Digital Commons Network^™

Effects Of Prebiotic Phytocompound Administration In Gestational Diabetic Dams And Its Influence On Offspring Cognitive Outcomes, Gayathri Jagadeesan, Tushar K Das, Jennifer M Mendoza, Ghalya Alrousan, Maria P Blasco-Conesa, Parimelazhagan Thangaraj, Bhanu Priya Ganesh

Faculty, Staff and Student Publications

Gestational diabetes mellitus (GD)-induced gut dysbiosis in pregnant mothers may increase the risk of cognitive impairment and neurological disorders in both the mother and offspring as they age. Restoring gut balance could improve cognitive outcomes for both. Despite advancements in GD treatment, side effects have increased, and long-term neurocognitive impacts on offspring born to GD mothers remain underexplored. This study uses a GD mouse model, inducing pancreatic dysfunction in 3-month-old pregnant C57BL/6J mice with Streptozotocin. The efficacy and mechanism of the prebiotic phytocompound green leaf extract (

Assessing Cancer Therapeutic Efficacy In Vivo Using [2h7]Glucose Deuterium Metabolic Imaging, Mario C Chang, Vinay R Malut, Rohit Mahar, Anna Rushin, Marc A Mcleod, Geraldine L Pierre, Indu R Malut, Stephen J Staklinski, Max E Glanz, Mukundan Ragavan, Gaurav Sharma, Manoj Madheswaran, Arshee Badar, Aparna D Rao, Brian K Law, Michael S Kilberg, James H P Collins, Vikram D Kodibagkar, James A Bankson, Ralph J Deberardinis, Matthew E Merritt

Faculty, Staff and Student Publications

Metabolic imaging produces powerful visual assessments of organ function in vivo. Current techniques can be improved by safely increasing metabolic contrast. The gold standard, 2-[18F]fluorodeoxyglucose-positron emission tomography (FDG-PET) imaging, is limited by radioactive exposure and sparse assessment of metabolism beyond glucose uptake and retention. Deuterium magnetic resonance imaging (DMRI) with [6,6-2H2]glucose is nonradioactive, achieves tumor metabolic contrast, but can be improved by enriched contrast from deuterated water (HDO) based imaging. Here, we developed a DMRI protocol employing [2H7]glucose. Imaging 2H-signal and measuring HDO production in tumor-bearing mice detected differential glucose utilization across baseline tumors, tumors treated with vehicle control or …

Characterization Of Hepatic Pathology During Azoxymethane-Induced Acute Liver Failure, Shadikchhya Maya Bhattarai, Ashwin Jhawer, Gabriel Frampton, Eleonora Troyanovskaya, Sharon Demorrow, Matthew Mcmillin

Faculty, Staff and Students Publications

Background: Acute liver failure (ALF) is a loss of liver function due to a severe hepatic insult. Studies utilizing the azoxymethane (AOM) mouse model of ALF, which also generates hepatic encephalopathy, have primarily focused on development of neurological deficits. However, the molecular processes that generate liver damage have not been fully characterized. Therefore, a more comprehensive characterization of the hepatic consequences of AOM toxicity is needed to better understand this disease model.

Aim: To identify molecular pathology contributing to hepatic injury during the progression of AOM-induced ALF.

Methods: C57BL/6 mice were injected with AOM to produce ALF and hepatic encephalopathy. …

An In Vivo Screen Identifies Nat10 As A Master Regulator Of Brain Metastasis, Jocelyn F Chen, Peng Xu, Wesley L Cai, Huacui Chen, Emily Wingrove, Xiaojian Shi, Wenxue Li, Giulia Biancon, Meiling Zhang, Amer Balabaki, Ethan D Krop, Elianna Asare, Yangyi Zhang, Mingzhu Yin, Toma Tebaldi, Jordan L Meier, Thomas F Westbrook, Stephanie Halene, Yansheng Liu, Hongying Shen, Don X Nguyen, Qin Yan

Faculty, Staff and Students Publications

Emerging evidence has shown that epigenetic regulation plays a fundamental role in cancer metastasis, the major cause of cancer-related deaths. Here, we conducted an in vivo screen for vulnerabilities of brain metastasis and identified N-acetyltransferase 10 (NAT10) as a driver of brain metastasis. Knockdown of NAT10 restrains cancer cell proliferation and migration in vitro and tumor growth and brain metastasis in vivo. The poorly characterized RNA helicase domain of NAT10 is critical for cell growth in vitro, while both RNA helicase and NAT domains are essential for primary tumor growth and brain metastasis in vivo. Mechanically, NAT10 promotes the …

Independent Origins And Non-Parallel Selection Signatures Of Triclabendazole Resistance In Fasciola Hepatica, Young-Jun Choi, Bruce A Rosa, Martha V Fernandez-Baca, Rodrigo A Ore, John Martin, Pedro Ortiz, Cristian Hoban, Miguel M Cabada, Makedonka Mitreva

2020-Current year OA Pubs

Triclabendazole (TCBZ) is the primary treatment for fascioliasis, a global foodborne zoonosis caused by Fasciola hepatica. Widespread resistance to TCBZ (TCBZ-R) in livestock and a rapid rise in resistant human infections are significant concerns. To understand the genetic basis of TCBZ-R, we sequenced the genomes of 99 TCBZ-sensitive (TCBZ-S) and 210 TCBZ-R adult flukes from 146 bovine livers in Cusco, Peru. We identify genomic regions of high differentiation (F

Lifespan Of Male And Female App/Ps1 And Appnl-F/Nl-F Mouse Models Of Alzheimer's Disease, Hannah Roberts, Yimin Fang, Kathleen Quinn, Tiarra Hill, Mackenzie R Peck, Andrzej Bartke, Kevin N Hascup, Erin R Hascup

Articles

Alzheimer's disease (AD) disproportionately affects women, yet most preclinical research studies are male-centric. We performed lifespan analyses of male and female AD mouse models (APP/PS1 and APP^NL-F/NL-F) and their shared genetic background control (C57BL/6). Survival curves support significant sex differences between genotypes. Minimal longevity revealed increased age in male APP/PS1, and decreased age in male APP^NL-F/NL-F mice. Maximal longevity revealed an increased average age in males. Furthermore, median lifespan differed between sex and genotype. This study supports dimorphic survival in two mouse models of AD, emphasizing the need to examine mechanisms and treatments in both sexes.

Combined Targeting Of Glioblastoma Stem Cells Of Different Cellular States Disrupts Malignant Progression, Chenfei Lu, Tao Kang, Junxia Zhang, Kailin Yang, Yang Liu, Kefan Song, Qiankun Lin, Deobrat Dixit, Ryan C Gimple, Qian Zhang, Zhumei Shi, Xiao Fan, Qiulian Wu, Daqi Li, Danyang Shan, Jiancheng Gao, Danling Gu, Hao You, Yangqing Li, Junlei Yang, Linjie Zhao, Zhixin Qiu, Hui Yang, Ningwei Zhao, Wei Gao, Weiwei Tao, Yingmei Lu, Yun Chen, Jing Ji, Zhe Zhu, Chunsheng Kang, Jianghong Man, Sameer Agnihotri, Qianghu Wang, Fan Lin, Xu Qian, Stephen C Mack, Zhibin Hu, Chaojun Li, Michael D Taylor, Ning Liu, Nu Zhang, Ming Lu, Yongping You, Jeremy N Rich, Wei Zhang, Xiuxing Wang

Faculty, Staff and Students Publications

Glioblastoma (GBM) is the most lethal primary brain tumor with intra-tumoral hierarchy of glioblastoma stem cells (GSCs). The heterogeneity of GSCs within GBM inevitably leads to treatment resistance and tumor recurrence. Molecular mechanisms of different cellular state GSCs remain unclear. Here, we find that classical (CL) and mesenchymal (MES) GSCs are enriched in reactive immune region and high CL-MES signature informs poor prognosis in GBM. Through integrated analyses of GSCs RNA sequencing and single-cell RNA sequencing datasets, we identify specific GSCs targets, including MEOX2 for the CL GSCs and SRGN for the MES GSCs. MEOX2-NOTCH and SRGN-NFκB axes play important …

Distinct Patterns Of Pv And Sst Gabaergic Neuronal Activity In The Basal Forebrain During Olfactory-Guided Behavior In Mice, Elizabeth H Moss, Evelyne K Tantry, Elaine Le, Pey-Shyuan Chin, Priscilla Ambrosi, Katie L Brandel-Ankrapp, Benjamin R Arenkiel

Duncan NRI Faculty and Staff Publications

Sensory perception relies on the flexible detection and interpretation of stimuli across variable contexts, conditions, and behavioral states. The basal forebrain (BF) is a hub for behavioral state regulation, supplying dense cholinergic and GABAergic projections to various brain regions involved in sensory processing. Of GABAergic neurons in the BF, parvalbumin (PV) and somatostatin (SST) subtypes serve opposing roles toward regulating behavioral states. To elucidate the role of BF circuits in sensory-guided behavior, we investigated GABAergic signaling dynamics during odor-guided decision-making in male and female mice. We used fiber photometry to record cell type-specific BF activity during an odor discrimination task …

Pmp2+ Schwann Cells Maintain The Survival Of Large-Caliber Motor Axons, Mikolaj M Kozlowski, Amy Strickland, Ana Morales Benitez, Robert E Schmidt, A Joseph Bloom, Jeffrey Milbrandt, Aaron Diantonio

2020-Current year OA Pubs

Neurodegenerative diseases of both the central and peripheral nervous system are characterized by selective neuronal vulnerability, i.e., pathology that affects particular types of neurons. While much of this cell type selectivity may be driven by intrinsic differences among the neuron subpopulations, neuron-extrinsic mechanisms such as the selective malfunction of glial support cells may also play a role. Recently, we identified a population of Schwann cells (SCs) expressing

Podoplanin-Positive Cell-Derived Small Extracellular Vesicles Contribute To Cardiac Amyloidosis After Myocardial Infarction., Maria Cimini, Ulrich H E Hansmann, Carolina Gonzalez, Andrew D Chesney, May M Truongcao, Erhe Gao, Tao Wang, Rajika Roy, Elvira Forte, Vandana Mallaredy, Charan Thej, Ajit Magadum, Darukeshwara Joladarashi, Cindy Benedict, Water J Koch, Çağla Tükel, Raj Kishore

Faculty Research 2025

Cardiac amyloidosis is a secondary phenomenon of an already pre-existing chronic condition. Whether car- diac amyloidosis represents one of the complications post myocardial infarction (MI) has yet to be fully under- stood. Here, we show that amyloidosis occurs after MI and that amyloid fibers are composed of macrophage- derived serum amyloid A 3 (SAA3) monomers. SAA3 overproduction in macrophages is triggered by exosomal communication from cardiac stromal cells (CSCs), which, in response to MI, activate the expression of a platelet aggregation-inducing type I transmembrane glycoprotein, Podoplanin (PDPN). CSC PDPN+ -derived small extracellular vesicles (sEVs) are enriched in SAA3, and exosomal …

The Tumor Microenvironment Is An Ecosystem Sustained By Metabolic Interactions, Emily Jane Kay, Sara Zanivan

Faculty, Staff and Student Publications

Cancer-associated fibroblasts (CAFs) and immune cells make up two major components of the tumor microenvironment (TME), contributing to an ecosystem that can either support or restrain cancer progression. Metabolism is a key regulator of the TME, providing a means for cells to communicate with and influence each other, modulating tumor progression and anti-tumor immunity. Cells of the TME can metabolically interact directly through metabolite secretion and consumption or by influencing other aspects of the TME that, in turn, stimulate metabolic rewiring in target cells. Recent advances in understanding the subtypes and plasticity of cells in the TME both open up …

Developmental Differentiation Of Mouse Inner Ear Neuron Subpopulations Resolved With A Peripherin-Promoter Reporter Within The Grm8 Locus, Lily J Pearson, Jeremy L Pinyon, Jennie M E Cederholm, Georg Von Jonquieres, Florence Bartlett, Xabier Vázquez-Campos, Fabien Delerue, Lars M Ittner, Gary D Housley

Faculty, Staff and Student Publications

Molecular profiling of inner ear neurons has broadened the classification of the primary afferents that support neural coding for hearing and balance. To extend spatiotemporal characterization of auditory and vestibular neuron diversity, we established a transgenic reporter mouse model (Prphp-mCherry), where elements of the peripherin promoter (Prphp) drive expression of the mCherry fluorescent reporter. Type III intermediate filament protein peripherin expression is a marker for type II spiral ganglion neurons (SGN) that innervate the cochlear outer hair cells, and the small diameter 'bouton' vestibular ganglion neurons (VGN) innervating the type II vestibular hair cells. Using Nanopore genome sequencing, the integration …

Spatial And Seasonal Dynamics Of Mosquito Species In Harris County, Texas, Highlight Risk Of Arbovirus Introduction And Transmission, Morgan Jibowu, Maximea Vigilant, Andre Luis Costa-Da-Silva, Alisa Nelson, Heather T Essigmann, Eric L Brown, Sarah M Gunter

Faculty, Staff and Student Publications

Mosquito-borne diseases pose a significant public health threat, particularly in densely populated urban areas. Climate change, urbanization, and global connectivity have fueled the expansion of mosquitoes and their associated pathogens, increasing the disease burden. Harris County, Texas, is among the most vulnerable regions in the United States for mosquito-borne disease outbreaks, underscoring the critical need for localized insights into mosquito population dynamics to inform vector surveillance and control strategies. This study provides a comprehensive analysis of the population dynamics of mosquito species in Harris County by exploring their species composition, spatial distribution, and seasonal patterns. Our findings reveal the extensive …

Rapid Laser Ablation-Based Fabrication Of High-Density Polymer Microwell Arrays For High-Throughput Cellular Studies, Desh Deepak Dixit, Kavya L Singampalli, Amit S Niyogi, Amanda Montoya, Alexandre Reuben, Peter B Lillehoj

Faculty, Staff and Student Publications

Polymer-based microwell platforms have garnered much interest due to their usefulness in culturing and analyzing small quantities of biological cells and spheroids. Existing methods for fabricating polymer microwell arrays involve complex fabrication processes and/or are limited in their ability to create dense arrays of very small (< 50 μm in diameter) microwells. Here, we present a simple and rapid technique for fabricating high-density arrays of microwells ranging from 20 to 160 μm in diameter on a variety of polymer substrates. In this approach, a polymer surface is ablated using a CO2 laser that is rastered over a stainless steel mesh, which serves as a shadow mask. A theoretical laser-polymer interaction model was developed for predicting the microwell volume based on the substrate properties and laser settings. Microwell volumes predicted by the model were within 5.4% of fabricated microwell volumes determined experimentally. Cellulose acetate microwell arrays fabricated using this technique were used to culture Lewis lung carcinoma cells expressing ovalbumin (LLC-OVA), which were maintained for up to 72 h with a negligible (< 5%) loss in viability. As a second proof of principle demonstration, LLC-OVA cells grown in microwell arrays were co-cultured with OT-I T cells and measurements of interferon gamma (IFN-γ), a marker for T cell activation, were performed which revealed a positive correlation between LLC-OVA cell-T cell interaction time and T cell activation. These two in vitro demonstrations showcase the capability of this technique in generating polymer microwell arrays for high-throughput cellular studies, including cell growth dynamics studies and cell interaction studies. Furthermore, we envision that these platforms can be used with different cell types and for other biological applications, such as spheroid formation and single cell analysis, …

Haploinsufficiency Of Itsn1 Is Associated With A Substantial Increased Risk Of Parkinson’S Disease, Thomas P Spargo, Chloe F Sands, Isabella R Juan, Jonathan Mitchell, Vida Ravanmehr, Jessica C Butts, Ruth B De-Paula, Youngdoo Kim, Fengyuan Hu, Quanli Wang, Dimitrios Vitsios, Manik Garg, Lawrence Middleton, Michal Tyrlik, Mirko Messa, Guillermo Del Angel, Daniel G Calame, Hiba Saade, Laurie Robak, Ben Hollis, Vishnu A Cuddapah, Huda Y Zoghbi, Joshua M Shulman, Slavé Petrovski, Ismael Al-Ramahi, Ioanna Tachmazidou, Ryan S Dhindsa

Faculty, Staff and Students Publications

Despite its significant heritability, the genetic basis of Parkinson's disease (PD) remains incompletely understood. Here, in analyzing whole-genome sequence data from 3,809 PD cases and 247,101 controls in the UK Biobank, we discover that protein-truncating variants in ITSN1 confer a substantially increased risk of PD (p = 6.1 × 10

Multicilia Dynamically Transduce Sonic Hedgehog Signaling To Regulate Choroid Plexus Functions, Suifang Mao, Michael J Holtzman, Et Al.

2020-Current year OA Pubs

The choroid plexus is a major site for cerebrospinal fluid (CSF) production, characterized by a multiciliated epithelial monolayer that regulates CSF production. We demonstrate that defective choroid plexus ciliogenesis or intraflagellar transport yields neonatal hydrocephalus, at least in part due to increased water channel Aqp1 and ion transporter Atp1a2 expression. We demonstrate choroid plexus multicilia as sensory cilia, transducing both canonical and non-canonical Sonic Hedgehog (Shh) signaling. Interestingly, it is the non-canonical Shh signaling that represses Aqp1 and Atp1a2 expression by the Smoothened (Smo)/Gαi/cyclic AMP (cAMP) pathway. Choroid plexus multicilia exhibit unique ciliary ultrastructure, carrying features of both primary and …

Cell-Matrix Feedback Controls Stretch-Induced Cellular Memory And Fibroblast Activation, Yuan Hong, Xiangjun Peng, Haomin Yu, Delaram Shakiba, Yuxuan Huang, Chengqing Qu, Aliza Mujahid, Yin-Yuan Huang, Jacob A Sandler, Kenneth M Pryse, Justin M Sacks, Elliot L Elson, Guy M Genin, Et Al.

2020-Current year OA Pubs

Mechanical stretch can activate long-lived changes in fibroblasts, increasing their contractility and initiating phenotypic transformations. This activation, critical to wound healing and procedures such as skin grafting, increases with mechanical stimulus for cells cultured in two-dimensional but is highly variable in cells in three-dimensional (3D) tissue. Here, we show that static mechanical stretch of cells in 3D tissues can either increase or decrease fibroblast activation depending upon recursive cell-extracellular matrix (ECM) feedback and demonstrate control of this activation through integrated in vitro and mathematical models. ECM viscoelasticity, signaling dynamics, and cell mechanics combine to yield a predictable, but nonmonotonic, relationship …

Tissue-Resident Ccr2+ Macrophage Trem-1/3 Signaling Is Necessary For Monocyte And Neutrophil Recruitment To Injured Hearts, Yuriko Terada, Wenjun Li, Junedh M Amrute, Amit I Bery, Charles R Liu, Venkatrao Nunna, Christian Corbin Frye, Hao Dun, Andrew L Koenig, Hannah P Luehmann, Gyu Seong Heo, Macee C Owen, Alexander N Wein, Yongjian Liu, Jon H Ritter, Sumanth D Prabhu, Ruben G Nava, Andrew E Gelman, Marina Cella, Marco Colonna, Kory J Lavine, Daniel Kreisel

2020-Current year OA Pubs

Triggering receptor expressed on myeloid cells 1 (TREM-1) has been shown to amplify inflammatory signals, such as Toll-like receptor signaling, after infection and sterile injury. While previous studies have demonstrated that TREM-1 activation in circulating immune cells promotes injury, the role of TREM-1 signaling in tissue-resident cells in the context of sterile inflammation remains poorly understood. Here, we used a cardiac transplantation model to dissect how Trem1/3 expression on heart-resident cells regulates sterile inflammation. TREM-1 is expressed in heart-resident C-C chemokine receptor 2 (CCR2)

Ovarian-Specific Cyp17a1 Overexpression In Female Mice: A Novel Model Of Endogenous Testosterone Excess, Serene Joseph, Vaibhave Ubba, Zhiqiang Wang, Mingxiao Feng, Milan K Dsilva, Sofia Suero, Danielle Waheed, Nathaniel W Snyder, Xiaofeng Yang, Hong Wang, Joanne S Richards, Chemyong J Ko, Sheng Wu

Faculty, Staff and Students Publications

Excessive androgen levels can severely affect female health. However, most existing models of androgen excess rely on exogenous androgen administration, which does not fully capture the effect of elevated local ovarian testosterone on reproductive and metabolic functions. Here, we report the development of a novel hyperandrogenic mouse model, Cyp17TM-625, generated by combining CRISPR-Cas9 and a Tet-On doxycycline system to induce Cyp17A1 overexpression in ovarian theca-interstitial cells. As a result, Cyp17TM-625 mice exhibited significantly elevated Cyp17A1 messenger RNA and protein levels, accompanied by increased testosterone concentrations without alterations in basal levels of estradiol, progesterone, luteinizing hormone, or follicle-stimulating hormone. These mice …

Radial Glia Integrin Avb8 Regulates Cell Autonomous Microglial Tgfβ1 Signaling That Is Necessary For Microglial Identity, Gabriel Mckinsey, Nicolas Santander, Xiaoming Zhang, Kilian Kleemann, Lauren Tran, Aditya Katewa, Kaylynn Conant, Matthew Barraza, Kian Waddell, Carlos Lizama, Marie La Russa, Ji Hyun Koo, Hyunji Lee, Dibyanti Mukherjee, Helena Paidassi, E. S. Anton, Kamran Atabai, Dean Sheppard, Oleg Butovsky, Thomas Arnold

Department of Medicine Faculty Papers

Microglial diversity arises from the interplay between inherent genetic programs and external environmental signals. However, the mechanisms by which these processes develop and interact within the growing brain are not yet fully understood. Here, we show that radial glia-expressed integrin beta 8 (ITGB8) activates microglia-expressed TGFβ1 to drive microglial development. Domain-restricted deletion of Itgb8 in these progenitors results in regionally restricted and developmentally arrested microglia that persist into adulthood. In the absence of autocrine TGFβ1 signaling, microglia adopt a similar phenotype, leading to neuromotor symptoms almost identical to Itgb8 mutant mice. In contrast, microglia lacking the canonical TGFβ signal transducers …

Dependence Of Mitochondrial Calcium Signalling And Dynamics On The Disaggregase, Clpb, Donato D'Angelo, Víctor H. Sánchez-Vázquez, Benjamín Cartes-Saavedra, Denis Vecellio Reane, Ryan R. Cupo, Hilda Delgado De La Herran, Giorgia Ghirardo, James Shorter, Ron A. Wevers, Saskia B. Wortmann, Fabiana Perocchi, Rosario Rizzuto, Anna Raffaello, György Hajnóczky

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Cells utilize protein disaggregases to avoid abnormal protein aggregation that causes many diseases. Among these, caseinolytic peptidase B protein homolog (CLPB) is localized in the mitochondrial intermembrane space and linked to human disease. Upon CLPB loss, MICU1 and MICU2, regulators of the mitochondrial calcium uniporter complex (mtCU), and OPA1, a main mediator of mitochondrial fusion, become insoluble but the functional outcome remains unclear. In this work we demonstrate that CLPB is required to maintain mitochondrial calcium signalling and fusion dynamics. CLPB loss results in altered mtCU composition, interfering with mitochondrial calcium uptake independently of cytosolic calcium and mitochondrial membrane potential. …

Islet Single-Cell Transcriptomic Profiling During Obesity-Induced Beta Cell Expansion In Female Mice, Peter M Masschelin, Scott A Ochsner, Sean M Hartig, Neil J Mckenna, Aaron R Cox

Faculty, Staff and Student Publications

Targeting beta cell proliferation is an appealing approach to restore glucose control in type 1 diabetes. However, the underlying mechanisms of beta cell proliferation remain incompletely understood, limiting identification of new therapeutic targets. Obesity is a naturally occurring process that potently induces human and rodent beta cell replication, representing an ideal model to study mechanisms of beta cell proliferation. We showed previously acute whole-body

Distinct Attentional Characteristics Of Neurons With Visual Feature Coding In The Primate Brain, Jie Zhang, Runnan Cao, Xiaocang Zhu, Huihui Zhou, Shuo Wang

2020-Current year OA Pubs

Visual attention and object recognition are two critical cognitive functions that shape our perception of the world. While these neural processes converge in the temporal cortex, the nature of their interactions remains largely unclear. Here, we systematically investigated the interplay between visual attention and stimulus feature coding by training macaques to perform a free-gaze visual search task with natural stimuli. Recording from a large number of units across multiple brain areas, we found that units exhibiting visual feature coding showed stronger attentional modulation of responses and spike-local field potential coherence than units without feature coding. Across brain areas, attention directed …

Protocol To Study Inter-Tissue Communication Between The Hypothalamus And White Adipose Tissue And Lifespan Using A Chemogenetic Approach In Aged Mice, Kyohei Tokizane, Shin-Ichiro Imai

2020-Current year OA Pubs

Here, we present a protocol for assessing the impact of a chemogenetic manipulation in a subpopulation of the hypothalamic neurons on aging and lifespan control using a mouse model developed specifically for this purpose. We describe steps for stereotaxic viral injection and assess inter-tissue communication between protein phosphatase 1 regulatory subunit 17 (Ppp1r17)-expressing neurons in the dorsomedial hypothalamus and white adipose tissue. We then detail procedures for lifespan measurements following chemogenetic manipulation in aged mice. For complete details on the use and execution of this protocol, please refer to Tokizane et al.

Ppdpf: Preventing Kidney Disease Through Nad+, Shin-Ichiro Imai

2020-Current year OA Pubs

Researchers have discovered PPDPF, a critical cellular factor that controls NAD

Inhibition Of The Metalloprotease Adam19 As A Novel Senomorphic Strategy To Ameliorate Gut Permeability And Senescence Markers By Modulating Senescence-Associated Secretory Phenotype (Sasp)., Sudipta Bar, Tyler A U Hilsabeck, B Pattavina, José Alberto López-Domínguez, Nathan Basisty, Joanna Bons, Mark Watson, Birgit Schilling, Judith Campisi, Pankaj Kapahi, Amit Sharma

Faculty Research 2025

Accumulation of DNA damage can accelerate aging through cellular senescence. Previously, we established a Drosophila model to investigate the effects of radiation-induced DNA damage on the intestine. In this model, we examined irradiation-responsive senescence in the fly intestine. Through an unbiased genome-wide association study (GWAS) utilizing 156 strains from the Drosophila Genetic Reference Panel (DGRP), we identified meltrin (the drosophila orthologue of mammalian ADAM19) as a potential modulator of the senescence-associated secretory phenotype (SASP). Knockdown of meltrin resulted in reduced gut permeability, DNA damage, and expression of the senescence marker β-galactosidase (SA-β-gal) in the fly gut following irradiation. Additionally, inhibition …

Adipose Progenitor Cell-Derived Extracellular Vesicles Suppress Macrophage M1 Program To Alleviate Midlife Obesity, Qing Zhou, Jia Gao, Guorao Wu, Chenwei Wang, Yan Yang, Teng Huang, Yi Wang, Tiantian Yue, Zhichao Gao, Hao Xie, Fei Xiong, Ke Xiang, Tuying Yong, Wanguang Zhang, Tongtong Zhang, Wen Kong, Cai Chen, Shu Zhang, Qilin Yu, Xuemei Fan, Shiwei Liu, Yanjun Liu, Cong-Yi Wang

Children’s Nutrition Research Center Staff Publications

Among different age groups, middle-aged individuals are particularly susceptible to obesity, with a 22% higher risk of all-cause mortality. However, the underlying mechanisms remain unclear. In this study, we identify adipose progenitor cells (APCs) in the white adipose tissue (WAT) of middle-aged subjects as potential causes of midlife obesity. Specifically, the extracellular vesicles (EVs) derived from APCs display an impaired ability to mitigate the inflammaging of adipose tissue macrophages (ATMs) in middle-aged individuals. Mechanistically, these EVs, lacking miR-145-5p, fail to suppress the expression of L-selectin in ATMs, thereby facilitating their M1 program via the NF-κB signaling pathway. In contrast, EVs …

Dna Damage Response Signatures Are Associated With Frontline Chemotherapy Response And Routes Of Tumor Evolution In Extensive Stage Small Cell Lung Cancer, Benjamin B Morris, Simon Heeke, Yuanxin Xi, Lixia Diao, Qi Wang, Pedro Rocha, Edurne Arriola, Myung Chang Lee, Darren R Tyson, Kyle Concannon, Kavya Ramkumar, C Allison Stewart, Robert J Cardnell, Runsheng Wang, Vito Quaranta, Jing Wang, John V Heymach, Barzin Y Nabet, David S Shames, Carl M Gay, Lauren A Byers

Faculty, Staff and Student Publications

Introduction: A hallmark of small cell lung cancer (SCLC) is its recalcitrance to therapy. While most SCLCs respond to frontline therapy, resistance inevitably develops. Identifying phenotypes potentiating chemoresistance and immune evasion is a crucial unmet need. Previous reports have linked upregulation of the DNA damage response (DDR) machinery to chemoresistance and immune evasion across cancers. However, it is unknown if SCLCs exhibit distinct DDR phenotypes.

Methods: To study SCLC DDR phenotypes, we developed a new DDR gene analysis method and applied it to SCLC clinical samples, in vitro, and in vivo model systems. We then investigated how DDR regulation is …

The Night's Watch: Exploring How Sleep Protects Against Neurodegeneration, Samira Parhizkar, David M Holtzman

2020-Current year OA Pubs

Sleep loss is often regarded as an early manifestation of neurodegenerative diseases given its common occurrence and link to cognitive dysfunction. However, the precise mechanisms by which sleep disturbances contribute to neurodegeneration are not fully understood, nor is it clear why some individuals are more susceptible to these effects than others. This review addresses critical unanswered questions in the field, including whether sleep disturbances precede or result from neurodegenerative diseases, the functional significance of sleep changes during the preclinical disease phase, and the potential role of sleep homeostasis as an adaptive mechanism enhancing resilience against cognitive decline and neurodegeneration.

Trpm2 Overactivation Drives Hyperlipidemia-Induced Dysfunction Of Myeloid Cells And Neurovascular Units., Pengyu Zong, Cindy Li, Jianlin Feng, Zhichao Yue, Nicholas Legere, Albert S Yu, Fahad Shah, Adrianna Perez, Zhu Li, Evan Jellison, Yasuo Mori, Barbara Miller, Rajkumar Verma, Bruce Liang, Lixia Yue

Faculty Research 2025

Hyperlipidemia induces cellular dysfunction and is strongly linked to various diseases. The transient receptor potential channel melastatin 2 (TRPM2) plays a critical role in endothelial injury, immune cell activation, and neuronal death. We reveal that TRPM2 expression in human peripheral leukocytes strongly correlates with plasma lipid levels. In middle-aged Apoe/ mice, global, myeloid, and endothelial TRPM2 knockout or TRPM2 inhibition abolishes the hyperlipidemia-induced exacerbation of ischemic brain injury suggesting that TRPM2 overactivity caused by hyperlipidemia predisposes these cells to dysfunction during ischemia. Using a clinically relevant ischemic brain injury mouse model, we demonstrate TRPM2’s pivotal role in medi- ating hyperlipidemia’s …