Digital Commons Network^™

Label-Free Multimodal Optical Biopsy Reveals Biomolecular And Morphological Features Of Diabetic Kidney Tissue In 2d And 3d, Anthony A Fung, Zhi Li, Craig Boote, Petar Markov, Joseph P Gaut, Sanjay Jain, Lingyan Shi

2020-Current year OA Pubs

Kidney disease, the ninth leading cause of death in the United States, suffers from poor diagnostic efficiency (10%). Traditional biopsies use molecular reagents to enhance diagnostic power but are limited by overlapping spatial and chromatic signals, product quality variability, and additional processing. To address these challenges without disrupting routine diagnostics, we implement label-free imaging modalities-stimulated Raman scattering (SRS), second harmonic generation (SHG), and two-photon fluorescence (TPF)-within a single setup. We identify morphological, lipidomic, and metabolic biomarkers in control and diabetic kidney samples at subcellular resolution. Label-free Stimulated Raman Histology (SRH) reveals distinct collagen morphology, mesangial-glomerular volumes, lipid saturation, redox status, …

Acute Kidney Injury Triggers Hypoxemia By Lung Intravascular Neutrophil Retention That Reduces Capillary Blood Flow, Yohei Komaru, Liang Ning, Carine Lama, Anusha Suresh, Eirini Kefaloyianni, Mark J. Miller, Shinichi Kawana, Hailey M Shepherd, Wenjun Li, Daniel Kreisel, Andreas Herrlich

2020-Current year OA Pubs

Sterile acute kidney injury (AKI) is common in the clinic and frequently associated with unexplained hypoxemia that does not improve with dialysis. AKI induces remote lung inflammation with neutrophil recruitment in mice and humans, but which cellular cues establish neutrophilic inflammation and how it contributes to hypoxemia is not known. Here we report that AKI induced rapid intravascular neutrophil retention in lung alveolar capillaries without extravasation into tissue or alveoli, causing hypoxemia by reducing lung capillary blood flow in the absence of substantial lung interstitial or alveolar edema. In contrast to direct ischemic lung injury, lung neutrophil recruitment during remote …

Maintenance Of Graft Tissue-Resident Foxp3+ Cells Is Necessary For Lung Transplant Tolerance In Mice, Wenjun Li, Yuriko Terada, Yun Zhu Bai, Yuhei Yokoyama, Hailey M. Shepherd, Junedh M. Amrute, Amit I. Bery, Zhiyi Liu, Jason M. Gauthier, Marina Terekhova, Jon H. Ritter, Varun Puri, Ramsey R. Hachem, Maxim N. Artyomov, Kory J. Lavine, Ruben G. Nava, Andrew E. Gelman, Daniel Kreisel, Et Al.

2020-Current year OA Pubs

Mechanisms that mediate allograft tolerance differ between organs. We have previously shown that Foxp3+ T cell-enriched bronchus-associated lymphoid tissue (BALT) is induced in tolerant murine lung allografts and that these Foxp3+ cells suppress alloimmune responses locally and systemically. Here, we demonstrated that Foxp3+ cells that reside in tolerant lung allografts differed phenotypically and transcriptionally from those in the periphery and were clonally expanded. Using a mouse lung retransplant model, we showed that recipient Foxp3+ cells were continuously recruited to the BALT within tolerant allografts. We identified distinguishing features of graft-resident and newly recruited Foxp3+ cells and showed that graft-infiltrating Foxp3+ …

Multifaceted Roles Of Epac Signaling In Renal Functions, Oleh Pochynyuk, Kyrylo Pyrshev, Xiaodong Cheng

The Brown Foundation: Institute of Molecular Medicine

3',5'-cyclic adenosine monophosphate (cAMP) is a fundamental secondary messenger capable of rapidly amplifying and propagating cellular signals in response to various extracellular stimuli. cAMP plays a significant role in hormone-mediated regulation of renal fluid and electrolyte balance. Impaired signaling of cAMP has been linked to a variety of pathological ramifications in the kidneys. This review explores the physiological functions of exchange proteins directly activated by cAMP (Epac) in renal water balance and the regulation of solute transport in the renal tubule. Additionally, the involvement of Epac signaling in renal pathologies such as acute kidney injury, chronic kidney disease, and polycystic …

Forward Genetic Screen In Zebrafish Identifies New Fungal Regulators That Limit Host-Protective Candida-Innate Immune Interaction, Bailey A Blair, Emma Bragdon, Gursimran Dhillon, Nnamdi Baker, Lena Stasiak, Mya Muthig, Pedro Miramon, Michael C Lorenz, Robert T Wheeler

Faculty, Staff and Student Publications

Candida is one of the most frequent causes of bloodstream infections, and our first line of defense against these invasive infections is the innate immune system. The early immune response is critical in controlling Candida albicans infection, but C. albicans has several strategies to evade host immune attack. Phagocytosis of C. albicans blocks hyphal growth, limiting host damage and virulence, but how C. albicans limits early recruitment and phagocytosis in vertebrate infection is poorly understood. To study innate immune evasion by intravital imaging, we utilized the transparent larval zebrafish infection model to screen 131 C. albicans mutants for altered …

Theta Oscillons In Behaving Rats, M S Zobaer, Nastaran Lotfi, Carli M Domenico, Clarissa Hoffman, Luca Perotti, Daoyun Ji, Yuri Dabaghian

Faculty, Staff and Students Publications

Recently discovered constituents of the brain waves—the oscillons—provide a high-resolution representation of the extracellular field dynamics. Here, we study the most robust, highest-amplitude oscillons recorded in actively behaving male rats, which underlie the traditional θ-waves. The resemblances between θ-oscillons and the conventional θ-waves are manifested primarily at the ballpark level—mean frequencies, mean amplitudes, and bandwidths. In addition, both hippocampal and cortical oscillons exhibit a number of intricate, behavior-attuned, transient properties that suggest a new vantage point for understanding the θ-rhythms’ structure, origins and functions. In particular, we demonstrate that oscillons are frequency-modulated waves, with speed-controlled …

Genome-Wide Allele-Specific Expression In Multi-Tissue Samples From Healthy Male Baboons Reveals The Transcriptional Complexity Of Mammals, Ramesh Ramasamy, Muthuswamy Raveendran, R Alan Harris, Hiep D Le, Ludovic S Mure, Giorgia Benegiamo, Ouria Dkhissi-Benyahya, Howard Cooper, Jeffrey Rogers, Satchidananda Panda

Faculty, Staff and Students Publications

Allele-specific expression (ASE) is pivotal in understanding the genetic underpinnings of phenotypic variation within species, differences in disease susceptibility, and responses to environmental factors. We processed 11 different tissue types collected from 12 age-matched healthy olive baboons (Papio anubis) for genome-wide ASE analysis. By sequencing their genomes at a minimum depth of 30×, we identified over 16 million single-nucleotide variants (SNVs). We also generated long-read sequencing data, enabling the phasing of all variants present within the coding regions of 96.5% of assayable protein-coding genes as a single haplotype block. Given the extensive heterozygosity of baboons relative to humans, we could …

Dnmt3a Regulates Murine Megakaryocyte-Biased Hematopoietic Stem Cell Fate Decisions, Sarah M Waldvogel, Virginia Camacho, Dandan Fan, Anna G Guzman, Alejandra Garcia-Martell, Elmira Khabusheva, Jacey Rodriguez Pridgen, Josephine De La Fuente, Rachel Rau, Ashlyn G Laidman, Maria N Barrachina, Estelle Carminita, Justin A Courson, Michael R Williamson, Joanne I Hsu, Chun-Wei Chen, Jaime Reyes, Subhashree Pradhan, Rolando E Rumbaut, Alan R Burns, Benjamin Deneen, Jianzhong Su, Kellie R Machlus, Margaret A Goodell

Center on Aging Staff Publications

Hematopoietic stem cells (HSCs) are defined by their capacity to regenerate all main components of peripheral blood, but individual HSCs exhibit a range of preferences for generating downstream cell types. Their propensities are thought to be epigenetically encoded, but few differential regulatory mechanisms have been identified. In this work, we explored the role of DNA methyltransferase 3A (DNMT3A) in the megakaryocyte-biased HSC population, which is thought to reside at the top of the hematopoietic hierarchy. We demonstrate that heterozygous loss of DNMT3A (Dnmt3a+/-) in these megakaryocyte-biased HSCs has distinct consequences compared with the rest of the HSC pool. These megakaryocyte-biased …

Ogg1s326c Variant Frequent In Human Populations Facilitates Inflammatory Responses Due To Its Extended Interaction With Dna Substrate, Jinling Han, Meichen Zhang, Jiakun Ge, Zhihua Ji, Jianyi Zhao, Yinchao Hu, Chunshuang Li, Yaoyao Xue, Xining Li, Haiwang Zhao, Zixu Cui, Miaomiao Tian, Xu Zheng, Dapeng Wang, Jing Wang, Min Wei, Zsolt Radak, Yusaku Nakabeppu, Istvan Boldogh, Xueqing Ba

Faculty, Staff and Student Publications

8-oxoguanine (8-oxoGua) is one of the most frequent forms of oxidative DNA base lesions, repaired by 8-oxoguanine DNA glycosylase 1 (OGG1) via base excision repair (BER) pathway to maintain genome fidelity. The human allelic variant hOGG1^S326C, prevalent in Caucasians and Asians, has been regarded as a susceptibility factor for various diseases, yet its pathogenic mechanism remains elusive. In this study, we demonstrate that Ogg1^S326C/S326C mice exhibit increased and sustained airway inflammation compared with wild-type (WT) Ogg1^S326/S326 mice. Mechanistically, in response to inflammatory stimulation, OGG1S326C undergoes reactive oxygen species-induced dimerization, which impairs its base excision function, but …

Loss Of Progesterone Receptor In Smooth Muscle Cells Has No Impact On Oviductal Contractions And Preimplantation Embryo Development†, Emily A Mcglade, Jiude Mao, Kalli K Stephens, Cayce N Rose, John P Lydon, Wipawee Winuthayanon

Faculty, Staff and Students Publications

No abstract provided.

Intraspecific Sensory Diversity And The Decapod Claw: Patterns Of Sensillation Are Heterochelic And Sexually Dimorphic In Pagurus Bernhardus, Ari Drummond, Summer Nash, Tianna Holloway, Alexander Wilson, Lucy Turner, Mark Briffa, David T Bilton

School of Biological and Marine Sciences

Information detection affects physiological performance and behaviour and is vital to survival and fitness. Despite the recognised importance of sensory adaptations in information acquisition and manipulation, many forms of sensory variation—from within individuals to between species—remain underexplored. To better understand the role of information in evolution, it is important to examine sensory variation as part of a cohesive framework of sensory diversity. Using the decapod claw, a structure well-recognised for its morphological variation, we investigated sensory diversity at the intraspecific level by assessing heterochely and sexual dimorphism in the chelar morphologies of Pagurus bernhardus hermit crabs. We employed a novel …

Disruption Of Oocyte Sumoylation Impacts Critical Regulatory Processes During Folliculogenesis In Mice, Zian Liao, Tessa E Steenwinkel, Bruno Moscoso, Ernesto Salas, Bethany K Patton, Amanda Rodriguez, Anna Malovannaya, Stephanie A Pangas

Faculty, Staff and Students Publications

The conjugation of small ubiquitin-like modifiers (SUMO) to target proteins, known as SUMOylation, plays a crucial role in regulating protein homeostasis, activity, interaction with other proteins, and subcellular localization. Loss of SUMOylation in nongrowing oocytes by conditional deletion of the E2 SUMO conjugating enzyme, Ube2i, at the primordial follicle stage leads to female sterility due to complex changes in oocyte development, including altered folliculogenesis, defective meiotic progression, and premature loss of the ovarian reserve. In this study, proteomics was used to compare control and Ube2i conditional knockout ovaries during the first wave of folliculogenesis to identify key differences that may …

Temporal Regulation Of Early-Stage Cytokine Expression In Diabetic Wound Healing Under Negative Pressure Wound Therapy, Hua-Sheng Chiu, Ting-Shuo Huang, Chien-Tzung Chen, Xin-Yu Lin, Po-Cheng Liao, Cai-Cin Liou, Chih-Chin Hsu, Sonal Somvanshi, Pavel Sumazin, Pang-Hung Hsu, Chi-Chin Sun, Yu-Chiau Shyu

Faculty, Staff and Students Publications

Negative pressure wound therapy (NPWT) is widely recognized for its efficacy in treating diabetic wounds, but the mechanisms involved in the wound healing process remain unclear. By examining changes in blood cytokine levels as molecular signaling precursors, we aim to provide a comprehensive cytokine profile to support adjunctive therapy research and clinical applications. A diabetic mouse wound model was established to compare cytokine profiles between NPWT-treated and standard dressing groups, identifying key signaling candidates that may facilitate wound healing. By integrating normal mouse data with large-scale cytokine analysis, we developed a time-stratified NPWT approach to track acute-phase cytokine fluctuations in …

Let-7 Restrains An Epigenetic Circuit In At2 Cells To Prevent Fibrogenic Intermediates In Pulmonary Fibrosis, Matthew J Seasock, Md Shafiquzzaman, Maria E Ruiz-Echartea, Rupa S Kanchi, Brandon T Tran, Lukas M Simon, Matthew D Meyer, Phillip A Erice, Shivani L Lotlikar, Stephanie C Wenlock, Scott A Ochsner, Anton Enright, Alex F Carisey, Freddy Romero, Ivan O Rosas, Katherine Y King, Neil J Mckenna, Cristian Coarfa, Antony Rodriguez

Faculty, Staff and Students Publications

MicroRNA-mediated post-transcriptional regulation of lung alveolar type 2 (AT2) and AT1 cell differentiation remains understudied. Here, we demonstrate that the let-7 miRNA family plays a homeostatic role in AT2 quiescence by preventing the uncontrolled accumulation of AT2 transitional cells and promoting AT1 differentiation. Using mouse and organoid models, we show that genetic ablation of let-7a1/let-7f1/let-7d cluster (let-7afd) in AT2 cells prevents AT1 differentiation and leads to KRT8 transitional cell accumulation in progressive pulmonary fibrosis. Integration of AGO2-eCLIP with RNA-sequencing identified direct let-7 targets within an oncogene feed-forward regulatory network, including BACH1/EZH2/MYC, which drives an aberrant fibrotic cascade. Additional CUT&RUN-sequencing analyses …

Molecular Basis Of Trpv3 Channel Blockade By Intracellular Polyamines, Jingying Zhang, Peng Yuan, Colin G Nichols, Grigory Maksaev

2020-Current year OA Pubs

ThermoTRPV1-4 channels are involved in the regulation of multiple physiological processes, including thermo- and pain perception, thermoregulation, itch, and nociception and therefore tight control of their activity is a critical requirement for correct perception of noxious stimuli and pain. We previously reported a voltage-dependent inhibition of TRPV1-4 channels by intracellular polyamines that could be explained by high affinity spermine binding in, and passage through, the permeation path. Here, using electrophysiology and cryo-electron microscopy, we elucidate molecular details of TRPV3 blockade by endogenous spermine and its analog NASPM. We identify a high-affinity polyamine interaction site at the intracellular side of the …

High-Throughput Echocardiography-Guided Induction Of Myocardial Ischemia/Reperfusion In Mice., Florian Sicklinger, Niklas Hartmann, Attila Kovacs, Carla Weinheimer, Jess Nigro, Tobias Thiemann, Junedh M Amrute, David Schumacher, Moritz P Kornadt, Laura M Wienecke, Lennart Rompel, Johannes Fischer, John F Bachman, Olivia Bedard, Shibali Das, Tim C Kuhn, Mirko Völkers, Ralf P Brandes, Rafael Kramann, Nadia Rosenthal, Norbert Frey, Kory J Lavine, Florian Leuschner

Faculty Research 2025

BACKGROUND: Mouse models of myocardial ischemia with subsequent heart failure are common approaches to examine heart failure pathology and possible treatment strategies. We sought to establish a high-throughput approach for echocardiography-guided induction of myocardial ischemia/reperfusion (IR) in mice.

METHODS: After visualization of the left coronary artery with high-resolution ultrasound imaging and echocardiographic definition of the level of coronary occlusion, the left anterior descending artery was temporarily occluded with 2 micromanipulator-controlled needles. Functional and molecular changes were assessed and compared with commonly performed surgical techniques.

RESULTS: Echocardiography-guided induction of myocardial IR enabled standardized induction of myocardial IR injury with subsequent left …

High-Throughput Echocardiography-Guided Induction Of Myocardial Ischemia/Reperfusion In Mice, Florian Sicklinger, Niklas Hartmann, Attila Kovacs, Carla Weinheimer, Jess Nigro, Junedh M. Amrute, Kory J. Lavine, Et Al.

2020-Current year OA Pubs

BACKGROUND: Mouse models of myocardial ischemia with subsequent heart failure are common approaches to examine heart failure pathology and possible treatment strategies. We sought to establish a high-throughput approach for echocardiography-guided induction of myocardial ischemia/reperfusion (IR) in mice.

METHODS: After visualization of the left coronary artery with high-resolution ultrasound imaging and echocardiographic definition of the level of coronary occlusion, the left anterior descending artery was temporarily occluded with 2 micromanipulator-controlled needles. Functional and molecular changes were assessed and compared with commonly performed surgical techniques.

RESULTS: Echocardiography-guided induction of myocardial IR enabled standardized induction of myocardial IR injury with subsequent left …

Metabolic Reprogramming Driven By Ant2 Deficiency Augments T Cell Function And Anti-Tumor Immunity In Mice, Omri Yosef, Leonor Cohen-Daniel, Oded Shamriz, Zahala Bar-On, Wajeeh Salaymeh, Amijai Saragovi, Ifat Abramovich, Bella Agranovich, Veronika Lutz, Joseph Tam, Anna Permyakova, Eyal Gottlieb, Magdalena Huber, Michael Berger

Faculty, Staff and Student Publications

T cell activation requires a substantial increase in NAD+ production, often exceeding the capacity of oxidative phosphorylation (OXPHOS). To investigate how T cells adapt to this metabolic challenge, we generate T cell-specific ADP/ATP translocase-2 knockout (Ant2-/-) mice. Loss of Ant2, a crucial protein mediating ADP/ATP exchange between mitochondria and cytoplasm, induces OXPHOS restriction by limiting ATP synthase activity, thereby impeding NAD+ regeneration. Interestingly, Ant2-/- naïve T cells exhibit enhanced activation, proliferation and effector functions compared to wild-type controls. Metabolic profiling reveals that these T cells adopt an activated-like metabolic program with increased mitobiogenesis and anabolism. Lastly, pharmacological inhibition of ANT …

Discovery Of Novel, Potent, And Orally Bioavailable Smarca2 Proteolysis-Targeting Chimeras With Synergistic Antitumor Activity In Combination With Kirsten Rat Sarcoma Viral Oncogene Homologue G12c Inhibitors, Sasikumar Kotagiri, Yawen Wang, Yanyan Han, Xiaobing Liang, Nicholas Blazanin, Hira Mazhar, Manu Sebastian, Phuong Kieu Nguyen, Yongying Jiang, Yonathan Lissanu

Faculty, Staff and Student Publications

Cancer genomic studies have identified frequent mutations in subunits of the SWI/SNF chromatin remodeling complex, including SMARCA4 in nonsmall cell lung cancer with a frequency of up to 33% in advanced-stage disease, making it the most frequently mutated complex. We and others have identified SMARCA2 to be synthetic lethal to SMARCA4, indicating that SMARCA2 is a high-value therapeutic target. Here, we disclose the discovery and characterization of potent, selective, and orally bioavailable cereblon-based SMARCA2 PROTACs. Biochemically, we showed that YDR1 and YD54 are potent SMARCA2 degraders. Further, we showed the antitumor growth inhibitory activity of YDR1 and YD54 in SMARCA4 …

Zanidatamab Monotherapy Or Combined With Chemotherapy In Her2-Expressing Gastroesophageal Adenocarcinoma: A Phase 1 Trial, Funda Meric-Bernstam, Sun Young Rha, Erika Hamilton, Yoon-Koo Kang, Diana L Hanna, Syma Iqbal, Keun-Wook Lee, Jeeyun Lee, Muralidhar Beeram, Do-Youn Oh, Jorge Chaves, Rachel A Goodwin, Jaffer A Ajani, Lin Yang, Rajen Oza, Elena Elimova

Faculty, Staff and Student Publications

There is a need for novel therapies for patients with previously treated HER2-positive gastroesophageal adenocarcinoma (GEA). This phase 1 (NCT02892123) dose-escalation and expansion trial evaluated zanidatamab (a dual HER2-targeted bispecific antibody) ± chemotherapy in previously treated patients with HER2-expressing, locally advanced/metastatic cancers. Here, we report the outcomes for GEA cohorts receiving zanidatamab monotherapy or with chemotherapy (paclitaxel or capecitabine). The primary endpoint was safety and tolerability. Secondary endpoints were objective response rate (ORR), disease control rate, progression-free survival, pharmacokinetics, and immunogenicity. Seventy patients were enrolled (n = 29 monotherapy; n = 41 combination therapy); most received prior HER2-targeted agents (monotherapy, …

Sirt6 Deficiency Promotes Senescence And Age-Associated Intervertebral Disc Degeneration In Mice, Pranay Ramteke, Bahiyah Watson, Mallory Toci, Victoria A Tran, Shira Johnston, Maria Tsingas, Ruteja A Barve, Ramkrishna Mitra, Richard F Loeser, John A Collins, Makarand V Risbud

2020-Current year OA Pubs

Intervertebral disc degeneration is a major risk factor contributing to chronic low back and neck pain. While the etiological factors for disc degeneration vary, age is still one of the most important risk factors. Recent studies have shown the promising role of SIRT6 in mammalian aging and skeletal tissue health, however its role in the intervertebral disc health remains unexplored. We investigated the contribution of SIRT6 to disc health by studying the age-dependent spinal phenotype of mice with conditional deletion of Sirt6 in the disc (Acan

Hippocampal-Prefrontal Functional Neural Networks In A Rat Model Of Fragile X Syndrome Are Poorly Organized With Limited Resiliency, Mohamed Ouardouz, Patrick Jasinski, Mohamed Khalife, J. Matthew Mahoney, Amanda E. Hernan, Rod C. Scott

Department of Neurology Faculty Papers

Fragile X Syndrome (FXS) is a common cause of autism spectrum symptoms. The genetic mutation results in multiple molecular alterations that are hypothesized to negatively impact neural circuit development although the nature of any functional neural dynamic consequences remain unclear. Therefore, the characteristics of hippocampal-prefrontal (H-PFC) network dysfunction were investigated in a rat model of FXS. FMR-KO and control rats underwent behavioral tests assessing sociability, memory, and anxiety to validate and replicate previously recognized deficits. Single-unit electrophysiology in the H-PFC circuit during exploration was used to measure patterns of action potential firing that were then compared between groups using generalized …

Human Pain Neuroscience And The Next Generation Of Pain Therapeutics, Bryan A Copits, Michele Curatolo, Patrick M Dougherty, Robert W Gereau, Wenqin Luo, Maryann Martone, Hakan Olausson, Theodore J Price, William Renthal, Clifford J Woolf, Guoyan Zhao

Faculty, Staff and Student Publications

The recent approval of suzetrigine for acute pain treatment highlights both the success of targeting peripheral sensory neurons for pain management and the potential of developing new pain therapies primarily in human-based systems. To realize this transformative potential, further research into somatosensation and pain neuroimmunology in human systems is essential.

A Honduran Prevalence Study On Soil-Transmitted Helminths Highlights Serological Antibodies To Tm-Wap49 As A Diagnostic Marker For Exposure To Human Trichuriasis, Neima Briggs, Leroy Versteeg, Rojelio Mejia, Jeroen Pollet, Maria Jose Villar, Bin Zhan, Graeme Segal, Stephanie Novak, Patricia Lenihan, Paul Musgrave, Viviana Ellis, Carol Florencia Coello, K Jagannadha Sastry, Joe Craft, Peter J Hotez, Maria Elena Bottazzi

Faculty, Staff and Student Publications

Soil-transmitted helminth (STH) infections rank among the most prevalent communicable diseases of humans, yet detection of these parasites is mostly restricted to identifying active infection through fecal examinations. Currently, there are no commercial diagnostic tools to identify a prior whipworm or hookworm exposure, and the few serological assays for roundworm infection have not been well validated for crossreactivity or infections in humans. Such diagnostic restrictions limit the range of scientific and clinical questions that surround STH exposures and their implicated relationship to chronic diseases, such as autoimmunity, allergy, and cancer. The goal of this investigation was to evaluate the diagnostic …

Axl Promotes Inflammatory Breast Cancer Progression By Regulating Immunosuppressive Macrophage Polarization, Lan T H Phi, Yating Cheng, Yohei Funakoshi, Francois Bertucci, Pascal Finetti, Steven J Van Laere, Fang Zou, James P Long, Suguru Ogata, Savitri Krishnamurthy, James M Reuben, Jason M Foulks, Steven L Warner, Jennifer M Rosenbluth, Anil K Sood, Debu Tripathy, Naoto T Ueno, Xiaoping Wang

Faculty, Staff and Student Publications

Background: Tumor-associated macrophages (TAMs) are key promoters of inflammatory breast cancer (IBC), the most aggressive form of breast cancer. The receptor tyrosine kinase AXL is highly expressed in various cancer types, including IBC, but its role in TAMs remains unexplored.

Methods: We examined the effects of AXL inhibitor TP-0903 on tumor growth and tumor microenvironment (TME) component M2 macrophages (CD206+) in IBC and triple-negative breast cancer mouse models using flow cytometry and immunohistochemical staining. Additionally, we knocked out AXL expression in human THP-1 monocytes and evaluated the effect of AXL signaling on immunosuppressive M2 macrophage polarization and IBC cell growth …

Alzheimer’S Disease Protective Allele Of Clusterin Modulates Neuronal Excitability Through Lipid-Droplet-Mediated Neuron-Glia Communication, Xiaojie Zhao, Yan Li, Siwei Zhang, Ari Sudwarts, Hanwen Zhang, Alena Kozlova, Matthew J Moulton, Lindsey D Goodman, Zhiping P Pang, Alan R Sanders, Hugo J Bellen, Gopal Thinakaran, Jubao Duan

Duncan NRI Faculty and Staff Publications

Background: Genome-wide association studies (GWAS) of Alzheimer's disease (AD) have identified a plethora of risk loci. However, the disease variants/genes and the underlying mechanisms have not been extensively studied.

Methods: Bulk ATAC-seq was performed in induced pluripotent stem cells (iPSCs) differentiated various brain cell types to identify allele-specific open chromatin (ASoC) SNPs. CRISPR-Cas9 editing generated isogenic pairs, which were then differentiated into glutamatergic neurons (iGlut). Transcriptomic analysis and functional studies of iGlut co-cultured with mouse astrocytes assessed neuronal excitability and lipid droplet formation.

Results: We identified a putative causal SNP of CLU that impacted neuronal chromatin accessibility to transcription-factor(s), with …

Clonal Dynamics And Somatic Evolution Of Haematopoiesis In Mouse., Chiraag D Kapadia, Nicholas Williams, Kevin J Dawson, Caroline Watson, Matthew J Yousefzadeh, Duy Le, Kudzai Nyamondo, Sreeya Kodavali, Alex Cagan, Sarah Waldvogel, Xiaoyan Zhang, Josephine De La Fuente, Daniel Leongamornlert, Emily Mitchell, Marcus A Florez, Krzysztof Sosnowski, Rogelio Aguilar, Alejandra Martell, Anna Guzman, David E Harrison, Laura J Niedernhofer, Katherine Y King, Peter J Campbell, Jamie Blundell, Margaret A Goodell, Jyoti Nangalia

Faculty Research 2025

Haematopoietic stem cells maintain blood production throughout life1 . Although extensively characterized using the laboratory mouse, little is known about clonal selection and population dynamics of the haematopoietic stem cell pool during murine ageing. We isolated stem cells and progenitors from young and old mice, identifying 221,890 somatic mutations genome-wide in 1,845 single-cell-derived colonies. Mouse stem cells and progenitors accrue approximately 45 somatic mutations per year, a rate only approximately threefold greater than human progenitors despite the vastly different organismal sizes and lifespans. Phylogenetic patterns show that stem and multipotent progenitor cell pools are established during embryogenesis, after which they …

Systematic Ocular Phenotyping Of Knockout Mouse Lines Identifies Genes Associated With Age-Related Corneal Dystrophies., Andrew Briere, Peter Vo, Benjamin Yang, David Adams, Takanori Amano, Oana Amarie, Zorana Berberovic, Lynette Bower, Steve D M Brown, Samantha Burrill, Soo Young Cho, Sharon Clementson-Mobbs, Abigail D'Souza, Mohammad Eskandarian, Ann M Flenniken, Helmut Fuchs, Valerie Gailus-Durner, Yann Hérault, Martin Hrabe De Angelis, Shundan Jin, Russell Joynson, Yeon Kyung Kang, Haerim Kim, Hiroshi Masuya, Hamid Meziane, Ki-Hoan Nam, Hyuna Noh, Lauryl M J Nutter, Marcela Palkova, Jan Prochazka, Miles Joseph Raishbrook, Fabrice Riet, Jason Salazar, Radislav Sedlacek, Mohammed Selloum, Kyoung Yul Seo, Je Kyung Seong, Hae-Sol Shin, Toshihiko Shiroishi, Michelle Stewart, Karen L. Svenson, Masaru Tamura, Heather Tolentino, Sara Wells, Wolfgang Wurst, Atsushi Yoshiki, Louise Lanoue, K C Kent Lloyd, Brian C Leonard, Michel J Roux, Colin Mckerlie, Ala Moshiri

Faculty Research 2025

PURPOSE: This study investigates genes contributing to late-adult corneal dystrophies (LACDs) in aged mice, with potential implications for late-onset corneal dystrophies (CDs) in humans.

METHODS: The International Mouse Phenotyping Consortium (IMPC) database, containing data from 8901 knockout mouse lines, was filtered to include late-adult mice (49+ weeks) with significant (P < 0.0001) CD phenotypes. Candidate genes were mapped to human orthologs using the Mouse Genome Informatics group, with expression analyzed via PLAE and a literature review for prior CD associations. Comparative analyses of LACD genes from IMPC and established human CD genes from IC3D included protein interactions (STRING), biological processes (PANTHER), and molecular pathways (KEGG).

RESULTS: Analysis identified 14 genes linked to late-adult abnormal corneal phenotypes. Of these, 2 genes were previously associated with CDs in humans, while 12 were novel. Seven of the 14 genes (50%) were expressed in the human cornea based on single-cell transcriptomics. Protein-protein interactions via STRING showed several significant interactions …

An Intranasal Subunit Vaccine Induces Protective Systemic And Mucosal Antibody Immunity Against Respiratory Viruses In Mouse Models., Aina Karen Anthi, Anette Kolderup, Eline Benno Vaage, Malin Bern, Sopisa Benjakul, Elias Tjärnhage, Fulgencio Ruso-Julve, Kjell-Rune Jensen, Heidrun Elisabeth Lode, Marina Vaysburd, Jeannette Nilsen, Marie Leangen Herigstad, Siri Aastedatter Sakya, Lisa Tietze, Diego Pilati, Mari Nyquist-Andersen, Mirjam Dürkoop, Torleif Tollefsrud Gjølberg, Linghang Peng, Stian Foss, Morten C Moe, Benjamin E. Low, Michael V. Wiles, David Nemazee, Frode L Jahnsen, John Torgils Vaage, Kenneth A Howard, Inger Sandlie, Leo C James, Gunnveig Grødeland, Fridtjof Lund-Johansen, Jan Terje Andersen

Faculty Research 2025

Although vaccines are usually given intramuscularly, the intranasal delivery route may lead to better mucosal protection and limit the spread of respiratory virus while easing administration and improving vaccine acceptance. The challenge, however, is to achieve delivery across the selective epithelial cell barrier. Here we report on a subunit vaccine platform, in which the antigen is genetically fused to albumin to facilitate FcRn-mediated transport across the mucosal barrier in the presence of adjuvant. Intranasal delivery in conventional and transgenic mouse models induces both systemic and mucosal antigen-specific antibody responses that protect against challenge with SARS-CoV-2 or influenza A. When benchmarked …

Targeting Bard1 Suppresses A Myc-Dependent Transcriptional Program And Tumor Growth In Pancreatic Ductal Adenocarcinoma, Sohum Patel, Eleanor Jenkins, Rutuj P. Kusurkar, Sherry Lee, Wei Jiang, Avinoam Nevler, Matthew Mccoy, Michael J. Pishvaian, Rosalie C. Sears, Jonathan R. Brody, Charles J. Yeo, Aditi Jain

Department of Surgery Faculty Papers

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers demanding better and more effective therapies. BARD1 or BRCA1-Associated -Ring Domain-1 plays a pivotal role in homologous recombination repair (HRR). However, its function and the underlying molecular mechanisms in PDAC are still not fully elucidated. Here, we demonstrate that BARD1 is overexpressed in PDAC and its genetic inhibition suppresses c-Myc and disrupts c-Myc dependent transcriptional program. Mechanistically, BARD1 stabilizes c-Myc through ubiquitin-proteasome system by regulating FBXW7. Importantly, targeting BARD1 using either siRNAs or CRISPR/Cas9 deletion blocks PDAC growth in vitro and in vivo, without any signs of toxicity to mice. …