Medical Specialties Commons^™

Mucin-Derived Sugars Act As Metabolic Brakes Controlling Growth Initiation In Akkermansia Muciniphila, Bryan D Lakey, Katherine J Wozniak, Robert A Britton, Jeffrey J Tabor

Faculty, Staff and Students Publications

Akkermansia muciniphila is a key member of the gut microbiota and plays important roles in host metabolism and health. In the colon, A. muciniphila extracts nutrients from oligosaccharide-rich mucin glycans that comprise the mucosa. However, this environment is complex and shaped by dietary inputs, microbiome metabolism, and mucin glycan composition varying across hosts, gastrointestinal regions, and physiological states. How strains of A. muciniphila integrate these nutrient signals into growth initiation and niche colonization remains unclear. Here, we compare physiological responses of a human- and mouse-derived strain of A. muciniphila, finding that dietary sugars differentially affect these isolates, suggesting host-associated …

Steroid Receptor Coactivator 3-Deficient Regulatory T Cells Eradicate Multiple Solid Tumors In Syngeneic Mouse Models, Yuri Park, Adam M Dean, Yan Xia, Jianming Xu, Clifford C Dacso, David M Lonard, Sang Jun Han

Faculty, Staff and Students Publications

Steroid receptor coactivator 3 (SRC-3) is highly expressed in regulatory T cells (Tregs) and is important for their immunosuppressive activity. Recently, we demonstrated that disrupting SRC-3 expression in Tregs eliminates triple-negative breast cancer (TNBC) and prostate cancer in syngeneic animal models by generating an anti-tumor immune microenvironment without inducing immune-related adverse events (irAEs). Further analysis of these mice revealed that SRC-3 knockout (KO) Tregs infiltrated breast tumors and facilitated the infiltration of CD8

Mtorc2-Nav1.2 Signaling Drives Early Hyperexcitability In Alzheimer’S Disease Mouse Model

Faculty, Staff and Students Publications

Hyperexcitability is a biomarker of early-stage Alzheimer’s Disease (AD) and hastens cognitive decline later in its course. Mechanistic target of rapamycin (mTOR) signaling contributes to the slope of this trajectory, as evidenced by early increased brain expression and the rescue of hyperexcitability by genetic deletion of mTOR complex 2 (mTORC2); however, a molecular mechanism directly linking mTOR signaling to membrane hyperexcitability in early-stage AD remains elusive. Here, we show that hyperactive mTOR signaling stimulates the voltage-gated Na+ channel 1.2 (Nav1.2), a previously identified downstream phosphorylation target of mTORC2 and a key regulator of membrane electrogenesis. Augmented Nav1.2 channel function induced …

A Massively Parallel Reporter Assay Of Mecp2 Cis-Regulatory Elements Reveals Genetic Candidates For Male-Biased Autism, Rebecca Meyer-Schuman, Fisher Cherry, Yang Sui, Athanasios Papastathopoulos-Katsaros, Yi Zhong, Yidan Li, Tianyun Wang, Kelsey Hennick, Druha Karunakaran, Hanna Berk-Rauch, Zhandong Liu, Aravinda Chakravarti, Tomasz Nowakowski, Evan E Eichler, Huda Zoghbi

Faculty, Staff and Students Publications

Autism affects male individuals four times more often than female individuals, yet the basis of this sex bias remains unclear. One hypothesis is that this sex bias is due to genetic variants in X chromosome genes where haploinsufficiency causes neurodevelopmental disorders (NDDs). In heterozygous XX female probands, a complete loss-of-function variant in one of these genes often causes syndromic NDD, but the same variant is too deleterious for survival in hemizygous XY males. A mild hypomorphic variant, however, may be tolerated in a female carrier but may produce milder neurological phenotypes in a male proband. We tested this by investigating …

Forniceal Deep Brain Stimulation Improves Memory In Rett Syndrome Mice By Promoting The Maturation Of Newborn Hippocampal Neurons, Qi Wang, Bin Tang, Zhenyu Wu, Huda Y Zoghbi, Jianrong Tang

Faculty, Staff and Students Publications

Deep brain stimulation (DBS) is associated with an increase in hippocampal neurogenesis and memory benefits, but the causal mechanism is unclear. Here, we use a mouse model of Rett syndrome, a severe learning disability syndrome caused by MECP2 loss of function, to find that DBS promotes the maturation and integration of newborn dentate granule cells (DGCs) into the neural circuit. Suppressing hippocampal neurogenesis prevented DBS from improving learning and memory. Newborn methyl-CpG-binding protein 2 (MeCP2)-deficient DGCs in Rett syndrome mice showed attenuated development and synaptic dysfunction, but DBS rescued DGC dendritic arborization, synaptogenesis, and long-term synaptic plasticity. DBS achieves this, …

Glial Dysfunction And Memory Impairments In A Model Of Pediatric Obstructive Sleep Apnea, Thea Zlatkov, Akdes Serin Harmanci, Christopher J Yates, Kenneth Nobleza, Roshan Ailani, Adam C Adler, Farrah Kheradmand, Hyun Kyoung Lee, Benjamin Deneen, Hyun-Hwan Jeong, Arvind Chandrakantan

Faculty, Staff and Students Publications

Pediatric obstructive sleep apnea (POSA) is a common childhood disease that often causes aberrant brain development and cognitive deficits. The pathophysiological underpinnings of cognitive impairments in POSA remain unclear. Here, we examined cellular and molecular aspects of pathology in a mouse model of POSA that features learning and memory deficits. We performed single-nucleus RNA-sequencing (snRNA-seq) of the hippocampus to examine gene expression changes in an unbiased and cell type-specific manner. This dataset revealed a striking perturbation of transcriptomes across all brain cell types, particularly within glia and neural stem cells. We validated reduced expression of several differentially expressed genes at …

Progressive Remodeling Of Global Protein Interaction Networks In A Mouse Model Of Tauopathy, Noah Lampl, Morgan C Stephens, Zihan Wang, Joseph T Nigro, Alejandro Rondon Ortiz, Ryan Hekman, Anna Lourdes F Cruz, Rebecca Roberts, Lulu Jiang, Juan Botas, Andrew Emili, Benjamin Wolozin

Faculty, Staff and Students Publications

Neurodegenerative disease is marked not just by loss of proteins or cells, but by dynamic rewiring of macromolecular interaction networks that precede and drive pathology. Here, we present a temporally resolved, systems-scale map of multi-protein complex remodeling in a tauopathy model, integrating co-fractionation mass spectrometry, quantitative phosphoproteomics, and machine learning to decode phosphorylation-dependent shifts in protein interactomes across disease progression. This interactomic atlas serves as a resource to investigate functional assemblies, including MAPT-Dpysl2 and Cyfip1-actin, as well as ptk2b-Kars/Dars and ptk2b-Msn-Farsb-complexes, that modulate early disease phenotypes in vivo. Notably, it captures the composition, dynamics, and regulatory state of protein complexes …

Progressive Remodeling Of Global Protein Interaction Networks In A Mouse Model Of Tauopathy, Noah Lampl, Morgan C Stephens, Zihan Wang, Joseph T Nigro, Alejandro Rondon Ortiz, Ryan Hekman, Anna Lourdes F Cruz, Rebecca Roberts, Lulu Jiang, Juan Botas, Andrew Emili, Benjamin Wolozin

Faculty, Staff and Students Publications

Neurodegenerative disease is marked not just by loss of proteins or cells, but by dynamic rewiring of macromolecular interaction networks that precede and drive pathology. Here, we present a temporally resolved, systems-scale map of multi-protein complex remodeling in a tauopathy model, integrating co-fractionation mass spectrometry, quantitative phosphoproteomics, and machine learning to decode phosphorylation-dependent shifts in protein interactomes across disease progression. This interactomic atlas serves as a resource to investigate functional assemblies, including MAPT-Dpysl2 and Cyfip1-actin, as well as ptk2b-Kars/Dars and ptk2b-Msn-Farsb-complexes, that modulate early disease phenotypes in vivo. Notably, it captures the composition, dynamics, and regulatory state of protein complexes …

Fgfr1/Klb-Mfg-E8 Maintains Microvascular Integrity And Adaptive Cardiac Remodeling, Sanskruti R Gare, Nasser H Alatawi, Xinyi Chen, Jiayan Zhang, Claire Ross, Oveena Fonseka, Yihua Han, Namrita Kaur, Andrea Ruiz-Velasco, Xiangjun Zhao, Yingjuan Liu, Riham R E Abouleisa, Susanne S Hille, Tao Wang, Sabu Abraham, Bernard D Keavney, Martin K Rutter, Elizabeth J Cartwright, Gareth Howell, Tamer M A Mohamed, Oliver J Müller, Wei Liu

Faculty, Staff and Students Publications

Background: Endothelial defects in the heart are a contributor to cardiac pathological remodeling and dysfunction, which can be influenced by cardiomyocytes. Here, we explore cardioprotective crosstalk between cardiomyocytes and endothelial cells under diabetic conditions.

Methods: Type 2 diabetes was induced in male and female mice using a high-fat, high-sucrose diet in conjunction with low-dose streptozotocin. Cardiomyocyte-specific deletion of FGFR1 (fibroblast growth factor receptor 1) or KLB (beta-Klotho) was achieved by crossing floxed mice with αMHC (alpha-myosin heavy chain)-Cre transgenic mice, while the treatment potential was assessed by recombinant adeno-associated virus 9 delivery systems or administration of recombinant protein. Various in …

Spriz (Ccdc127) Protein Conserved In Deuterostome Animals Is A Rigid Omm-Imm Tether That Locally Sets Mitochondrial Ims Volume, Raman Shulinski, Roman Loban, Danny Farhat, Benjamín Cartes-Saavedra, Matthew J. Magda, Pavel Kotchetkov, Victoria Caminiti, Linda David, Yuri I. Wolf, Conor O'Dwyer, Morgan Fullerton, Yan Burelle, Jyh-Yeuan E. Lee, Andrea Raimondi, Eugene V. Koonin, György Hajnóczky, Mary-Ellen Harper, Luca Pellegrini

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

The double-membrane nature of mitochondria generates an intermembrane volume through which ions, reactive oxygen species, and metabolites must flux to reach the matrix or cytosol, but whether this volume is a genetically specified structure remains unknown. We identify SPRIZ (spatial regulator of the intermembrane zone), the product of Ccdc127, a gene conserved across deuterostome animals. SPRIZ assembles into an ∼18-nanometer homodimeric tether anchored in the outer mitochondrial membrane (OMM) and inserted into the inner mitochondrial membrane (IMM) through vertebrate-specific hydrophobic loops, physically spacing the two membranes and setting local intermembrane volume. Cryo-electron tomography of native mitochondria revealed rod-like densities …

A Metabolic-Epigenetic Switch Governs Multicellular Cardiac Repair Following Succinate Dehydrogenase Inhibition, Dina Abbasian, Clarissa Shoffler, Christopher Petucci, Wyatt G Paltzer, Yu-Ling Chang, James Marchant, Diana Presas-Ramos, Kai P Atlass, Stephen A Nemr, Jiyoung Bae, Sanjeev S Ranade, Alexandre R Colas, Xiao Li, James F Martin, Ahmed I Mahmoud

Faculty, Staff and Students Publications

Cardiac regeneration is limited in the adult mammalian heart because of restricted cardiomyocyte proliferation and persistent fibrosis. We previously demonstrated that transient pharmacological inhibition of succinate dehydrogenase (SDH) with malonate promotes regeneration after myocardial infarction. Here, we integrate single-nucleus RNA sequencing and ATAC-seq to reveal multicellular transcriptional and epigenetic reprogramming underlying this response. Cell-specific Sdhb deletion dissected contributions of SDH inhibition; cardiomyocyte-specific Sdhb deletion transiently increased cardiomyocyte proliferation but did not improve post-myocardial infarction function, whereas myofibroblast-specific Sdhb deletion suppressed myofibroblast activation and fibrosis and improved cardiac function. SDH inhibition promoted reductive mitochondrial metabolism and remodeled H3K4me3-marked and H3K27me3-marked chromatin …

Cadherin-11 Regulation Of Type Ii Alveolar Epithelial Cells During Pulmonary Fibrosis, Mesias Pedroza, Sarah To, Jennifer Smith, Tingting W Mills, Thandiwe Chavula, Harry Karmouty-Quintana, Sandeep K Agarwal

Faculty, Staff and Students Publications

Type II alveolar epithelial cell (AT2) injury has been hypothesized to contribute to pulmonary fibrosis. Cadherin-11 (CDH11) is a mediator of fibrosis and is upregulated on AT2s during lung fibrosis. Herein, the regulation of AT2 by CDH11 during pulmonary fibrosis was investigated. CDH11 levels were increased in lung samples from patients with idiopathic pulmonary fibrosis compared with those from healthy controls. CDH11 expression was inversely correlated with lung function. Cdh11-deficient mice were compared with wild-type mice in the intraperitoneal bleomycin model (IP BLM), and the role of AT2 was investigated using Cdh11 floxed-SPC-Cre mice and in vitro techniques. In …

High-Level Estrogen Impairs Memory Via Estrogen Receptor Signaling In A Hypothalamic-Hippocampal Neural Circuit, Yuxiang Sun, Udhaya Kumar Siva Kumar, Mengyu Hua, Wenjun Zhou, Yanyan Qi, Hu Chen, Longqing Xia, Jun Qin, Lei Sun, Chaitra Rai, Chao Cheng, Zhandong Liu, Li Chen, Yong Xu, Zhaoyong Hu, Hongjie Li, Xinguo Hou, Yanlin He, Xianghua Zhuang, Zheng Sun

Faculty, Staff and Students Publications

Normal estrogen exposure, as observed in eumenorrheic women of reproductive age, is important for neurocognition, as demonstrated by postmenopausal hormone replacement. However, the cognitive effects of sustained high-level estrogen in the context of oral contraceptives or pregnancy are unclear. Here, we show that high estrogen induces temporary memory dysfunction in mice without affecting mood-related behaviors or exploratory motivation, which is associated with altered gene expression in the lateral hypothalamus (LH). Depletion of neuronal estrogen receptor α/β (ERα/β) in the LH rescues estrogen- or pregnancy-induced cognitive dysfunction. Single-nucleus RNA-seq revealed that ERα, the predominant ER in the LH, is enriched in …

Endothelial Perk Restricts Lymphoid Regeneration By Reducing Dll4-Notch3 Signaling At The Pre-B Niche, Yimin Ma, Jay Myers, Yinghui Shang, Mofei Huang, Paul Christensen, Stanley Adoro, Chih-Hang Anthony Tang, Chih-Chi Andrew Hu, Sai Ravi Kiran Pingali, Wei Xin, Keith Syson Chan, Stephen Wong, Youli Zu, Hamed Jafar-Nejad, Lan Zhou

Faculty, Staff and Students Publications

Delayed immune recovery after hematopoietic stem cell (HSC) transplantation is associated with a poor clinical outcome. We study the role of unfolded protein response (ER stress) in hematopoietic regeneration within the bone marrow (BM) microenvironment. We reveal that BM endothelium PERK activation is a prominent feature of patients with leukemia and is a hallmark response in mice following ionizing irradiation. Ablating endothelial Perk boosts NOTCH ligand DLL4 expression and promotes DLL4-dependent early HSC and B progenitor regeneration. Single-cell analysis reveals that endothelial DLL4 activates NOTCH3 expressed by mesenchymal stroma cells, and that the PERK-DLL4 axis coordinates the regulation of lymphoid …

Nemp1 Organizes The Meiotic Telomere-Linc Interface To Control Chromosome Movement And Telomere Integrity, Andrea Jurisicova, Helen Mcneill

Faculty, Staff and Students Publications

Nuclear Envelope Membrane Protein 1 (NEMP1) is highly expressed in oocytes and required for fertility, yet its meiotic function remains poorly understood. Here, we identify NEMP1 as a critical organizer of meiotic telomere-nuclear envelope coupling and chromosome dynamics. Loss of NEMP1 causes telomere aggregation, loss of shelterin protection, telomere shortening, persistent DNA damage, aberrant non-homologous end joining, and chromosome end-to-end fusion, ultimately leading to aneuploidy in mouse oocyte. NEMP1 is required during early fetal meiotic prophase I for telomere-nuclear envelope attachment, bouquet formation, homolog pairing, and synapsis. Live-cell imaging revealed robust rapid prophase movements in wild-type meiocytes, which were nearly …

Reintroducing Fabp5 In Adulthood Activates Cell Cycle In Cardiomyocytes, Abou Bakr M Salama, Qinghui Ou, Marc Dwenger, Collin K Wells, Ahmad Gebreil, Jessica Miller, Kamal Abou Farraj, Yibing Nong, Reham M Wahid, Hania Abdelhafez, Momo Arai, Muzammil Dastagir, Mohammad Salman Khan, Pretty R Mathew, Mohamed Hamouda, Nourhan M Baraka, Waleed M Elhelaly, Jordan Rhamfield, Om Kulkarni, Joern Huelsmann, Sara Taha, Rebecca Liu, Sarah Bench, Sung Wook Kang, Victoria Rodriguez, Daniel Kraushaar, Hyun-Sung Lee, Livia S Eberlin, Bradford G Hill, Todd K Rosengart, Riham R E Abouleisa, Tamer M A Mohamed

Faculty, Staff and Students Publications

Background and aims: Adult cardiomyocytes (CMs) have minimal proliferative capacity, limiting the heart's ability to regenerate after injury. While neonatal CMs can proliferate, the signaling pathways governing this process are poorly understood. This study aims to identify and reintroduce the neonatal-specific CM proliferation sensitizing signal to restore cell-cycle in adult CMs.

Methods and results: We identified CD36 as a marker for the neonatal spontaneously proliferating CMs. Bulk and Single cell RNAseq, and spatial transcriptomics analyses of the P1 WT, CD36KO and CD36CKO hearts revealed that a CD36/FABP5/PPARδ signaling axis was uniquely expressed in spontaneously proliferating CMs. Using unbiased metabolomics and …

Follistatin Regulates Tooth Root Furcation Morphogenesis, Tak-Heun Kim, Hyuk-Jae Edward Kwon, Sung-Won Cho, Martin Matthew Matzuk, Eui-Sic Cho

Faculty, Staff and Students Publications

Follistatin (Fst), an extracellular inhibitor of the TGF-β signaling pathway, plays a critical role in tooth development, particularly in crown morphogenesis and enamel patterning. While molar root number is conserved within species and between upper and lower jaws, the molecular mechanisms governing root patterning remain largely unknown. To investigate the role of Fst in root formation, we analyzed K14-Cre-mediated Fst knockout mice. During embryonic and early postnatal stages, Fst was dynamically expressed in the dental epithelium including the lingual epithelium, and primary and secondary enamel knots, as well as in the dental mesenchyme at the base of the dental papilla. …

Intravascular Immune Cell Labeling As A Critical Methodological Tool For Characterizing Cd4+ T Cells In The Lung In Eae, Gholamreza Azizi, Mohamad Rostami

Department of Neurology Faculty Papers

INTRODUCTION: Growing evidence highlights the lung -brain axis as a key contributor to CNS autoimmunity. However, accurate characterization of lung immune cells remains technically challenging because standard transcardial perfusion does not eliminate the lung's extensive marginated intravascular leukocyte pool, allowing circulating cells to contaminate analyses of the lung parenchyma.

METHODS: Experimental autoimmune encephalomyelitis (EAE) was induced in mice by immunization with MOG35-55 peptide in complete Freund's adjuvant, followed by pertussis toxin administration. Lung mononuclear cells were isolated after intravascular (IV) CD45 labeling, transcardial perfusion, and enzymatic digestion. Immune cell populations and intracellular cytokine production were analyzed by multicolor flow cytometry …

Phenotypic Analysis Of Human And Murine Endometrial Organoids Using A Machine Learning Approach, Baku Nakakita, Suni Tang, Linda Alpuing Radilla, Brooke Thigpen, Xiaoming Guan, Diana Monsivais

Faculty, Staff and Students Publications

In brief: Endometrial organoids are a powerful 3D in-vitro system to study reproductive function and disease; however, available models for quantitative analysis of organoids are still developing and have not been assessed for endometrial organoids. This paper uses models to reliably segment individual organoids and phenotypically analyze human and murine endometrial organoids. Abstract: Endometrial organoids are a powerful, 3D in vitro system for studying reproductive function and disease since they are more physiologically representative than 2D cell models. However, optimal methods for the analysis of individual organoids are still developing and remain inconsistent throughout the field. To independently evaluate and …

Ceramide-Induced Endoplasmic Reticulum Stress Reveals A Targetable Vulnerability In Endocrine Therapy-Resistant Breast Cancer, Aanshi Vashi, Vipin Rawat, Fatimah Alani, Huiping Zhao, Malik Ata, Jun Qu, Rachel Schiff, Debra Tonetti, Geoffrey L Greene, Jonna Frasor, Gunes Ekin Atilla-Gokcumen, Jonathan L Coloff

Faculty, Staff and Students Publications

UNLABELLED: Despite the success of endocrine therapy (ET) in treating hormone receptor-positive breast cancer, a significant proportion of patients relapse during or after treatment, making ET resistance a major clinical challenge. Previously, we have shown that ET-resistant breast cancer cells exhibit reduced ceramide levels and an increased sensitivity to ceramide-induced cell death. In this study, we demonstrate that ceramides induce a distinct transcriptional reprogramming in ET-resistant cells, characterized by upregulation of endoplasmic reticulum stress (EnRS) pathways. Ceramide-induced EnRS is PERK-dependent and functionally linked to cell death in multiple models of ET resistance. Using a photoactivatable ceramide probe, we identify TRAM1 …

Loss Of Function Dnmt3a Mutation Leads To Aberrant Neutrophil Migration, Ruoqiong Cao, Sarah M Waldvogel, Apoorva Thatavarty, Bryan Bahoua, Brandon T Tran, Arushana A Maknojia, Margaret A Goodell, Antony Rodriguez, Katie A Matatall, Katherine Y King

Faculty, Staff and Students Publications

Clonal hematopoiesis (CH), an age-related expansion of somatically mutated hematopoietic clones, is associated with increased risk of severe infections including coronavirus disease (COVID)-19, yet the underlying mechanisms remain unclear. Here, we investigated the impact of Dnmt3a deficiency in a murine model of influenza A virus (IAV) pneumonia. Dnmt3a-deficient mice exhibited increased pulmonary viral burden and reduced neutrophil accumulation in IAV-infected lungs despite comparable circulating neutrophil numbers. Functional analyses of neutrophils showed impaired chemotactic migration in vitro, whereas maturation, antimicrobial enzyme content, and metabolic capacity were unchanged. Transcriptomic profiling revealed downregulation of pathways involved in chemotaxis, cytokine signaling, and cellular activation, …

Rhino: An Integrative Multi-Omics Framework Linking Circadian Physiology To Precision Medicine, Panpan Liu, Roberto E López-Valiente, Yuan Liu, Cam Mong La, Isabella Beraldo Xavier, Sean M Hartig, Pradip Saha, Zheng Sun, Leng Han, Dongyin Guan

Faculty, Staff and Students Publications

Circadian rhythms are involved in nearly all physiological processes, and their disruption increases disease risk. Aligning drug administration timing with the body's internal clock, known as circadian medicine, holds promise for improving treatment efficacy and safety. However, systematic strategies to identify circadian‐regulated therapeutic targets remain limited. Here, we develop RHINO (RHythmic Interacting Network for multi‐Omics), an integrative multi‐omics framework for exploring circadian regulation across diverse genetic and disease contexts, and prioritizing druggable circadian targets. Applying RHINO reveals that human genetic variation broadly shapes rhythmic gene expression, with approximately 80% of FDA‐approved drug targets exhibiting genotype‐dependent rhythmicity, thereby substantially expanding the …

A Small Molecule Inhibits Ebola Virus Entry Through Glycoprotein Stabilization, Bruno La Rosa, Murugesan Palaniappan, Martin M Matzuk, Damian W Young, Hailey Turner-Hubbard, Kimberly Morsheimer, Callum Owen, Katalin Toth, Michael Cameron, Robert Davey, Srinivas Chamakuri, Peter Dosa, Fang Li

Faculty, Staff and Students Publications

Ebola virus (EBOV) causes outbreaks with high fatality rates, yet potent small-molecule inhibitors targeting EBOV glycoprotein (GP) remain limited. Here, using DNA-encoded chemical libraries, we screen 4.73 billion compounds against EBOV GP and, through stereochemical optimization, identify MWAC-3634. This compound binds GP with high affinity (Kd=40.7 nM), potently neutralizes infection (IC₅₀ = 0.65 nM), shows no detectable cytotoxicity, and exhibits favorable pharmacokinetics in mice. This potency substantially exceeds that of known small-molecule inhibitors targeting EBOV GP. Cryo-EM at 2.54 Å resolution reveals that MWAC-3634 occupies a hydrophobic cavity at the GP subunit interface and stabilizes GP, supporting an entry-blocking mechanism …

Nf1 Loss In Estrogen Receptor-Positive Breast Cancer Induces Osteoclast Formation And Immunosuppression To Promote Bone Metastasis, Matthew J Baik, Yi-Hsuan Wu, Lauren K Somes, Andres F Mosquera Paternina, Omar A Harb, Owen A Chang, Fengshuo Liu, Matthew V Holt, Junkai Wang, Igor Bado, Hai Wang, George Miles, Zbigniew Gugala, Meenakshi Anurag, Ahmed Elkhanany, Yi Li, Valentina Hoyos, Xiang H-F Zhang, Eric C Chang

Faculty, Staff and Students Publications

Estrogen receptor-positive (ER+) breast cancer exhibits a marked propensity for skeletal metastasis; however, the molecular drivers of bone colonization remain incompletely defined. We investigated the tumor suppressor neurofibromin (NF1), a dual repressor for RAS and ER signaling, whose inactivation promotes endocrine therapy (ET) resistance and is associated with inferior relapse-free survival. NF1 copy number loss was detected in 62% of ER+ patients who subsequently developed metastases and was associated with an increased likelihood of bone metastases at initial diagnosis. In mouse xenograft models, NF1-depleted ER+ breast cancer cells demonstrated enhanced dissemination to skeletal sites following surgical resection of primary tumors. …

Heritable Transgenic Schistosomes As A Living Platform For Sars-Cov-2 Neutralizing Antibody Secretion, Wannaporn Ittiprasert, Michael J Smout, Victoria H Mann, Matthew Moyle, Sean M Kinahan, Daniel N Ackerman, Danielle N Rivera, Joshua L Santarpia, Eric C Carnes, Margaret M Mentink-Kane, Marina Reis Costa, Cornelis H Hokke, Meta Roestenberg, Maria Elena Bottazzi, Bethany K Bracken, Bruce A Rosa, Sergej Djuranovic, Darren A Pickering, Paul R Giacomin, Daniel Watterson, Naphak Modhiran, Max F Moescheid, Christoph G Grevelding, Makedonka Mitreva, Alex Loukas, Paul J Brindley

Faculty, Staff and Students Publications

We report the generation and propagation of not only the first heritable transgenic schistosome line but also a line that secretes a functional therapeutic protein in vivo. Using multiplexed CRISPR/Cas-mediated homology-directed knock-in targeted to a predicted genomic safe-harbor, we inserted a VHH-IgG1 Fc (termed C5-Fc) transgene into Schistosoma mansoni eggs. Single-miracidium infections of Biomphalaria glabrata yielded parental P0 lines; serial passage through snail and mouse hosts produced an F2 cohort in which all parasites carried the C5-Fc transgene and secreted C5-Fc into the murine venous circulation. Molecular assays confirmed chromosomal insertion, germline transmission and systemic secretion. Sera from mice harboring …

Identification Of Potent Inhibitors Of Jun N-Terminal Kinases For Treatment Of Endometriosis And Associated Pain, Kiran L Sharma, Kurt M Bohren, Srinivas Chamakuri, Zian Liao, Feng Li, John M Hakenjos, Jian-Yuan Li, Yuji Mishina, Haichun Pan, Xuan Qin, Matthew B Robers, Banumathi Sankaran, Zhi Tan, Suni Tang, Yasmin M Vasquez, Jennifer Wilkinson, Damian W Young, Stephen S Palmer, Kevin R Mackenzie, Choel Kim, Martin M Matzuk

Faculty, Staff and Students Publications

Endometriosis, defined as the ectopic growth of endometrial tissue outside of the uterine cavity, is an inflammatory and hormone-dependent disease that causes excruciating pelvic pain, infertility, and significantly decreases quality of life in affected patients. The JUN N-terminal kinases (JNKs) are a leading class of nonhormonal therapeutic targets that have been validated in preclinical models of endometriosis and in a Phase 1/2 clinical trial. Despite their therapeutic potential, JNK inhibitors with increased potency and specificity are needed to address the inflammatory pathology of endometriosis and to prevent disease progression. Leveraging a DNA-encoded chemical library collection of ~4 billion compounds, we …

Selective Loss Of Primary Cilia And Neurotrophic Signaling In G51d Α-Synuclein Mice Highlights A Common Pathway To Parkinson’S Disease, Yu-En Lin, Ebsy Jaimon, Youngdoo Kim, Annabeth Loftman, Aaran Vijayakumaran, Benjamin D W Belfort, Claire Y Chiang, Benjamin R Arenkiel, Huda Y Zoghbi, Suzanne R Pfeffer

Duncan NRI Faculty and Staff Publications

Parkinson's disease is characterized by dopaminergic neuron loss and accumulation of α-synuclein aggregates in the brain. G51D α-synuclein knock-in mice provide a genetically and clinically relevant model of disease, exhibiting early olfactory deficits, age-dependent motor impairment, and progressive phospho-α-synuclein accumulation. In multiple Parkinson's disease models, striatal cholinergic and parvalbumin interneurons, as well as astrocytes, lose primary cilia and the neurotrophic signaling needed to sustain dopaminergic neurons. We show here that G51D α-synuclein mice share these phenotypes. Phospho-Ser129 α-synuclein accumulation correlates with cilia loss in cholinergic interneurons but not in spiny projection neurons that accumulate higher phospho-α-synuclein levels. In the piriform …

Ultrasound-Guided Renal Artery Administration Of Angiopoietin-1 Rna Therapy Slows The Progression Of Preclinical Wt1 Glomerular Disease, Maria Kolatsi-Joannou, William J Mason, Lauren G Russell, Shunping Han, Yanis Harfouche, Daniyal J Jafree, Emily A E Moore, Hanna Gautier, Christina Katsiva, Reem Al-Saadi, Kathy Pritchard-Jones, Daniel J Stuckey, Andrew V Benest, David O Bates, Paul J Winyard, Aoife M Waters, Luigi Gnudi, Stephen L Hart, Tammy L Kalber, David A Long

Faculty, Staff and Students Publications

Mutations in the transcription factor gene Wilms Tumor 1 (WT1) are one of the leading causes of congenital glomerular disease, characterized by severe urinary protein loss and glomerular scarring. No disease-modifying therapies exist for WT1 glomerulopathies, and affected children rely on dialysis or kidney transplantation. We evaluated a previously uncharacterized treatment in a mouse model with an orthologous human mutation in Wt1 (Wt1+/R394W) that replicates the pathology of WT1 glomerulopathy. Lipid nanocomplexes were engineered to target integrin αvβ3 for efficient delivery of mRNA to primary podocytes and glomerular endothelial cells in vitro. A minimally …

Th17 Effector Cytokines Induce Shared And Distinct Microglial And Endothelial Cell Responses In A Mouse Model For Post-Streptococcal Encephalitis, Charlotte Wayne, Uğur Akcan, Travis Faust, Violeta Durán-Laforet, Danny Jamoul, Luca Bremner, Nicole Ampatey, Büşra Akcan, Sarah Ho, Bogoljub Ciric, Shannon Delaney, Wendy Vargas, Susan Swedo, Vilas Menon, Dorothy Schafer, Tyler Cutforth, Dritan Agalliu

Department of Neurology Faculty Papers

Group A Streptococcus (GAS) infections cause neuropsychiatric complications in children, but the mechanisms linking peripheral infection to brain dysfunction remain unclear. Using mouse genetics, single-cell RNA sequencing, and spatial transcriptomics, we show that GAS infections induce inflammatory transcriptional programs in microglia and brain endothelial cells (BECs), accompanied by loss of blood-brain barrier (BBB) gene expression in female mice. Spatial transcriptomic analyses reveal that GAS-responsive microglia localize near infiltrating CD4+ T cells. Several microglial chemokines induced in mice are elevated in sera from affected patients. Deletion of GM-CSF in CD4⁺ T cells partially reduces microglial chemokine gene expression, without restoring BBB …

Malt1 Protease Inhibition Restrains Glioblastoma Progression By Reversing Tumor-Associated Macrophage-Dependent Immunosuppression In Mice, Juliana Hofstätter Azambuja, Saigopalakrishna Yerneni, Lisa Maurer, Hannah Crentsil, Gabriela Debom, Linda Klei, Mei Smyers, Chaim Sneiderman, Kristina Schwab, Rajesh Acharya, Aivi Nguyen, Josie Emery, John Little, Jeffrey Meridew, Yijen Lin Wu, Prasanna Ekambaram, Dong Hu, Pete Gough, John Bertin, Ari Melnick, Gary Kohanbash, Riyue Bao, Peter Lucas, Linda Mcallister-Lucas

College of Life Sciences Faculty Papers

MALT1 protease is an intracellular signaling molecule that promotes tumor progression via cancer cell-intrinsic and cancer cell-extrinsic mechanisms. MALT1 has been mostly studied in lymphocytes, and little is known about its role in tumor-associated macrophages. We show that MALT1 is expressed in glioblastoma (GBM)-associated macrophages. Mechanistically, GBM tumor cells induce a MALT1-NF-κB signaling axis in macrophages, leading to enhanced macrophage migration and polarization toward an immunosuppressive ('M2-like') phenotype. Inactivation of MALT1 protease promotes transcriptional reprogramming that reduces migration and restores a macrophage anti-tumor 'M1-like' phenotype. Preclinical in vivo analysis shows that MALT1 inhibitor treatment results in immuno-reactivity of GBM-associated macrophages …