Medical 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

Myeloid Mmp14 Couples Extracellular Proteolysis To Inflammatory And Metabolic Remodeling During Obesity, Long J Shao, Fathima Elizondo, Feng Gao, Elizabeth L Lieu, Bharati Reddi, Maryam Elizondo, Iqbal Mahmud, Kristin Eckel-Mahan, Philipp E Scherer, Xin Ge, Huaizhu Wu, Sean Hartig, Kai Sun

The Brown Foundation: Institute of Molecular Medicine

Macrophages orchestrate tissue remodeling, inflammation, and metabolic dysfunction in obesity, but the role of macrophage-intrinsic extracellular proteolysis in immunometabolic regulation remains unclear. Matrix metalloproteinase-14 (MMP14), a membrane-bound protease, is strongly induced during monocyte-to-macrophage differentiation and further elevated in adipose tissue macrophages from high-fat diet (HFD)-fed mice. Pharmacological inhibition or myeloid-specific deletion of Mmp14 impaired macrophage differentiation, proliferation, migration, phagocytosis, and inflammatory activation in response to obesity-associated adipose tissue signals. Mechanistically, MMP14 promoted inflammatory programming by increasing endotrophin generation and enhancing TLR4-NFκB signaling. MMP14 also reprogrammed macrophage lipid metabolism by suppressing lipolysis and promoting lipid accumulation, altering metabolic communication with neighboring …

Amc-F1 Regulates Mitochondria-Autophagy Crosstalk Independent Of Nutrient Stress, Yuqin Wang, Raksha K Rao, Trung Vu, Ayano Sekine, Zhengmei Mao, Nami Mccarty

The Brown Foundation: Institute of Molecular Medicine

Mitochondria and autophagy are fundamental yet distinct regulators of cellular homeostasis. Here, we identify AMC-F1 (Autophagy-Mitochondria Coupling Factor 1; formerly TRIM44) as a central integrator of mitochondrial bioenergetics and autophagy. Using Amcf1 knockout and knock-in mouse models, we demonstrate that AMC-F1 bidirectionally regulates these pathways: its loss reduces mitochondrial respiration and autophagic flux, whereas its overexpression promotes mitochondrial elongation and increases autophagy independently of nutrient stress. Transcriptomic analyses reveal AMC-F1-dependent regulation of mitochondrial biogenesis programs that engage autophagy, involving mitochondrial respiratory chain complex genes under basal conditions and mitochondrial organization factors under starvation-induced autophagy. Although dispensable under homeostasis, this coupling …

An Obligatory Role For Agrp Neurons In Maintaining Body Temperature During Time-Restricted Feeding, Cunjin Su, Jing Cai, Yuanzhong Xu, Benjamin R Arenkiel, Qingchun Tong

The Brown Foundation: Institute of Molecular Medicine

Homeotherms maintain a steady body temperature through thermoregulation, a process critical for survival during fasting, in which the brain has to defend energy-costly body temperature while reducing energy expenditure to conserve energy reserve; however, the neural basis for defending body temperature remains unclear. Here, we demonstrated that AgRP neuron lesion led to lethality during time-restricted feeding on chow but not on HFD, and caused no obvious impact on HFD-induced obesity or obesity-reducing responses to glucagon-like peptide-1 receptor agonism. The lesion disrupted adaptive feeding behaviors during time-restricted feeding and reduced motivational feeding on chow. Notably, the lethality was caused by hypothermia …

Generation And Characterization Of Twist1 Acetyl-Mimic And Acetyl-Deficient Mouse Models, Mary Elmeniawi, Xiaobin Yu, Samuel Wen, Gunjan A Bhatia, Lan Liao, Jianming Xu, Walid D Fakhouri

Faculty, Staff and Students Publications

TWIST1 encodes a highly conserved basic helix–loop–helix transcription factor essential for embryonic development from Drosophila to humans. TWIST1 activity is regulated by post‐translational modifications, including phosphorylation during development and cancer metastasis. Recent cancer studies identified acetylation of lysines K73 and K76 as a novel regulatory modification that shifts TWIST1 from a repressive to an activating state during epithelial‐to‐mesenchymal transition (EMT). However, the developmental and in vivo functions of TWIST1 acetylation remain unknown. To investigate the physiological role, we generated the first acetyl‐deficient Twist1 K73,76R K73,76R and acetyl‐mimic Twist1 K73,76Q K73,76Q mouse models using CRISPR/Cas9‐mediated genome editing. Targeted sequencing confirmed substitutions, …

Selective And Differential Roles Of Pvhcrh Neurotransmitters In Diet-Induced Obesity In Mice, Zhiying Jiang, Yuhan Cao, Michelle He, Cunjin Su, Runzhou Yang, Maojie Yang, Jing Cai, Hongli Li, Yuanzhong Xu, Shi-Bin Li, Hiroshi Yamaguchi, Luis De Lecea, Benjamin R Arenkiel, Qingchun Tong

The Brown Foundation: Institute of Molecular Medicine

Stress and diet are known to synergistically promote risks of obesity but the underlying neural basis remains elusive. Corticotropin-releasing hormone neurons in the paraventricular hypothalamus (PVHCRH) are stress responsive and release both CRH and glutamate. Here we generated a mouse model with gain or loss of release in CRH or glutamate from PVHCRH neurons. While these models showed no changes in body weight when fed chow, they exhibited contrasting effects when fed high-fat high-caloric diets (HFD). Whereas disrupting glutamate release from PVHCRH neurons led to diet-induced obesity (DIO), that of CRH caused no impact. Conversely, augmented CRH release led to …

Water-Soluble Fullerene Derivatives Mitigate Cranial Radiation-Induced Neuroinflammation And Cognitive Dysfunction, Naren Gundapaneni, Iona Hill, Lydia W T Cheung, Khadijeh Koushki, Alyssa Fausnaught, Phuoc Minh Quan Mai, Arjun Vasan, Prapannajeet Biswal, Ashutosh Tripathi, Anilkumar Pillai, Vijayasree V Giridharan, Tatiana Barichello, Yuri Mackeyev, Sunil Krishnan

Faculty, Staff and Student Publications

Radiotherapy is widely used to treat malignant and benign brain tumors. A major constraint, however, is the low tolerance of normal brain tissue to radiation. Cranial irradiation-induced injury manifests as inflammatory responses and neurodegeneration, which jointly contribute to progressive cognitive decline. These complications can restrict the delivery of optimal therapeutic doses, cause persistent neurological symptoms, and ultimately compromise quality of life. Thus, neuroprotective agents have emerged as a strategy to safeguard normal tissues from radiation-induced neurotoxicity. This study investigated the efficacy of a highly soluble [60]fullerene (C60) derivative, C60-ser, a carbon-based nanomaterial, to mitigate radiation-induced brain injury. Oral administration of …

Plasma Constituents Promote Endothelial Thromboinflammatory Dysfunction After Hemorrhagic Shock, Kelly E Sanders, Marissa D Pokharel, Baron K Osborn, Yao-Wei Wang, Charles E Wade, Lucy Z Kornblith, Mitchell J Cohen, Jessica C Cardenas

Faculty, Staff and Student Publications

Background: Hemorrhagic shock (HS) following traumatic injury is hallmarked by innate immune activation, hypercoagulability, and thromboinflammatory complications. To date, the direct link between HS, injury severity, and endothelial cell (EC) contributions to thromboinflammation remains poorly understood. The goals of this study were to determine the impact of injury severity and HS on endothelial-mediated thromboinflammation and examine whether these changes increase the propensity for thrombosis.

Methods: Plasma from 89 male trauma patients, stratified by HS and injury severity, and 10 healthy subjects were assessed for inflammatory mediators by BioPlex. Human lung microvascular endothelial cells were exposed to patient plasma for 4 …

Dapk2 Regulates Pkm2 Phosphorylation At Threonine 45 To Facilitate Disturbed Flow-Induced Atherosclerosis, Shuai Guo, Long Xu, Yixin Chen, Yuan Zhao, Yuting Zhang, Runfa Yu, Kaixiang Cao, Litao Wang, Wenjia Ai, Jiang-Yun Luo, Lu Lu, Jun He, Yuan Zhou, Li Wang, Andrew H Baker, Yuqing Huo, Yiming Xu

Faculty, Staff and Students Publications

Background: Oscillatory shear stress (OSS), resulting from disturbed blood flow, is implicated in atherosclerotic plaque formation by incompletely understood mechanisms. This study aims to elucidate the involvement of death-associated protein kinase (DAPK) 2 in OSS-induced endothelial cell (EC) activation and atherosclerosis.

Methods: Publicly available resources, including genome-wide microarray, RNA sequencing, and single-cell RNA sequencing, were utilized to identify key OSS-sensitive regulatory factors. Techniques such as mass spectrometry, immunoprecipitation, proximity ligation assay, and RNA sequencing were employed to identify pyruvate kinase M2 (PKM2) as the binding protein of DAPK2 and determine the specific site of PKM2 phosphorylation by DAPK2. To assess …

Nuclear Receptor Subfamily 4 Group A Member 2 Induces A Warburg-Like Effect And Promotes Phospholipids Synthesis In The Mouse Heart, Sadia Ashraf, Dorcas Odogwu, David D Mcpherson, Romain Harmancey

Faculty, Staff and Student Publications

Myocardial metabolic flexibility is critical to ensuring the heart's capacity to maintain contraction and cellular functions under rapidly evolving environmental conditions. Although it is a tightly regulated process, loss of metabolic flexibility is often regarded as a contributing factor to heart failure. This study aims to determine the effects of the early response transcription factor nuclear receptor subfamily 4 group A member 2 (NR4A2) on cardiac metabolism and the resulting impact on left ventricular function. A multiomics approach combining the analysis of global ventricular gene expression, genome-wide NR4A2 binding, and untargeted metabolomics was used to track the molecular effects of …

Platelets Cause Microvascular Occlusion And Delayed Neurological Deficits After Subarachnoid Hemorrhage In Mice., Ari Dienel, Sung-Ha Hong, Kiara Torres, Kanako Matsumura, Jose Guzman, Peeyush Thankamani Pandit, Bibek Samal, Harveen Kaur, Samitha Nemirajaiah, Angelica Bernal, H Alex Choi, Louise D Mccullough, Spiros L Blackburn, Jaroslaw Aronowski, Devin W Mcbride

Faculty, Staff and Student Publications

After subarachnoid hemorrhage (SAH), some patients develop delayed neurological deficits (DND). Microthrombi are considered a contributing factor to DND, but clinical trials of antiplatelets had mixed results. Existing research suggests that platelets play a role in the etiology of DND, but no comprehensive study has tested causality between platelets and DND after SAH. Here we hypothesize that after SAH, platelet activation promotes microthrombi formation, occlusion of the brain microvasculature and contributes to DND, and that inhibiting platelet aggregation is a therapeutic strategy. Mice experiencing SAH were administered various interventions. The animals were subjected to stimulation of platelets, platelet depletion, or …

Functional Bipartite Invariance In Mouse Primary Visual Cortex Receptive Fields, Zhiwei Ding, Dat Tran, Kayla Ponder, Zhuokun Ding, Rachel Froebe, Lydia Ntanavara, Paul G Fahey, Erick Cobos, Luca Baroni, Maria Diamantaki, Eric Y Wang, Andersen Chang, Stelios Papadopoulos, Jiakun Fu, Taliah Muhammad, Christos Papadopoulos, Santiago A Cadena, Alexandros Evangelou, Konstantin Willeke, Fabio Anselmi, Sophia Sanborn, Jan Antolik, Emmanouil Froudarakis, Saumil Patel, Edgar Y Walker, Jacob Reimer, Fabian H Sinz, Alexander S Ecker, Katrin Franke, Xaq Pitkow, Andreas S Tolias

Faculty, Staff and Students Publications

Sensory systems support generalization by representing features that persist under input variation; however, identifying the neuronal basis of these invariances remains difficult due to high-dimensional and nonlinear neural computations. Here we leverage the inception loop paradigm, iterating between large-scale recordings, predictive models and in silico experiments with in vivo verification, to characterize neuronal invariances in mouse primary visual cortex (V1). We synthesize varied exciting inputs (VEIs), dissimilar images that drive target neurons. These VEIs revealed a new bipartite invariance: one subfield encodes a shift-tolerant high-frequency texture and the other encodes a fixed low-frequency pattern. This division aligns with object boundaries …

Weaning Drives Microbiome-Mediated Epigenetic Regulation To Shape Immune Memory In Mice, Li Yang, Robert C Peery, Shirui Zhou, Xiaomin Chen, Leah M Farmer, Fabiola Gutierrez, Stephanie Fowler, Lanjing Zhang, Julia M Salamat, Karen Riggins, Jiejun Shi, Lanlan Shen

Children’s Nutrition Research Center Staff Publications

During weaning, the transition to solid food diversifies the gut microbiome, triggering a programmed immune response critical for long-lasting mucosal immunity. Previous work showed that the gut microbiome mediates epigenetic development in intestinal stem cells (ISCs) during suckling, but what happens during weaning is unclear. Here, genome-wide profiling revealed that weaning-driven microbiome changes shape the DNA methylome and transcriptome of murine ISCs in an IFNγ-dependent manner. Specifically, we observe demethylation of enhancer elements essential for MHC class II genes, which results in a transcriptional memory that persists through differentiation into adulthood. IFNγ blockade, or low-dose penicillin to target Gram-positive bacteria, …

Multiparametric Mri To Predict Response To Irreversible Electroporation Plus Anti-Pd-1 Immunotherapy In Pancreatic Ductal Adenocarcinoma, Qizhen Cao, Mark D Pagel, Charles V Kingsley, Jingfei Ma, James P Long, Xiaoxia Wen, Seth T Gammon, Jorge Delacerda, Sanaz Javadi, Chun Li

Faculty, Staff and Student Publications

Purpose: To investigate contrast-enhanced T1-weighted MRI and diffusion-weighted magnetic resonance imaging (DWI) for early prediction of tumor response to combined irreversible electroporation (IRE) and anti-PD-1 immunotherapy.

Methods: Murine pancreatic ductal adenocarcinoma (PDAC) cells KRAS* were inoculated into the pancreas of C57BL/6 mice. IRE was performed when tumors became palpable. After IRE, mice received six intraperitoneal injections of anti-PD-1 over 2 weeks. T2-weighted MRI, T1-weighted MRI with macromolecular contrast agent poly(L-glutamic acid)-conjugated gadolinium (PG-Gd), and DWI were performed before and after IRE. Survival was analyzed using Kaplan-Meier curves. Mice surviving at least 100 days without recurrence after IRE were considered complete …

Telomerase Knockout In Myeloid Cells Predisposes Mice To Foam Cell Formation, Dyslipidemia, Lung Fibrosis, And Cardiac Dysfunction, Zhanguo Gao, Yongmei Yu, David Wiggins, Eva M Sevick-Muraca, Mikhail G Kolonin

The Brown Foundation: Institute of Molecular Medicine

Aging-associated changes in myeloid cells are incompletely understood. One of the culprits of aging is the downregulation of the Tert gene coding for the catalytic subunit of telomerase. Studies of mouse models with Tert knockout (KO) in specific cells have revealed the importance of the telomere-independent noncanonical function of TERT in supporting mitochondrial metabolism and protection from cell senescence. To investigate the role of TERT in myeloid cells (MCs), we analyzed mice with Tert KO in the LysM+ lineage, indelibly labeled with membrane green fluorescent protein (mG). Macrophage numbers and properties in various organs were compared. Changes in the vasculature, …

Mouse White Matter Matters: Cortical Origins And Spatial Organization Of Mouse White Matter Tracts, Sofia D Gordeev, Melissa Franch, Sarah R Heilbronner

Faculty, Staff and Students Publications

White matter—the fundamental structure underlying network connectivity—lies at the heart of the brain’s computational power. White matter is organized into fiber tracts, or bundles, in both human and nonhuman primate brains. These bundles consist of long-range axonal projections with a set of shared origin and termination points and exhibit a predictable organization. However, the organization of white matter in the mouse brain remains relatively unknown. This knowledge gap is surprising given the central role of mice in neuroscience, with mouse brains serving as the dominant model for transgenics, in vivo calcium imaging, and circuit manipulation. To address this gap, we …

Heterogeneity And Plasticity Of The Naive Cd4+ T Cell Compartment, Alia Sajani, Evelien Schaafsma, Walburga Croteau, Mohamed Eltanbouly, Elizabeth C Nowak, Chao Cheng, Christopher M Burns, Mary Jo Turk, Randolph J Noelle, J Louise Lines

Faculty, Staff and Students Publications

This study describes the transcriptional heterogeneity of murine and human naive CD4+ T cells as comprising multiple discrete clusters that impact CD4+ T cell fate and trajectories. Naive CD4+ T cells experiencing inflammatory environments exhibit an altered transcriptional state that biases their differentiation trajectories.

Mechanometabolism Instructs Hematopoietic Stem Cell Specification, Paulina D Horton, Alina Syed, Michelle Winkler, Abishek B Vaidya, Michael Rariden, Neha Arora, Yong Zhou, Michihiro Kobayashi, Momoko Yoshimoto, Hyun Jung Lee, Hyun-Eui Kim, John P Hagan, Catherine Denicourt, Travis I Moore, Pamela L Wenzel

Faculty, Staff and Student Publications

Mechanical force generated by blood flow stimulates emergence of the first hematopoietic stem cells (HSCs) that populate the blood system. Force drives the transition of HSC precursors from an endothelial to hematopoietic identity, yet the molecular regulation of this fate switch remains poorly understood. We report that shear stress triggers adaptation in mitochondrial composition, ultrastructure, and function, which are essential for hematopoietic fate and engraftment potential. Shear stress remodels mitochondria in hemogenic endothelium by promoting mitochondrial gene transcription and protein synthesis. Laminar flow selectively initiates translation of 5' terminal polypyrimidine (5'TOP) motif-containing transcripts, which commonly encode ribosome and translation machinery. …

Ectopic B Lymphocyte Follicles Exacerbate Ischemic Brain Damage Via Mif-Cd74/Cxcr4 And Interferon Signaling, Sheng Yang, Hang Zhang, Lu-Lu Xu, Luo-Qi Zhou, Yun-Hui Chu, Lian Chen, Xiao-Wei Pang, Lu-Yang Zhang, Li-Fang Zhu, Ming-Hao Dong, Ke Shang, Jun Xiao, Long-Jun Wu, Wei Wang, Dai-Shi Tian, Chuan Qin

Faculty, Staff and Student Publications

Neuroinflammation, encompassing both innate and adaptive immune responses, plays a crucial role in ischemic stroke. Although B lymphocytes are central to adaptive immunity, their contributions to ischemic stroke remain poorly understood. Here, we demonstrated that B lymphocytes accumulate in ischemic lesions, forming germinal center-like structures at the later stage after stroke, which mainly depended on in situ proliferation. This accumulation correlated with worsened neuroinflammation and ischemic injury, whereas B cell depletion reduced chronic brain damage during stroke. Mechanistically, microglia recruited B cells into ischemic lesions through MIF-CD74/CXCR4 signaling during the early phase of stroke, while IFN-related pathways in B cells …

Activin A Secretion By Muscle-Repairing Macrophages Induces Heterotopic Ossification In Mice, Wenqiang Yin, Kazuo Okamoto, Asuka Terashima, Warunee Pluemsakunthai, Takehito Ono, Taku Ito-Kureha, Shizuo Akira, Yoshinobu Hashizume, Roland Baron, Satoshi Ueha, Kouji Matsushima, Martin M Matzuk, Yuji Mishina, Hiroshi Takayanagi

Faculty, Staff and Students Publications

The immune system is not only essential for host defense, but it is also involved in tissue maintenance and disease pathogenesis. Macrophages play a key role in tissue repair, fibrosis, and tumorigenesis, but the mechanisms underlying their multifunctionality have not been fully explored. Here, we identified Mrep (Ly6ChiCX3CR1loPDPN+CD9+) as a crucial subset of macrophages for muscle regeneration after muscle injury. Muscle regeneration required Mrep-derived activin A, which was produced via the TLR4/TIR domain-containing adapter-inducing interferon-β/TANK-binding kinase 1/interferon regulatory factor 3/7 signaling pathway in response to muscle injury. Mrep exerted pathological effects by secreting activin A in a model of genetically …

Selective Deletion Of Fgfr1 In Agrp Neurons Impairs Energy Homeostasis Under High-Fat Diet In Mice, Daniel Shookster, Shea O'Connell, Patel Darshan, Taylor Landry, Wyatt Bunner, Zhiying Jiang, Qingchun Tong, Hu Huang

Faculty, Staff and Student Publications

Background: The global obesity crisis and the limited success of current treatments underscore the need to identify novel regulatory pathways. While central administration of α-Klotho exerts anti-obesity effects in rodents through AgRP neurons, the intracellular signaling mechanisms that mediate this process remain undefined.

Methods: To define the role of FGFR1 within the α-Klotho signaling pathway in AgRP neurons, we performed a targeted deletion of the receptor in adult mice using an AAV-mediated CRISPR/Cas9 system alongside transgenic models.

Results: Deletion of FGFR1 in AgRP neurons disrupted energy homeostasis, promoting weight gain induced by a high-fat diet. Electrophysiological recordings revealed that FGFR1 …

Histone Demethylase Jmjd1a Protects Mice From Enteric Bacterial Infection By Upregulating Ccl8 Expression To Recruit Macrophages And Cd4+ T Cells, Guifang Lin, Lichun Yang, Shuyan Jiang, Yong Zhang, Ping Luo, Weihua Li, Jianming Xu, Gongpeng Xiong, Chundong Yu, Wenbo Chen

Faculty, Staff and Students Publications

Jumonji domain-containing 1A (JMJD1A, also known as KDM3A) is a histone demethylase that specifically demethylates H3K9me1/2 to enhance gene expression. The roles of JMJD1A in many physiological and pathological processes have been revealed. However, it is unclear whether JMJD1A is involved in host defense against enteric pathogen infection. In this study, we found that enteric infection with C. rodentium induced JMJD1A expression in colonic epithelial cells at the transcriptional level partly mediated by IRF1. After C. rodentium infection, JMJD1A-/- mice exhibited increased mortality, colonic injury, and C. rodentium load and systemic spread, suggesting that JMJD1A protects host against C. rodentium …

Alpha 7 Nicotinic Acetylcholine Receptor Contributes To Long-Term Cognitive Recovery Following Ischemic Stroke, Dustin T Nguyen, Kate Mendoza, Cassandra Hall, Chunfeng Tan, Anjali Chauhan

Faculty, Staff and Student Publications

Stroke is associated with autonomic dysfunction and reduced acetylcholine (ACh), a neurotransmitter critical for cognition. ACh signals in part through the alpha-7 nicotinic acetylcholine receptor (α7nAChR), a ligand-gated ion channel involved in synaptic plasticity, learning, and memory. Impaired α7nAChR signaling has been linked to heightened neuroinflammation and poor acute stroke recovery. Here, we investigated whether α7nAChR contributes to post-stroke cognitive recovery in young male mice. Wild-type (WT) and α7nAChR knockout (α7n0KO) mice underwent 60-min middle cerebral artery occlusion (MCAO). In a pharmacology cohort, the α7nAChR agonist GTS-21 was administered immediately after reperfusion and then daily for 20 days. Cognitive performance …

Fgl2-Knockout Tumor Cells Serve As A Vaccine Inducing Long-Duration Brain-Resident Memory T Cells That Reject Subsequent Intracranial Tumor Cell Challenges, Sheng Zhang, Yining Jin, Zhiliang Jia, Xueqing Xia, Yang Li, Qi Wang, Jing Wang, Jian Wang, Joya Chandra, Gregory K Friedman, Shulin Li

Faculty, Staff and Student Publications

The failure to prevent brain tumors, including both recurrent primary and metastatic brain tumors, is the primary cause of patients' mortality. We developed a novel whole tumor-cell vaccine to rapidly induce long-duration brain-resident memory T (TRM) cells that prevent brain tumor progression. Ten Fgl2-KO primary and metastatic tumor cell lines, generated via CRISPR/Cas9, were used to vaccinate mice and for intracranial challenges with the WT tumor cells. Not only did vaccinated mice reject these tumor cell challenges, but also more than half of these mice became long-duration survivors. Transplanting brain immune cells from vaccinated mice into naïve mice enabled this …

Diversity And Immune Dynamics Of Choroid Plexus Macrophages Are Shaped By Distinct Developmental Origins, Siling Du, Khai M Nguyen, Alina Ulezko Antonova, Jose L Fachi, Patrick Fernandes Rodrigues, Alice Verdiani, Martina Molgora, Igor Smirnov, Jasmin Herz, Tornike Mamuladze, Jennifer Ponce, Amanda Swain, Mattia Bugatti, Susan Gilfillan, Marina Cella, William Vermi, Jonathan Kipnis, Marco Colonna, Simone Brioschi

The Brown Foundation: Institute of Molecular Medicine

The choroid plexus forms a key barrier and signaling interface between the brain and peripheral circulation, yet its immune landscape remains incompletely understood. Using single-cell transcriptomics combined with lineage and spatial tracing methods, we identified three biologically distinct populations of choroid plexus macrophages, defined by differential expression of CD163, MHCII or CD9. These subsets arise from separate hematopoietic waves, occupy distinct anatomical niches and differentially rely on CSF1 and IL-34 for survival. We found that TGFβ signaling is essential to maintain their tissue-specific identities, and deletion of Tgfbr2 in these cells induces broad phenotypic reprogramming. During neuroinflammation, choroid plexus macrophages …

Glutamatergic Dysfunction Of Astrocytes In Paraventricular Nucleus Of Thalamus Contributes To Adult Anxiety Susceptibility In Adolescent Ethanol Exposed Mice, Aubrey Bennett, Hyunjung Kim, David Thomas, Peter Biggs, Roxan Ara, Asamoah Bosomtwi, Seungwoo Kang

The Brown Foundation: Institute of Molecular Medicine

Repeated ethanol exposure during adolescence increases adult anxiety risk, but the underlying mechanisms remain unclear. The paraventricular nucleus of the thalamus (PVT) has been considered a hub for controlling anxiety and is affected by experiences from early life. Thus, this study investigated how adolescent intermittent repeated ethanol exposure (AIE) affects the PVT activities and anxiety-related behaviors in adulthood. We found that AIE triggers anxiety-like behaviors and parallelly exhibited elevated firing rates and increased calcium signaling in the PVT neurons compared to control counterpart mice. Chemogenetic inhibition of PVT neurons reduced anxiety-like behaviors in AIE-treated animals, confirming PVT's role in adolescent …

Cerebral Hypoperfusion Causes Behavioral Changes And Impairs The Rod Photoreceptor Pathway In The Retina Of Aged Mice, Spencer Talmage Barney, Daniela Becerril, Sheelu Monga, Samantha Flores, Audrey Lee, Marlon Fraga Mattos, Ross M Perez, Frank W Blixt, Michael Maniskas, Shuning Huang, Hongyu Wu, Chunfeng Tan, Louise D Mccullough, Elizabeth Zuniga-Sanchez, Jose Felix Moruno-Manchon

Faculty, Staff and Student Publications

Gradual reduction of cerebral blood flow occurs with aging, and it is a major cause of vascular dementia, a group of dementias with a cerebrovascular component. Interestingly, patients who have suffered a vascular insult may develop retinopathy, which may occur as an early symptom of vascular dementia. Several rodent models using young animals have been generated to mimic retinopathy caused by cerebral hypoperfusion; however, given that aging is an important factor in developing vascular dementia and hypoperfusion retinopathy, we propose to use aged (17-month-old) mice in a model of cerebral hypoperfusion. In this model, we implant two metallic micro-coils (0.16 …

Sex-Specific Differences In Mediobasal Hypothalamus In Response To Nutritional States, Jonathan C Bean, Jinjing Jian, Tzu-Chiao Lu, Hailan Liu, Kristine Conde, Darah A Threat, Sanika V Jossy, Megan E Burt, Jingjing Cheng, Yue Deng, Xing Fang, Xiaoyu Geng, Junying Han, Yongxiang Li, Hesong Liu, Qingzhuo Liu, Yutian Liu, Yuhan Shi, Longlong Tu, Mengjie Wang, Xu Xu, Yuxue Yang, Meng Yu, Xinming Liu, Meixin Sun, Fuhui Wang, Olivia Z Ginnard, Yongjie Yang, Yang He, Chunmei Wang, Yanyan Qi, Hongjie Li, Yong Xu

Children’s Nutrition Research Center Staff Publications

The arcuate nucleus of the hypothalamus plays a central role in sensing and integrating nutritional, hormonal, and neural signals that regulate feeding, energy homeostasis, growth, and reproduction, all of which show pronounced sex differences. However, the cellular mechanisms underlying these responses remain poorly understood. We performed snRNA-seq of the mediobasal hypothalamus, focusing on the arcuate nucleus, in female and male mice under different nutritional states. Analysis of 42 cell types revealed that Agrp neurons were most sensitive to nutritional changes, dopaminergic neurons showed strong sex-specific differences, and KNDy neurons were highly responsive to both sex and nutrition. Pomc neurons displayed …

Sting-Induced Blood-Brain Barrier Opening Combined With Radiotherapy Potentiates Antitumor Response In A High-Grade Glioma Model, Shashwat Tripathi, Hinda Najem, Lisa Hurley, Ruochen Du, Crismita Dmello, Heba Ali, Kathleen Mccortney, Karl J Habashy, Peng Zhang, Craig M Horbinski, Lara Leoni, Ryan J Avery, Rimas V Lukas, Timothy L Sita, David R Raleigh, Sean Sachdev, Roger Stupp, Maciej S Lesniak, David M Ashley, Daniele Procissi, Michael A Curran, Irina Balyasnikova, Amy B Heimberger

Faculty, Staff and Student Publications

Radiation therapy (RT) is the standard of care for glioblastoma but is not curative. Triggering the cGAS/stimulator of interferon genes (STING) pathway with potent agonists, such as 8803, exerts activity across high-grade glioma preclinical models. To determine if the combination of 8803 with RT warrants consideration in the up-front treatment setting and to clarify the underlying mechanisms of therapeutic activity, C57BL/6J mice harboring intracerebral CT-2A or QPP8v gliomas were treated with RT, intratumoral 8803, or both. The treatment with the combination resulted in 80% long-term survival in the CT-2A model but not in the radiation-resistant QPP8v model. This therapeutic effect …

Targeting Oxalate Production By Combining Enzyme Inhibition And Proteolysis Activation: A Novel Therapeutic Approach For Primary Hyperoxaluria Type 1, Fabio Arias, Sumati Rohilla, Yudibeth Sixto-López, Koral S E Richard, Sandeep Das, Sumit K Anand, Pilar Maria Luque-Navarro, Guillermo Bañuelos-Sanchez, Juan Luis Pacheco-García, Reethika Gade, M Peyton Mckinney, Dhananjay Kumar, Jemiah Maxie, W Rylan Corr, Nilesh Pandey, Harpreet Kaur, Jibin Ding, Lin Tan, Elisha Scott, Hyung Nam, Eyal Gottlieb, A Wayne Orr, Nirav Dhanesha, Arif Yurdagul, Angel L Pey, Francisco Franco-Montalbán, José A Gómez Vidal, Oren Rom, Mónica Díaz-Gavilán

Faculty, Staff and Student Publications

Primary hyperoxaluria type 1 (PH1) is a rare genetic disorder caused by hepatic oxalate overproduction due to alanine-glyoxylate aminotransferase (AGXT) deficiency. Therapeutic strategies targeting glycolate oxidase (GO) and lactate dehydrogenase A (LDHA), key enzymes in glyoxylate metabolism, have shown promise in reducing oxalate burden. However, recently approved siRNA therapies remain limited by high cost, unfavorable pharmacokinetics, and limited global accessibility. We report the development of compound 2, a dual GO/LDHA inhibitor (K i = 390 and 40 nM, respectively) that also promotes hydrophobic tag-mediated autophagic degradation of LDHA. Its efficacy was evaluated in Agxt –/– mice, both in primary …