of MYC, MYB, CDK4/6, PIM1, and CCND1 but increased expression of CDKN1A and BCL2L1. Mass spectrometry of SY-5609-treated MPN-sAML cells also reduced c-Myc, c-Myb, PIM1, and CDK4/6 …

Brd7 Loss Reawakens Dormant Metastasis Initiating Cells In Lung By Forging An Immunosuppressive Niche, Jayanta Mondal, Junfeng Zhang, Feng Qing, Shunping Li, Dhiraj Kumar, Jason T Huse, Filippo G Giancotti

Faculty, Staff and Student Publications

Metastasis in cancer is influenced by epigenetic factors. Using an in vivo screen, we demonstrate that several subunits of the polybromo-associated BAF (PBAF) chromatin remodeling complex, particularly Brd7, are required for maintaining breast cancer metastatic dormancy in the lungs of female mice. Brd7 loss induces metastatic reawakening, along with modifications in epigenomic landscapes and upregulated oncogenic signaling. Breast cancer cells harboring Brd7 inactivation also reprogram the surrounding immune microenvironment by downregulating MHC-1 expression and promoting a pro-metastatic cytokine profile. Flow cytometric and single-cell analyses reveal increased levels of pro-tumorigenic inflammatory and transitional neutrophils, CD8+ exhausted T cells, and CD4+ stress …

Acute Mecp2 Loss In Adult Mice Reveals Transcriptional And Chromatin Changes That Precede Neurological Dysfunction And Inform Pathogenesis, Sameer S Bajikar, Jian Zhou, Ryan O'Hara, Harini P Tirumala, Mark A Durham, Alexander J Trostle, Michelle Dias, Yingyao Shao, Hu Chen, Wei Wang, Hari Krishna Yalamanchili, Ying-Wooi Wan, Laura A Banaszynski, Zhandong Liu, Huda Y Zoghbi

Faculty, Staff and Students Publications

Mutations in the X-linked methyl-CpG-binding protein 2 (MECP2) gene cause Rett syndrome, a severe childhood neurological disorder. MeCP2 is a well-established transcriptional repressor, yet upon its loss, hundreds of genes are dysregulated in both directions. To understand what drives such dysregulation, we deleted Mecp2 in adult mice, circumventing developmental contributions and secondary pathogenesis. We performed time series transcriptional, chromatin, and phenotypic analyses of the hippocampus to determine the immediate consequences of MeCP2 loss and the cascade of pathogenesis. We find that loss of MeCP2 causes immediate and bidirectional progressive dysregulation of the transcriptome. To understand what drives gene downregulation, we …

Ddo-Adjuvanted Influenza A Virus Nucleoprotein Mrna Vaccine Induces Robust Humoral And Cellular Type 1 Immune Responses And Protects Mice From Challenge, Victoria Gnazzo, Hanaa Saleh, Ítalo A Castro, Adrianus C M Boon, Amelia K. Pinto, James D Brien, Carolina B López

2020-Current year OA Pubs

A challenge in viral vaccine development is to produce vaccines that generate both neutralizing antibodies to prevent infection and cytotoxic CD8

Targeting Tiam1 Enhances Hippocampal-Dependent Learning And Memory In The Adult Brain And Promotes Nmda Receptor-Mediated Synaptic Plasticity And Function, Francisco A Blanco, Md Ali Bin Saifullah, Jinxuan X Cheng, Carlota Abella, Federico Scala, Karen Firozi, Sanyong Niu, Jin Park, Jeannie Chin, Kimberley F Tolias

Faculty, Staff and Students Publications

Excitatory synapses and the actin-rich dendritic spines on which they reside are indispensable for information processing and storage in the brain. In the adult hippocampus, excitatory synapses must balance plasticity and stability to support learning and memory. However, the mechanisms governing this balance remain poorly understood. Tiam1 is an actin cytoskeleton regulator prominently expressed in the dentate gyrus (DG) throughout life. Previously, we showed that Tiam1 promotes dentate granule cell synapse and spine stabilization during development, but its role in the adult hippocampus remains unclear. Here, we deleted Tiam1 from adult forebrain excitatory neurons (Tiam1^fKO) and assessed …

Diet Therapy Abates Mutant Apc And Kras Effects By Reshaping Plasma Membrane Cholesterol Nanodomains, Eunjoo Kim, Alfredo Erazo-Oliveras, Mónica Muñoz-Vega, Natividad R Fuentes, Michael L Salinas, Miranda J George, Roger S Zoh, Martha E Hensel, Bhimanagouda S Patil, Ivan Ivanov, Nancy D Turner, Robert S Chapkin

Faculty, Staff and Student Publications

Cholesterol-enriched plasma membrane domains are known to serve as signaling platforms in a diverse array of cellular processes. However, the link between cholesterol homeostasis and mutant APC-KRas-associated colorectal tumorigenesis remains to be established. Thus, we investigated the impact of Apc-Kras on 1) colonocyte plasma membrane cholesterol homeostasis, order, and receptor nanoclustering, 2) colonocyte cell proliferation, and 3) whether these effects are modulated by select membrane active dietaries (MADs). We observed that oncogenic APC-KRas increased membrane order by perturbing cholesterol homeostasis when cell proliferation is upregulated, in part by altering the expression of genes associated with cholesterol influx, export and de …

Estrogen Receptor-Α Ablation Reverses Muscle Fibrosis And Inguinal Hernias, Tanvi Potluri, Tianming You, Ping Yin, John Coon, Jonah J Stulberg, Yang Dai, David J Escobar, Richard L Lieber, Hong Zhao, Serdar E Bulun

Faculty, Staff and Student Publications

Fibrosis of the lower abdominal muscle (LAM) contributes to muscle weakening and inguinal hernia formation, an ailment that affects a noteworthy 50% of men by age 75 and necessitates surgical correction as the singular therapy. Despite its prevalence, the mechanisms driving LAM fibrosis and hernia development remain poorly understood. Using a humanized mouse model that replicates the elevated skeletal muscle tissue estrogen concentrations seen in aging men, we identified estrogen receptor-α (ESR1) as a key driver of LAM fibroblast proliferation, extracellular matrix deposition, and hernia formation. Fibroblast-specific ESR1 ablation effectively prevented muscle fibrosis and herniation, while pharmacological ESR1 inhibition with …

Sleep-Wake Variation In Body Temperature Regulates Tau Secretion And Correlates With Csf And Plasma Tau, Geoffrey Canet, Brendan P. Lucey, Et Al.

2020-Current year OA Pubs

Sleep disturbance is bidirectionally associated with an increased risk of Alzheimer's disease and other tauopathies. While the sleep-wake cycle regulates interstitial and cerebrospinal fluid (CSF) tau levels, the underlying mechanisms remain unknown. Understanding these mechanisms is crucial, given the evidence that tau pathology spreads through neuron-to-neuron transfer, involving the secretion and internalization of pathological tau forms. Here, we combined in vitro, in vivo, and clinical methods to reveal a pathway by which changes in body temperature (BT) over the sleep-wake cycle modulate extracellular tau levels. In mice, a higher BT during wakefulness and sleep deprivation increased CSF and plasma tau …

Retinoic Acid Antagonizes Estrogen Signaling To Maintain Adult Uterine Cell Fate, Yan Yin, Meade Haller, Lauren Goldinger, Shivani Bharadwaj, Emily So, Vivian Robles-Pinos, David Chen, Liang Ma

2020-Current year OA Pubs

Classical tissue recombination experiments demonstrate that cell-fate determination along the anterior-posterior axis of the Müllerian duct occurs prior to postnatal day 7 in mice. However, little is known about how these cell types are maintained in adults. In this study, we provide genetic evidence that a balance between antagonistic retinoic acid (RA) and estrogen signaling activity is required to maintain simple columnar cell fate in adult uterine epithelium. Transdifferentiation of simple columnar uterine epithelium into stratified cervicovaginal-like epithelium was observed in three related mouse genetic models, in which RA signaling was perturbed in the postnatal uterus. Single-cell RNA sequencing analysis …

Toxoplasma Chitinase-Like Protein Orchestrates Cyst Wall Glycosylation To Facilitate Effector Export And Cyst Turnover, Yong Fu, Tadakimi Tomita, Louis M Weiss, Christopher M West, L David Sibley

2020-Current year OA Pubs

No abstract provided.

Antitumor Activity And Biomarker Analysis For Trop2 Antibody-Drug Conjugate Datopotamab Deruxtecan In Patient-Derived Breast Cancer Xenograft Models, Funda Meric-Bernstam, Erkan Yuca, Kurt W Evans, Ming Zhao, Takanori Maejima, Tsuyoshi Karibe, Maria Gabriela Raso, Ximing Tang, Xiaofeng Zheng, Yasmeen Qamar Rizvi, Argun Akcakanat, Stephen M Scott, Bailiang Wang, Lauren A Byers, Debu Tripathy, Daisuke Okajima, Senthil Damodaran

Faculty, Staff and Student Publications

PURPOSE: Datopotamab deruxtecan (Dato-DXd) is a humanized anti-trophoblast cell-surface antigen-2 (TROP2) IgG1 mAb linked to a potent topoisomerase I inhibitor payload (DXd). Dato-DXd has already shown antitumor activity in breast cancer; however, the determinants of response, including the importance of TROP2 expression, remain unclear. We tested the activity of Dato-DXd in a panel of breast cancer patient-derived xenografts (BCX) varying in TROP2 expression.

EXPERIMENTAL DESIGN: The antitumor activity of Dato-DXd and isotype-control-DXd (IgG-DXd) was assessed against 11 BCXs varying in TROP2 expression, 10 representing tumors postneoadjuvant chemotherapy. Pharmacodynamic effects were assessed at 24 and 72 hours. The effects of TROP2 …

Plant-Nanoparticles Enhance Anti-Pd-L1 Efficacy By Shaping Human Commensal Microbiota Metabolites, Yun Teng, Chao Luo, Xiaolan Qiu, Jingyao Mu, Mukesh K Sriwastva, Qingbo Xu, Minmin Liu, Xin Hu, Fangyi Xu, Lifeng Zhang, Juw Won Park, Jae Yeon Hwang, Maiying Kong, Zhanxu Liu, Xiang Zhang, Raobo Xu, Jun Yan, Michael L Merchant, Craig J Mcclain, Huang-Ge Zhang

Faculty, Staff and Student Publications

Diet has emerged as a key impact factor for gut microbiota function. However, the complexity of dietary components makes it difficult to predict specific outcomes. Here we investigate the impact of plant-derived nanoparticles (PNP) on gut microbiota and metabolites in context of cancer immunotherapy with the humanized gnotobiotic mouse model. Specifically, we show that ginger-derived exosome-like nanoparticle (GELN) preferentially taken up by Lachnospiraceae and Lactobacillaceae mediated by digalactosyldiacylglycerol (DGDG) and glycine, respectively. We further demonstrate that GELN aly-miR159a-3p enhances anti-PD-L1 therapy in melanoma by inhibiting the expression of recipient bacterial phospholipase C (PLC) and increases the accumulation of docosahexaenoic acid …

From Bench To Bedside: Murine Models Of Inherited And Sporadic Brain Arteriovenous Malformations, Ashely R Ricciardelli, Gael Genet, Nafiisha Genet, Samuel T Mcclugage, Peter T Kan, Karen K Hirschi, Jason E Fish, Joshua D Wythe

Faculty, Staff and Students Publications

Brain arteriovenous malformations are abnormal vascular structures in which an artery shunts high pressure blood directly to a vein without an intervening capillary bed. These lesions become highly remodeled over time and are prone to rupture. Historically, brain arteriovenous malformations have been challenging to treat, using primarily surgical approaches. Over the past few decades, the genetic causes of these malformations have been uncovered. These can be divided into (1) familial forms, such as loss of function mutations in TGF-β (BMP9/10) components in hereditary hemorrhagic telangiectasia, or (2) sporadic forms, resulting from somatic gain of function mutations in genes involved in …

Cancer Cells Avoid Ferroptosis Induced By Immune Cells Via Fatty Acid Binding Proteins, Maria Angelica Freitas-Cortez, Fatemeh Masrorpour, Hong Jiang, Iqbal Mahmud, Yue Lu, Ailing Huang, Lisa K Duong, Qi Wang, Tiffany A Voss, Claudia S Kettlun Leyton, Bo Wei, Wai-Kin Chan, Kevin Lin, Jie Zhang, Efrosini Tsouko, Shonik Ganjoo, Hampartsoum B Barsoumian, Thomas S Riad, Yun Hu, Carola Leuschner, Nahum Puebla-Osorio, Jing Wang, Jian Hu, Michael A Davies, Vinay K Puduvalli, Cyrielle Billon, Thomas P Burris, Philip L Lorenzi, Boyi Gan, James W Welsh

Faculty, Staff and Student Publications

Background: Cancer creates an immunosuppressive environment that hampers immune responses, allowing tumors to grow and resist therapy. One way the immune system fights back is by inducing ferroptosis, a type of cell death, in tumor cells through CD8 + T cells. This involves lipid peroxidation and enzymes like lysophosphatidylcholine acyltransferase 3 (Lpcat3), which makes cells more prone to ferroptosis. However, the mechanisms by which cancer cells avoid immunotherapy-mediated ferroptosis are unclear. Our study reveals how cancer cells evade ferroptosis and anti-tumor immunity through the upregulation of fatty acid-binding protein 7 (Fabp7).

Methods: To explore how cancer cells resist immune cell-mediated …

Differential Impact Of Lymphatic Outflow Pathways On Cerebrospinal Fluid Homeostasis, Zachary Papadopoulos, Leon C D Smyth, Igor Smirnov, Daniel A Gibson, Jasmin Herz, Jonathan Kipnis

2020-Current year OA Pubs

Dysfunctional lymphatic drainage from the central nervous system (CNS) has been linked to neuroinflammatory and neurodegenerative disorders, but our understanding of the lymphatic contribution to CNS fluid autoregulation remains limited. Here, we studied forces that drive the outflow of the cerebrospinal fluid (CSF) into the deep and superficial cervical lymph nodes (dcLN and scLN) and tested how the blockade of lymphatic networks affects CNS fluid homeostasis. Outflow to the dcLN occurred spontaneously in the absence of lymphatic pumping and was coupled to intracranial pressure (ICP), whereas scLN drainage was driven by pumping. Impaired dcLN drainage led to elevated CSF outflow …

Investigating The In Vivo Effects Of Anti-Prion Protein Nanobodies On Prion Disease With Aav Vector, Jingjing Zhang, Mengfei Wang, Dan Wang, Xiangyi Zhang, Yue Ma, Els Pardon, Jan Steyaert, Romany Abskharon, Fei Wang, Jiyan Ma

Faculty, Staff and Student Publications

Prion diseases are fatal neurodegenerative disorders affecting humans and animals, and the central pathogenic event is the conversion of normal prion protein (PrPC) into the pathogenic PrPSc isoform. Previous studies have identified nanobodies that specifically recognize PrPC and inhibit the PrPC to PrPSc conversion in vitro. In this study, we investigated the potential for in vivo expression of anti-PrPC nanobodies and evaluated their impact on prion disease. The coding sequences of three nanobodies were packaged into recombinant adeno-associated virus (rAAV) and were administered via intracerebroventricular (ICV) injection in newborn mice. We found that the expression of these nanobodies remained robust …

Arginine Metabolism Is A Biomarker Of Red Blood Cell And Human Aging., Julie A Reisz, Eric J Earley, Travis Nemkov, Alicia Key, Daniel Stephenson, Gregory R Keele, Monika Dzieciatkowska, Steven L Spitalnik, Eldad A Hod, Steven Kleinman, Nareg H Roubinian, Mark T Gladwin, Kirk C Hansen, Philip J Norris, Michael P Busch, James C Zimring, Gary Churchill, Grier P Page, Angelo D'Alessandro

Faculty Research 2025

Increasing global life expectancy motivates investigations of molecular mechanisms of aging and age-related diseases. This study examines age-associated changes in red blood cells (RBCs), the most numerous host cell in humans. Four cohorts, including healthy individuals and patients with sickle cell disease, were analyzed to define age-dependent changes in RBC metabolism. Over 15,700 specimens from 13,757 humans were examined, a major expansion over previous studies of RBCs in aging. Multi-omics approaches identified chronological age-related alterations in the arginine pathway with increased arginine utilization in RBCs from older individuals. These changes were consistent across healthy and sickle cell disease cohorts and …

Polyploid Superficial Uroepithelial Bladder Barrier Cells Express Features Of Cellular Senescence Across The Lifespan And Are Insensitive To Senolytics., Iman M Al-Naggar, Maria Antony, Dylan Baker, Lichao Wang, Lucas Da Cunha Godoy, Chia-Ling Kuo, Matthew O Fraser, Phillip P Smith, Ming Xu, George A Kuchel

Faculty Research 2025

Lower urinary tract dysfunction (LUTD) increases with aging. Ensuing symptoms including incontinence greatly impact quality of life, isolation, depression, and nursing home admission. The aging bladder is hypothesized to be central to this decline, however, it remains difficult to pinpoint a singular strong driver of aging-related bladder dysfunction. Many molecular and cellular changes occur with aging, contributing to decreased resilience to internal and external stressors, affecting urinary control and exacerbating LUTD. In this study, we examined whether cellular senescence, a cell fate involved in the etiology of most aging diseases, contributes to LUTD. We found that umbrella cells (UCs), luminal …

Activin E Is A New Guardian Protecting Against Hepatic Steatosis Via Inhibiting Lipolysis In White Adipose Tissue., Shi-Young Park, Yoonil Cho, Sae-Mi Son, Jang Ho Hur, Yeongmin Kim, Hyunhee Oh, Hui-Young Lee, Sungwon Jung, Sanghee Park, Il-Young Kim, Se-Jin Lee, Cheol Soo Choi

Faculty Research 2025

Hepatic endoplasmic reticulum (ER) stress is implicated in the development of steatosis and its progression to nonalcoholic steatohepatitis (NASH). The ER in the liver can sustain metabolic function by activating defense mechanisms that delay or prevent the progression of nonalcoholic fatty liver disease (NAFLD). However, the precise mechanisms by which the ER stress response protects against NAFLD remain largely unknown. Recently, activin E has been linked to metabolic diseases such as insulin resistance and NAFLD. However, the physiological conditions and regulatory mechanisms driving hepatic Inhbe expression (which encodes activin E) as well as the metabolic role of activin E in …

Nrf2/Cyclooxygenase 2 Signaling In Cr(Vi)-Induced Carcinogenesis, Lei Zhao, Yi-Fang Wang, Andrea Adamcakova-Dodd, Peter Thorne, Ranakul Islam, Ke Jian Liu, Fei Chen, Jia Luo, Ling-Zhi Liu

Kimmel Cancer Center Faculty Papers

Long-term exposure to hexavalent chromium [Cr(VI)] has been linked to lung cancer, and cyclooxygenase-2 (COX-2) is a well-known inflammatory factor. However, the role and mechanism of COX-2 in Cr(VI)-induced carcinogenesis are not clear yet. To address this question, we employed a mouse model exposed to Cr(VI) through intranasal instillation of particulate zinc chromate (ZnCrO4) for 12 weeks. Metabolomics and RNA-seq assays revealed enhanced activity of the arachidonic acid (AA)/eicosanoid metabolism pathway in lung tissues from mice exposed to Cr(VI). COX-2, the key enzyme of the AA/eicosanoid pathway, was significantly upre- gulated in Cr(VI)-exposed lung tissues, as well as in the …

Notch3 Deletion Regulates Hiv-1 Gene Expression And Systemic Inflammation To Ameliorate Chronic Kidney Disease, Mackenzie Thornton, Nicole Sommer, Mercedes Mcgonigle, Anil Kumar Ram, Sireesha Yerrathota, Henrietta Ehirim, Aakriti Chaturvedi, Johnny Dinh Phan, Anubhav Chakraborty, V. Praveen Chakravarthi, Sumedha Gunewardena, Mudit Tyagi, Jaya Talreja, Tao Wang, Pravin Singhal, Pamela V. Tran, Timothy A. Fields, Patricio E. Ray, Navneet K. Dhillon, Madhulika Sharma

Center for Translational Medicine Faculty Papers

Anti-retroviral therapy (ART) has decreased human immunodeficiency virus (HIV)-1-associated morbidity. However, despite ART, immune cells remain latently infected, leading to chronic inflammation and HIV-1-associated comorbidities. New strategies are needed to target viral proteins and inflammation. We found activation of Notch3 in renal cells of the HIV-1 transgenic mouse model (HIV-Tg26) and in patients with HIV-associated nephropathy. We hypothesized that targeting NOTCH3 activation constitutes an effective therapy for HIV-related chronic kidney disease. We generated HIV-Tg26 mice with Notch3 knocked out (Tg-N3KO). Compared to HIV-Tg26 mice at 3 months, Tg-N3KO mice showed a marked reduction in renal injury, skin lesions and mortality …