Digital Commons Network^™

Neutrophils And Neutrophil Extracellular Traps Cause Vascular Occlusion And Delayed Cerebral Ischemia After Subarachnoid Hemorrhage In Mice, Hussein A Zeineddine, Sung-Ha Hong, Pedram Peesh, Ari Dienel, Kiara Torres, Peeyush Thankamani Pandit, Kanako Matsumura, Shuning Huang, Wen Li, Anjali Chauhan, John P Hagan, Sean P Marrelli, Louise D Mccullough, Spiros L Blackburn, Jaroslaw Aronowski, Devin W Mcbride

Faculty, Staff and Student Publications

Background: After subarachnoid hemorrhage (SAH), neutrophils are deleterious and contribute to poor outcomes. Neutrophils can produce neutrophil extracellular traps (NETs) after ischemic stroke. Our hypothesis was that, after SAH, neutrophils contribute to delayed cerebral ischemia (DCI) and worse outcomes via cerebrovascular occlusion by NETs.

Methods: SAH was induced via endovascular perforation, and SAH mice were given either a neutrophil-depleting antibody, a PAD4 (peptidylarginine deiminase 4) inhibitor (to prevent NETosis), DNAse-I (to degrade NETs), or a vehicle control. Mice underwent daily neurological assessment until day 7 and then euthanized for quantification of intravascular brain NETs (iNETs). Subsets of mice were used …

Oxidized Activated Charcoal Nanozymes: Synthesis, And Optimization For In Vitro And In Vivo Bioactivity For Traumatic Brain Injury, Emily A Mchugh, Anton V Liopo, Kimberly Mendoza, Claudia S Robertson, Gang Wu, Zhe Wang, Weiyin Chen, Jacob L Beckham, Paul J Derry, Thomas A Kent, James M Tour

Faculty, Staff and Student Publications

Carbon-based superoxide dismutase (SOD) mimetic nanozymes have recently been employed as promising antioxidant nanotherapeutics due to their distinct properties. The structural features responsible for the efficacy of these nanomaterials as antioxidants are, however, poorly understood. Here, the process-structure-property-performance properties of coconut-derived oxidized activated charcoal (cOAC) nano-SOD mimetics are studied by analyzing how modifications to the nanomaterial's synthesis impact the size, as well as the elemental and electrochemical properties of the particles. These properties are then correlated to the in vitro antioxidant bioactivity of poly(ethylene glycol)-functionalized cOACs (PEG-cOAC). Chemical oxidative treatment methods that afford smaller, more homogeneous cOAC nanoparticles with higher …

Oxidation Of Hydrogen Sulfide To Polysulfide And Thiosulfate By A Carbon Nanozyme: Therapeutic Implications With An Emphasis On Down Syndrome, Paul J Derry, Anton V Liopo, Karthik Mouli, Emily A Mchugh, Anh T T Vo, Ann Mckelvey, Larry J Suva, Gang Wu, Yan Gao, Kenneth R Olson, James M Tour, Thomas A Kent

Faculty, Staff and Student Publications

Hydrogen sulfide (H2S) is a noxious, potentially poisonous, but necessary gas produced from sulfur metabolism in humans. In Down Syndrome (DS), the production of H2S is elevated and associated with degraded mitochondrial function. Therefore, removing H2S from the body as a stable oxide could be an approach to reducing the deleterious effects of H2S in DS. In this report we describe the catalytic oxidation of hydrogen sulfide (H2S) to polysulfides (HS2+n−) and thiosulfate (S2O32−) by poly(ethylene glycol) hydrophilic carbon clusters (PEG-HCCs) and poly(ethylene glycol) oxidized activated charcoal (PEG-OACs), examples of oxidized carbon nanozymes (OCNs). We show that OCNs oxidize H2S …

The Fatigue-Inducing Effects Of Cancer And Its Therapy Are Characterized By Decreased Physical Activity In The Absence Of Any Motivational Deficit, Thien T Phan, Kiersten S Scott, Brandon Chelette, A Phillip West, Robert Dantzer

Faculty, Staff and Student Publications

Although cancer and its therapy are well known to be associated with fatigue, the exact nature of cancer-related fatigue remains ill-defined. We previously reported that fatigue-like behavior induced independently by tumor growth and by the chemotherapeutic agent cisplatin is characterized by reduced voluntary wheel running and an intact motivation to expand effort for food rewards. The present set of experiments was initiated to characterize the functional consequences of fatigue induced by chemoradiotherapy in tumor-bearing mice and relate them to changes in the expression of genes coding for inflammation, mitochondria dynamics and metabolism. Two syngeneic murine models of cancer were selected …

Clonal Hematopoiesis Of Indeterminate Potential Is Associated With Acute Kidney Injury, Caitlyn Vlasschaert, Cassianne Robinson-Cohen, Jianchun Chen, Elvis Akwo, Alyssa C Parker, Samuel A Silver, Pavan K Bhatraju, Hannah Poisner, Shirong Cao, Ming Jiang, Yinqiu Wang, Aolei Niu, Edward Siew, Joseph C Van Amburg, Holly J Kramer, Anna Kottgen, Nora Franceschini, Bruce M Psaty, Russell P Tracy, Alvaro Alonso, Dan E Arking, Josef Coresh, Christie M Ballantyne, Eric Boerwinkle, Morgan Grams, Ming-Zhi Zhang, Bryan Kestenbaum, Matthew B Lanktree, Michael J Rauh, Raymond C Harris, Alexander G Bick

Faculty, Staff and Student Publications

Age is a predominant risk factor for acute kidney injury (AKI), yet the biological mechanisms underlying this risk are largely unknown. Clonal hematopoiesis of indeterminate potential (CHIP) confers increased risk for several chronic diseases associated with aging. Here we sought to test whether CHIP increases the risk of AKI. In three population-based epidemiology cohorts, we found that CHIP was associated with a greater risk of incident AKI, which was more pronounced in patients with AKI requiring dialysis and in individuals with somatic mutations in genes other than DNMT3A, including mutations in TET2 and JAK2. Mendelian randomization analyses supported a causal …

Targeting Glutamine Dependence With Drp-104 Inhibits Proliferation And Tumor Growth Of Castration-Resistant Prostate Cancer, David Moon, J Spencer Hauck, Xue Jiang, Holly Quang, Lingfan Xu, Fan Zhang, Xia Gao, Robert Wild, Jeffrey I Everitt, Everardo Macias, Yiping He, Jiaoti Huang

Faculty, Staff and Students Publications

BACKGROUND: Prostate cancer (PCa) continues to be one of the leading causes of cancer deaths in men. While androgen deprivation therapy is initially effective, castration-resistant PCa (CRPC) often recurs and has limited treatment options. Our previous study identified glutamine metabolism to be critical for CRPC growth. The glutamine antagonist 6-diazo-5-oxo-l-norleucine (DON) blocks both carbon and nitrogen pathways but has dose-limiting toxicity. The prodrug DRP-104 is expected to be preferentially converted to DON in tumor cells to inhibit glutamine utilization with minimal toxicity. However, CRPC cells' susceptibility to DRP-104 remains unclear.

METHODS: Human PCa cell lines (LNCaP, LAPC4, C4-2/MDVR, PC-3, 22RV1, …

Highlights Of How Single-Cell Analyses Are Illuminating Differentiation And Disease In The Gastric Corpus, Mahliyah Adkins-Threats, Yang-Zhe Huang, Jason C Mills

Faculty, Staff and Students Publications

Single-cell RNA-sequencing (scRNA-seq) has emerged as a powerful technique to identify novel cell markers, developmental trajectories, and transcriptional changes during cell differentiation and disease onset and progression. In this review, we highlight recent scRNA-seq studies of the gastric corpus in both human and murine systems that have provided insight into gastric organogenesis, identified novel markers for the various gastric lineages during development and in adults, and revealed transcriptional changes during regeneration and tumorigenesis. Overall, by elucidating transcriptional states and fluctuations at the cellular level in healthy and disease contexts, scRNA-seq may lead to better, more personalized clinical treatments for disease …

Centriole And Transition Zone Structures In Photoreceptor Cilia Revealed By Cryo-Electron Tomography, Zhixian Zhang, Abigail R Moye, Feng He, Muyuan Chen, Melina A Agosto, Theodore G Wensel

Faculty, Staff and Students Publications

Primary cilia mediate sensory signaling in multiple organisms and cell types but have structures adapted for specific roles. Structural defects in them lead to devastating diseases known as ciliopathies in humans. Key to their functions are structures at their base: the basal body, the transition zone, the "Y-shaped links," and the "ciliary necklace." We have used cryo-electron tomography with subtomogram averaging and conventional transmission electron microscopy to elucidate the structures associated with the basal region of the "connecting cilia" of rod outer segments in mouse retina. The longitudinal variations in microtubule (MT) structures and the lumenal scaffold complexes connecting them …

Postsynaptic Β1 Spectrin Maintains Na+ Channels At The Neuromuscular Junction, Ozlem Sert, Xiaoyun Ding, Chuansheng Zhang, Ruifa Mi, Ahmet Hoke, Matthew N Rasband

Faculty, Staff and Students Publications

Spectrins function together with actin as obligatory subunits of the submembranous cytoskeleton. Spectrins maintain cell shape, resist mechanical forces, and stabilize ion channel and transporter protein complexes through binding to scaffolding proteins. Recently, pathogenic variants of SPTBN4 (β4 spectrin) were reported to cause both neuropathy and myopathy. Although β4 spectrin's role in neurons is mostly understood, its function in skeletal muscle, another excitable tissue subject to large forces, is unknown. Here, using a muscle specific β4 spectrin conditional knockout mouse, we show that β4 spectrin does not contribute to muscle function. In addition, we show β4 spectrin is not present …

Retrograde Endocannabinoid Signaling At Inhibitory Synapses In Vivo, Barna Dudok, Linlin Z Fan, Jordan S Farrell, Shreya Malhotra, Jesslyn Homidan, Doo Kyung Kim, Celestine Wenardy, Charu Ramakrishnan, Yulong Li, Karl Deisseroth, Ivan Soltesz

Faculty, Staff and Students Publications

Endocannabinoid (eCB)-mediated suppression of inhibitory synapses has been hypothesized, but this has not yet been demonstrated to occur in vivo because of the difficulty in tracking eCB dynamics and synaptic plasticity during behavior. In mice navigating a linear track, we observed location-specific eCB signaling in hippocampal CA1 place cells, and this was detected both in the postsynaptic membrane and the presynaptic inhibitory axons. All-optical in vivo investigation of synaptic responses revealed that postsynaptic depolarization was followed by a suppression of inhibitory synaptic potentials. Furthermore, interneuron-specific cannabinoid receptor deletion altered place cell tuning. Therefore, rapid, postsynaptic, activity-dependent eCB signaling modulates inhibitory …

Autophagy Differentially Regulates Tissue Tolerance Of Distinct Target Organs In Graft-Versus-Host Disease Models, Katherine Oravecz-Wilson, Emma Lauder, Austin Taylor, Laure Maneix, Jeanine L Van Nostrand, Yaping Sun, Lu Li, Dongchang Zhao, Chen Liu, Pavan Reddy

Faculty, Staff and Students Publications

Tissue-intrinsic mechanisms that regulate severity of systemic pathogenic immune-mediated diseases, such as acute graft-versus-host disease (GVHD), remain poorly understood. Following allogeneic hematopoietic stem cell transplantation, autophagy, a cellular stress protective response, is induced in host nonhematopoietic cells. To systematically address the role of autophagy in various host nonhematopoietic tissues, both specific classical target organs of acute GVHD (intestines, liver, and skin) and organs conventionally not known to be targets of GVHD (kidneys and heart), we generated mice with organ-specific knockout of autophagy related 5 (ATG5) to specifically and exclusively inhibit autophagy in the specific organs. When compared with wild-type recipients, …

Cub Domains Are Not Required For Ovch2 Function In Sperm Maturation In The Mouse Epididymis, Katarzyna Kent, Kaori Nozawa, Courtney Sutton, Frey Daniel, Masahito Ikawa, Thomas X Garcia, Martin M Matzuk

Faculty, Staff and Students Publications

BACKGROUND: Ovochymase 2 (Ovch2) is an epididymis-specific gene that is required for male fertility. While a multitude of reproductive tract-specific genes required for male fertility have been identified, OVCH2 is thus far the first protein required for male fertility that contains Complement C1r/C1s, Uegf, Bmp1 (CUB) domains located in tandem in the C-terminus of the protein. Identifying the functional significance of this unique domain has implications in better understanding fertility and infertility and as a potential contraceptive target.

OBJECTIVE: The goals of these studies were to understand the influence and requirement of OVCH2 CUB domains in the localization and functional …

Cholinergic Basal Forebrain Connectivity To The Basolateral Amygdala Modulates Food Intake, Joshua Ortiz-Guzman, Jessica L Swanson, Evelyne K Tantry, Mikhail Kochukov, Kevin Ung, Angela P Addison, Snigdha Srivastava, Benjamin D Belfort, Emily Ji, Sean W Dooling, Sarah A Chen, Qingchun Tong, Benjamin R Arenkiel

Faculty, Staff and Student Publications

Obesity results from excessive caloric input associated with overeating and presents a major public health challenge. The hypothalamus has received significant attention for its role in governing feeding behavior and body weight homeostasis. However, extrahypothalamic brain circuits also regulate appetite and consumption by altering sensory perception, motivation, and reward. We recently discovered a population of basal forebrain cholinergic (BFc) neurons that regulate appetite suppression. Through viral tracing methods in the mouse model, we found that BFc neurons densely innervate the basolateral amygdala (BLA), a limbic structure involved in motivated behaviors. Using channelrhodopsin-assisted circuit mapping, we identified cholinergic responses in BLA …

Decreased Sarcoplasmic Reticulum Phospholipids In Human Skeletal Muscle Are Associated With Metabolic Syndrome, Samantha E Adamson, Sangeeta Adak, Max C Petersen, Dustin Higgins, Larry D Spears, Rong Mei Zhang, Andrea Cedeno, Alexis Mckee, Aswathi Kumar, Sudhir Singh, Fong-Fu Hsu, Janet B Mcgill, Clay F Semenkovich

2020-Current year OA Pubs

Metabolic syndrome affects more than one in three adults and is associated with increased risk of diabetes, cardiovascular disease, and all-cause mortality. Muscle insulin resistance is a major contributor to the development of the metabolic syndrome. Studies in mice have linked skeletal muscle sarcoplasmic reticulum (SR) phospholipid composition to sarcoplasmic/endoplasmic reticulum Ca

Mfsd7c Functions As A Transporter Of Choline At The Blood-Brain Barrier, Xuan Thi Anh Nguyen, Angela Lee, Jorge L Granadillo, Catherine Gooch, Et Al.

2020-Current year OA Pubs

Mutations in the orphan transporter MFSD7c (also known as Flvcr2), are linked to Fowler syndrome. Here, we used Mfsd7c knockout (Mfsd7c

Distributed Feature Representations Of Natural Stimuli Across Parallel Retinal Pathways, Jen-Chun Hsiang, Ning Shen, Florentina Soto, Daniel Kerschensteiner

2020-Current year OA Pubs

How sensory systems extract salient features from natural environments and organize them across neural pathways is unclear. Combining single-cell and population two-photon calcium imaging in mice, we discover that retinal ON bipolar cells (second-order neurons of the visual system) are divided into two blocks of four types. The two blocks distribute temporal and spatial information encoding, respectively. ON bipolar cell axons co-stratify within each block, but separate laminarly between them (upper block: diverse temporal, uniform spatial tuning; lower block: diverse spatial, uniform temporal tuning). ON bipolar cells extract temporal and spatial features similarly from artificial and naturalistic stimuli. In addition, …

The Card8 Inflammasome Dictates Hiv/Siv Pathogenesis And Disease Progression, Qiankun Wang, Kolin M Clark, Ritudhwaj Tiwari, Nagarajan Raju, Gregory K Tharp, Jeffrey Rogers, R Alan Harris, Muthuswamy Raveendran, Steven E Bosinger, Tricia H Burdo, Guido Silvestri, Liang Shan

Faculty, Staff and Students Publications

While CD4+ T-cell depletion is key to disease progression in people living with HIV and SIV-infected macaques, the mechanisms underlying this depletion remain incompletely understood, with most cell death involving uninfected cells. In contrast, SIV infection of “natural” hosts such as sooty mangabeys do not cause CD4+ depletion and AIDS despite high-level viremia. Here, we report that the CARD8 inflammasome is activated immediately after HIV entry by the viral protease encapsulated in incoming virions. Sensing of HIV protease activity by CARD8 leads to rapid pyroptosis of quiescent cells without productive infection, while T-cell activation abolishes CARD8 function and increases permissiveness …

Gamma Delta T Cells In Acute Myeloid Leukemia: Biology And Emerging Therapeutic Strategies, Adishwar Rao, Akriti Agrawal, Gautam Borthakur, Venkata Lokesh Battula, Abhishek Maiti

Faculty, Staff and Student Publications

γδ T cells play an important role in disease control in acute myeloid leukemia (AML) and have become an emerging area of therapeutic interest. These cells represent a minor population of T lymphocytes with intrinsic abilities to recognize antigens in a major histocompatibility complex-independent manner and functionally straddle the innate and adaptive immunity interface. AML shows high expression of phosphoantigens and UL-16 binding proteins that activate the Vδ2 and Vδ1 subtypes of γδ T cells, respectively, leading to γδ T cell-mediated cytotoxicity. Insights from murine models and clinical data in humans show improved overall survival, leukemia-free survival, reduced risk of …

Rbpms Regulates Cardiomyocyte Contraction And Cardiac Function Through Rna Alternative Splicing, Peiheng Gan, Zhaoning Wang, Svetlana Bezprozvannaya, John R Mcanally, Wei Tan, Hui Li, Rhonda Bassel-Duby, Ning Liu, Eric N Olson

Faculty, Staff and Student Publications

Aims: RNA binding proteins play essential roles in mediating RNA splicing and are key post-transcriptional regulators in the heart. Our recent study demonstrated that RBPMS (RNA binding protein with multiple splicing) is crucial for cardiac development through modulating mRNA splicing, but little is known about its functions in the adult heart. In this study, we aim to characterize the post-natal cardiac function of Rbpms and its mechanism of action.

Methods and results: We generated a cardiac-specific knockout mouse line and found that cardiac-specific loss of Rbpms caused severe cardiomyocyte contractile defects, leading to dilated cardiomyopathy and early lethality in adult …

Loss Of The Endoplasmic Reticulum Protein Tmem208 Affects Cell Polarity, Development, And Viability, Debdeep Dutta, Oguz Kanca, Rishi V Shridharan, Paul C Marcogliese, Benjamin Steger, Marie Morimoto, F Graeme Frost, Ellen Macnamara, Michael F Wangler, Shinya Yamamoto, Andreas Jenny, David Adams, May C Malicdan, Hugo J Bellen

Faculty, Staff and Students Publications

Nascent proteins destined for the cell membrane and the secretory pathway are targeted to the endoplasmic reticulum (ER) either posttranslationally or cotranslationally. The signal-independent pathway, containing the protein TMEM208, is one of three pathways that facilitates the translocation of nascent proteins into the ER. The in vivo function of this protein is ill characterized in multicellular organisms. Here, we generated a CRISPR-induced null allele of the fruit fly ortholog

Trex Tetramer Disruption Alters Rna Processing Necessary For Corticogenesis In Thoc6 Intellectual Disability Syndrome., Elizabeth A Werren, Geneva R Laforce, Anshika Srivastava, Delia R Perillo, Shaokun Li, Katherine Johnson, Safa Baris, Brandon Berger, Samantha L Regan, Christian D Pfennig, Sonja De Munnik, Rolph Pfundt, Malavika Hebbar, Raúl Jimenez-Heredia, Elif Karakoc-Aydiner, Ahmet Ozen, Jasmin Dmytrus, Ana Krolo, Ken Corning, E J Prijoles, Raymond J Louie, Robert Roger Lebel, Thuy-Linh Le, Jeanne Amiel, Christopher T Gordon, Kaan Boztug, Katta M Girisha, Anju Shukla, Stephanie L Bielas, Ashleigh E Schaffer

Faculty Research 2024

THOC6 variants are the genetic basis of autosomal recessive THOC6 Intellectual Disability Syndrome (TIDS). THOC6 is critical for mammalian Transcription Export complex (TREX) tetramer formation, which is composed of four six-subunit THO monomers. The TREX tetramer facilitates mammalian RNA processing, in addition to the nuclear mRNA export functions of the TREX dimer conserved through yeast. Human and mouse TIDS model systems revealed novel THOC6-dependent, species-specific TREX tetramer functions. Germline biallelic Thoc6 loss-of-function (LOF) variants result in mouse embryonic lethality. Biallelic THOC6 LOF variants reduce the binding affinity of ALYREF to THOC5 without affecting the protein expression of TREX members, implicating …

Comparative Genomics Incorporating Translocation Renal Cell Carcinoma Mouse Model Reveals Molecular Mechanisms Of Tumorigenesis, Gopinath Prakasam, Akhilesh Mishra, Alana Christie, Jeffrey Miyata, Deyssy Carrillo, Vanina T Tcheuyap, Hui Ye, Quyen N Do, Yunguan Wang, Oscar Reig Torras, Ramesh Butti, Hua Zhong, Jeffrey Gagan, Kevin B Jones, Thomas J Carroll, Zora Modrusan, Steffen Durinck, Mai-Carmen Requena-Komuro, Noelle S Williams, Ivan Pedrosa, Tao Wang, Dinesh Rakheja, Payal Kapur, James Brugarolas

Faculty, Staff and Student Publications

Translocation renal cell carcinoma (tRCC) most commonly involves an ASPSCR1-TFE3 fusion, but molecular mechanisms remain elusive and animal models are lacking. Here, we show that human ASPSCR1-TFE3 driven by Pax8-Cre (a credentialed clear cell RCC driver) disrupted nephrogenesis and glomerular development, causing neonatal death, while the clear cell RCC failed driver, Sglt2-Cre, induced aggressive tRCC (as well as alveolar soft part sarcoma) with complete penetrance and short latency. However, in both contexts, ASPSCR1-TFE3 led to characteristic morphological cellular changes, loss of epithelial markers, and an epithelial-mesenchymal transition. Electron microscopy of tRCC tumors showed lysosome expansion, and functional studies revealed simultaneous …

Inhibiting Centrosome Clustering Reduces Cystogenesis And Improves Kidney Function In Autosomal Dominant Polycystic Kidney Disease, Tao Cheng, Aruljothi Mariappan, Ewa Langner, Kyuhwan Shim, Jay Gopalakrishnan, Moe R. Mahjoub

2020-Current year OA Pubs

Autosomal dominant polycystic kidney disease (ADPKD) is a monogenic disorder accounting for approximately 5% of patients with renal failure, yet therapeutics for the treatment of ADPKD remain limited. ADPKD tissues display abnormalities in the biogenesis of the centrosome, a defect that can cause genome instability, aberrant ciliary signaling, and secretion of pro-inflammatory factors. Cystic cells form excess centrosomes via a process termed centrosome amplification (CA), which causes abnormal multipolar spindle configurations, mitotic catastrophe, and reduced cell viability. However, cells with CA can suppress multipolarity via "centrosome clustering," a key mechanism by which cells circumvent apoptosis. Here, we demonstrate that inhibiting …

Tubular Cpt1a Deletion Minimally Affects Aging And Chronic Kidney Injury, Safaa Hammoud, Yosuke Osaki, Steven Funk, Dongliang Lu, Benjamin D. Humphreys, Jeffrey Koenitzer, Justin Kern, Nidia Messias, Irfan J Lodhi, Leslie S. Gewin, Et Al.

2020-Current year OA Pubs

Kidney tubules use fatty acid oxidation (FAO) to support their high energetic requirements. Carnitine palmitoyltransferase 1A (CPT1A) is the rate-limiting enzyme for FAO, and it is necessary to transport long-chain fatty acids into mitochondria. To define the role of tubular CPT1A in aging and injury, we generated mice with tubule-specific deletion of Cpt1a (Cpt1aCKO mice), and the mice were either aged for 2 years or injured by aristolochic acid or unilateral ureteral obstruction. Surprisingly, Cpt1aCKO mice had no significant differences in kidney function or fibrosis compared with wild-type mice after aging or chronic injury. Primary tubule cells from aged Cpt1aCKO …

Nrf2 Activation In Trp53;P16-Deficient Mice Drives Oral Squamous Cell Carcinoma, Samera H Hamad, Rani S Sellers, Nathan Wamsley, Paul Zolkind, Travis P Schrank, Michael B Major, Bernard E Weissman

2020-Current year OA Pubs

UNLABELLED: Aberrant activation of the NRF2/NFE2L2 transcription factor commonly occurs in head and neck squamous cell carcinomas (HNSCC). Mouse model studies have shown that NRF2 activation alone does not result in cancer. When combined with classic oncogenes and at the right dose, NRF2 activation promotes tumor initiation and progression. Here we deleted the tumor suppressor genes p16INK4A and p53 (referred to as CP mice), which are commonly lost in human HNSCC, in the presence of a constitutively active NRF2E79Q mutant (CPN mice). NRF2E79Q expression in CPN mice resulted in squamous cell hyperplasia or dysplasia with hyperkeratosis in the esophagus, oropharynx, …

Multi-Molecular Hyperspectral Prm-Srs Microscopy, Wenxu Zhang, Yajuan Li, Anthony A Fung, Zhi Li, Hongje Jang, Honghao Zha, Xiaoping Chen, Fangyuan Gao, Jane Y Wu, Huaxin Sheng, Junjie Yao, Dorota Skowronska-Krawczyk, Sanjay Jain, Lingyan Shi

2020-Current year OA Pubs

Lipids play crucial roles in many biological processes. Mapping spatial distributions and examining the metabolic dynamics of different lipid subtypes in cells and tissues are critical to better understanding their roles in aging and diseases. Commonly used imaging methods (such as mass spectrometry-based, fluorescence labeling, conventional optical imaging) can disrupt the native environment of cells/tissues, have limited spatial or spectral resolution, or cannot distinguish different lipid subtypes. Here we present a hyperspectral imaging platform that integrates a Penalized Reference Matching algorithm with Stimulated Raman Scattering (PRM-SRS) microscopy. Using this platform, we visualize and identify high density lipoprotein particles in human …

Sting Licensing Of Type I Dendritic Cells Potentiates Antitumor Immunity, Jian Wang, Suxin Li, Maggie Wang, Xu Wang, Shuqing Chen, Zhichen Sun, Xiubao Ren, Gang Huang, Baran D Sumer, Nan Yan, Yang-Xin Fu, Jinming Gao

Faculty, Staff and Student Publications

Stimulator of interferon genes (STING) is an immune adaptor protein that senses cyclic GMP-AMP (cGAMP) in response to self or microbial cytosolic DNA as a danger signal. STING is ubiquitously expressed in diverse cell populations including cancer cells with distinct cellular functions such as activation of type I interferons, autophagy induction, or triggering apoptosis. It is not well understood whether and which subsets of immune cells, stromal cells, or cancer cells are particularly important for STING-mediated antitumor immunity. Here using a polymeric STING-activating nanoparticle (PolySTING) with a “shock-and-lock” dual activation mechanism, we show type 1 conventional dendritic cell (cDC1) is …

Mutant P53 Protects Triple-Negative Breast Adenocarcinomas From Ferroptosis In Vivo, Denada Dibra, Shunbin Xiong, Sydney M Moyer, Adel K El-Naggar, Yuan Qi, Xiaoping Su, Elisabeth K Kong, Anil Korkut, Guillermina Lozano

Faculty, Staff and Student Publications

The TP53 tumor suppressor gene is mutated early in most of the patients with triple-negative breast cancer (TNBC). The most frequent TP53 alterations are missense mutations that contribute to tumor aggressiveness. Here, we used an autochthonous somatic TNBC mouse model, in which mutant p53 can be toggled on and off genetically while leaving the tumor microenvironment intact and wild-type for p53 to identify physiological dependencies on mutant p53. In TNBCs that develop in this model, deletion of two different hotspot p53R172H and p53R245W mutants triggers ferroptosis in vivo, a cell death mechanism involving iron-dependent lipid peroxidation. Mutant p53 protects cells …

High Resolution Spatial Profiling Of Kidney Injury And Repair Using Rna Hybridization-Based In Situ Sequencing, Haojia Wu, Eryn E Dixon, Qiao Xuanyuan, Juanru Guo, Yasuhiro Yoshimura, Chitnis Debashish, Anezka Niesnerova, Hao Xu, Morgane Rouault, Benjamin D Humphreys

2020-Current year OA Pubs

Emerging spatially resolved transcriptomics technologies allow for the measurement of gene expression in situ at cellular resolution. We apply direct RNA hybridization-based in situ sequencing (dRNA HybISS, Cartana part of 10xGenomics) to compare male and female healthy mouse kidneys and the male kidney injury and repair timecourse. A pre-selected panel of 200 genes is used to identify cell state dynamics patterns during injury and repair. We develop a new computational pipeline, CellScopes, for the rapid analysis, multi-omic integration and visualization of spatially resolved transcriptomic datasets. The resulting dataset allows us to resolve 13 kidney cell types within distinct kidney niches, …

Combined Effects Of Exercise And Immuno-Chemotherapy Treatments On Tumor Growth In Mc38 Colorectal Cancer-Bearing Mice., Manon Gouez, Amélie Rébillard, Amandine Thomas, Sabine Beaumel, Eva-Laure Matera, Etienne Gouraud, Luz Orfila, Brice Martin, Olivia Pérol, Cédric Chaveroux, Erica N. Chirico, Charles Dumontet, Béatrice Fervers, Vincent Pialoux

Cooper Medical School of Rowan University Departmental Research

Acute exercise induces transient modifications in the tumor microenvironment and has been linked to reduced tumor growth along with increased infiltration of immune cells within the tumor in mouse models. In this study, we aimed to evaluate the impact of acute exercise before treatment administration on tumor growth in a mice model of MC38 colorectal cancer receiving an immune checkpoint inhibitor (ICI) and chemotherapy. Six-week-old mice injected with colorectal cancer cells (MC38) were randomized in 4 groups: control (CTRL), immuno-chemotherapy (TRT), exercise (EXE) and combined intervention (TRT/EXE). Both TRT and TRT-EXE received ICI: anti-PD1-1 (1 injection/week) and capecitabine + oxaliplatin …