Medicine and Health Sciences Commons^™

Steroid Receptor Coactivator 3-Deficient Regulatory T Cells Eradicate Multiple Solid Tumors In Syngeneic Mouse Models, Nuri Sung, Eunsu Kim, Yosef Gilad, 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, Nolan M Dvorak, Jeffrey L Noebels

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 …

Glial Dysfunction And Memory Impairments In A Model Of Pediatric Obstructive Sleep Apnea, Michael R Williamson, Jorge Botas, Mahyar J Hedayatpour, 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, Weiwei Lin, Sadhna Phanse, Sophie J F Van Der Spek, 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, Weiwei Lin, Sadhna Phanse, Sophie J F Van Der Spek, 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 …

Functional Role Of Skull Lymphoid Structures In Cns Immunosurveillance, Jang Hyun Park, Daviti Abramishvili, Gustavo Gastão Davanzo, Ruben Silva, Xingxing Gu, Siling Du, Daniel D Lee, Bernd H Zinselmeyer, Jackson S Turner, Gwendalyn J Randolph, Igor Smirnov, Jonathan Kipnis

2020-Current year OA Pubs

Accumulating evidence demonstrates that the central nervous system (CNS) is not disconnected from the peripheral immune system; however, precisely how the adaptive immune system surveils the CNS remains a critical question. Recent findings reveal that channels between the skull and the dura mater facilitate the exchange of cerebrospinal fluid and immune cells between the CNS and skull bone marrow of mice under both homeostatic and disease conditions

Bambara Groundnut (Vigna Subterranea L.) Supplementation Ameliorates The Histological Structure Of Skeletal Muscle In Protein-Deficient Mice, Raquellynda Fadilla Syafanisa, Rimonta Febby Gunanegara, Sunarti Sunarti, Siti Aeniah, Ardaning Nuriliani

Makara Journal of Science

Protein deficiency may cause histological alterations and pathological effects in skeletal muscle, leading to reduced mus-cle size and functional degeneration. Bambara groundnuts contain essential amino acids that have the potential to meet the body’s protein requirements. Therefore, this study aimed to investigate the effect of bambara groundnut supplemen-tation on skeletal muscle in protein-deficient mice. Twenty-five female mice were divided into five groups (control, pro-tein deficiency, and protein deficiency with 100, 200, and 300 g of bambara groundnut supplementation/kg of feed). The treatment was administered for 2 months. At the end of the experiment, the left gastrocnemius muscles of the mice …

Endothelial Perk Restricts Lymphoid Regeneration By Reducing Dll4-Notch3 Signaling At The Pre-B Niche, Bingqing Zou, Qiuyun Chen, Junjun Zheng, 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, Hui Zhang, Ling Zhang, Stephanie A Pangas, 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 …

Follistatin Regulates Tooth Root Furcation Morphogenesis, Liu Yang, Ju-Kyung Jeong, Hwajung Choi, 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. …

Spatial Control Of Parathyroid Hormone Receptor-1 Signaling Dictates Ligand-Specific Biological Outcomes, Jakob Höppner, Harald Jüppner, Monica Reyes, Prem Swaroop Yadav, Dian Wang, Thomas Dean, Patrick Hanna, Roberto Civitelli, Asuka Inoue, Ernestina Schipani, Ignacio Portales-Castillo, Thomas J Gardella

2020-Current year OA Pubs

Parathyroid hormone receptor-1 (PTH1R) is a class B GPCR that regulates mineral ion homeostasis via parathyroid hormone (PTH) and skeletal development via parathyroid hormone-related peptide (PTHrP). While PTHrP signaling is thought to occur predominantly at the plasma membrane, PTH is considered to also signal from endosomes; however, the mechanisms that encode subcellular PTH1R actions, as well as the biological relevance of plasma membrane vs internalized PTH1R activation, remain unclear. Here, by examining the Eiken syndrome mutant R485X-PTH1R, in which C-tail truncation removes key βarrestin docking sites, we identified βarrestins as critical modulators of compartmentalized PTH1R signaling in response to endogenous …

The C3-C3ar Axis Modulates Trained Immunity In Alveolar Macrophages, Alexander P Earhart, Rafael Aponte Alburquerque, Marick Starick, Lorena Garnica, Ayse Naz Ozanturk, Rahul Kumar Maurya, Xiaobo Wu, Jeffrey Haspel, Hrishikesh S Kulkarni, Et Al.

2020-Current year OA Pubs

Complement protein C3 is crucial for immune responses in mucosal sites such as the lung, where it aids in microbe elimination, and enhances inflammation. While trained immunity - enhanced secondary responses of innate immune cells after prior exposure - is well-studied, the role of the complement system in trained immune responses remains unclear. We investigated the role of C3 in trained immunity and found that alveolar macrophage (AM)

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, Anna Catherine Unser, Genesis J Herrera, Sydney E Parks, 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 …

Complementary Vertebrate Wac Models Exhibit Phenotypes Relevant To Desanto-Shinawi Syndrome, Kang-Han Lee, Marwan Shinawi, Et Al.

2020-Current year OA Pubs

Monogenic syndromes are associated with neurodevelopmental changes that result in cognitive impairments and neurobehavioral phenotypes, including autism and seizures. Limited studies and resources are available to make meaningful headway into the underlying molecular mechanisms that result in these symptoms. One such example is DeSanto-Shinawi Syndrome (DESSH), a rare disorder caused by pathogenic variants in the

Ceramide-Induced Endoplasmic Reticulum Stress Reveals A Targetable Vulnerability In Endocrine Therapy-Resistant Breast Cancer, Purab Pal, Shweta Chitkara, Godwin K Sarpey, 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 …

Nf1 Loss In Estrogen Receptor-Positive Breast Cancer Induces Osteoclast Formation And Immunosuppression To Promote Bone Metastasis, Zifan Zhao, Ze-Yi Zheng, Jonathan T Lei, 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. …

A Small Molecule Inhibits Ebola Virus Entry Through Glycoprotein Stabilization, Fan Bu, Gang Ye, Kiran L Sharma, 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 …

Loss Of Function Dnmt3a Mutation Leads To Aberrant Neutrophil Migration, Frieda Zimmer, Daniel E Kennedy, Spencer L Redding, 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, Ying Chen, Chengxuan Chen, Dishu Zhou, 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 …

Modular In Vivo Antibody-Adc Click To Reverse Drug Resistance In Tumours, Cristina Simó, Alexander C Vanover, Ricardo D'Oliveira Albanus, Sandeep Surendra Panikar, Shayla Shmuel, Alex Benton, Jader Giraldo-Guzman, José M Luna, Yifei Xu, Na-Keysha Berry, Nai Keltee, Jingxia Liu, Farrokh Dehdashti, Patrícia M R Pereira

2020-Current year OA Pubs

Antibody-drug conjugates (ADCs) have significantly advanced cancer therapy by enabling the selective delivery of cytotoxic agents to tumour cells. However, ADC efficacy remains constrained by its dependence on a single target antigen, which limits tumour targeting and promotes resistance in heterogeneous tumours with variable and low antigen expression

Gamclust: Identification Of Regulated Metabolic Modules In Bulk, Single Cell And Spatial Gene Expression Data, Anastasiia Gainullina, Evgeniia Chikina, Maxim N Artyomov, Alexey Sergushichev

2020-Current year OA Pubs

MOTIVATION: Metabolism operates as a highly interconnected biochemical network, and its regulation emerges from coordinated changes across many reactions and metabolites. The integration of gene expression profiling data with organism-scale metabolic networks has proven to be a valuable tool for understanding cellular metabolic regulation. However, the increasing complexity of profiling technologies and experimental designs requires the development of specialized tools.

RESULTS: Here, we present GAMclust, an R package implementing and extending the previously published GAM-clustering pipeline for identifying transcriptionally regulated metabolic modules in complex gene expression datasets. GAMclust supports bulk, single-cell, and spatial gene expression profiling. It includes built-in KEGG …

Mitochondrial Trna-Derived Fragments As Candidate Metastasis-Modifying Rna, Katy L. Swancutt, R. Mckinnon Walsh, Sydney Quijano, Emily Schueddig, Devin C. Koestler, Adam D. Scheid, Tony Vanden Bush, Yi Jing, Isidore Rigoutsos, Danny R. Welch

Computational Medicine Center Faculty Papers

UNLABELLED: How mitochondrial DNA (mtDNA) polymorphisms influence complex phenotypes remains poorly understood. Using mitochondrial-nuclear exchange mice, we previously showed that mtDNA single-nucleotide polymorphisms (SNP) modify metastasis, cardiovascular disease, and epigenetic marks independently of metabolic differences. The only mtDNA SNP correlating with these phenotypes resides in the gene encoding mitochondrial transfer RNA (tRNA)-arginine [mt-tRNAArg (UCG), mt-TR], suggesting a role for non-protein-coding loci. In this study, we identify and preliminarily characterize previously undescribed tRNA-derived fragments (tRF) generated from mt-TRs. Northern blotting revealed distinct tRF that are differentially expressed among mtDNA SNPs, between lung and liver, and between sexes. Surprisingly, small RNA sequencing …

Heritable Transgenic Schistosomes As A Living Platform For Sars-Cov-2 Neutralizing Antibody Secretion, Wannaporn Ittiprasert, Bruce A Rosa, Sergej Djuranovic, Makedonka Mitreva, Et Al.

2020-Current year OA Pubs

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 …

Altered Postnatal Chromatin Development In The Nucleus Accumbens Primes Enduring Stress Sensitivity, Rebekah L Rashford, Lisa Z Fang, Michael Deberardine, Hye Ji J Kim, Laura W Hirschfield, Ella Cervi, Mason R Barrett, Jeremy M Thompson, Meaghan C Creed, Catherine Jensen Peña

2020-Current year OA Pubs

Early life stress (ELS) sensitizes individuals to subsequent stressors to increase lifetime risk for psychiatric disorders. Within the nucleus accumbens (NAc)-a key limbic and reward-associated brain region-ELS sensitizes both cellular and transcriptional response to later stress, which are programmed by enduring epigenetic changes. Among the histone modifications persistently enriched by ELS in NAc is H3K4me1, which is associated with open chromatin and epigenetic priming of genomic enhancers. Here, we sought to determine whether H3K4me1 enrichment in NAc was sufficient to prime cellular and behavioral responses to adult stress. Viral-mediated overexpression of the histone H3 monomethyltransferase

Identification Of Potent Inhibitors Of Jun N-Terminal Kinases For Treatment Of Endometriosis And Associated Pain, Ravikumar Jimmidi, Diana Monsivais, Hai Minh Ta, 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 …

Peritoneal Ovarian Cancer Growth In The Omentum Proceeds Independently Of Mature Adipocytes, Rachel L Mintz, Jichang Han, Emily G Butka, Alexandre Gallerand, Shuai Gao, Ayoung Kim, Sarah Ning, Nicole K H Yiew, Mary Wohltmann, Galina Fedotova, Wei Zou, Nan Zhang, Samantha A Morris, Bernd H Zinselmeyer, Gwendalyn J Randolph

2020-Current year OA Pubs

The omentum, a specialized adipose tissue within the peritoneum, is a primary niche of ovarian cancer dissemination. Omental adipocytes are widely thought to promote tumor growth by supplying lipids, supported in part by studies using global FABP4 deficiency. Here, we directly test whether mature adipocytes are required for peritoneal ovarian cancer growth using mice congenitally lacking mature adipocytes within the peritoneal cavity, including the omentum. Across several ovarian cancer models (ID8p53

Ultrasound-Guided Renal Artery Administration Of Angiopoietin-1 Rna Therapy Slows The Progression Of Preclinical Wt1 Glomerular Disease, Saif N Malik, Jennifer C Chandler, Ruhina Maeshima, 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 …