Digital Commons Network^™

Site-Specific Drug Release Of Monomethyl Fumarate To Treat Oxidative Stress Disorders, Thomas D Avery, Jiahe Li, Dion J L Turner, Mohd S U Rasheed, Fisher R Cherry, Damian L Stachura, Fátima Rivera-Escalera, David M Ruiz, Michael J Lacagnina, Caitlyn M Gaffney, Clarissa Aguilar, Jingxian Yu, Yang Wang, Huan Xie, Dong Liang, Andrew J Shepherd, Andrew D Abell, Peter M Grace

Faculty, Staff and Student Publications

Treatment of diseases of oxidative stress through activation of the antioxidant nuclear factor E2-related factor 2 (NRF2) is limited by systemic side effects. We chemically functionalize the NRF2 activator monomethyl fumarate to require Baeyer-Villiger oxidation for release of the active drug at sites of oxidative stress. This prodrug reverses chronic pain in mice with reduced side effects and could be applied to other disorders of oxidative stress.

Tofacitinib Ameliorates Campylobacter-Induced Intestinal Pathology By Suppressing Ifnγ Producing Ilcs And T Cells, Anna A Korchagina, Sergey A Shein, Wayne T Muraoka, Justin Nguyen, Qiangxing Chen, Anna A Tumanova, Austin W Todd, Carlos E Rivera, Rita Tamayo, Paolo Casali, Ekaterina Koroleva, Alexei V Tumanov

Faculty, Staff and Student Publications

Patients with autoimmune diseases are more susceptible to foodborne infections, which can be exacerbated by immunosuppressive therapy. Tofacitinib, a JAK/STAT pathway inhibitor, was recently approved for the treatment of ulcerative colitis, yet its effects on the pathogenesis of intestinal infections remain unclear. Here, we examined the impact of oral tofacitinib treatment in a mouse model of Campylobacter jejuni (C. jejuni) infection. Our results show that early tofacitinib administration attenuates intestinal pathology without affecting bacterial colonization. Specifically, tofacitinib suppressed CXCL1, CXCL2, CCL2 chemokine expression by intestinal epithelial cells, limiting recruitment of monocytes and neutrophils to the gut. In addition, JAK/STAT inhibition …

Cancer-Associated Fibroblasts As Mediators Of Tissue Microenvironment Remodeling In Cancer, Fernanda G Kugeratski, Emily J Kay, Sara Zanivan

Faculty, Staff and Student Publications

Cancer-associated fibroblasts (CAFs) are a multifunctional cell population of solid tumors that substantially remodel the tumor microenvironment (TME). The combination of single-cell and spatial technologies with elegant mouse models and analysis of patient samples is enabling unprecedented advances in the characterization of CAF origins, heterogeneity, and functions within the TME. As such, the field is now evolving to delineate tissue-specific subpopulations of CAFs, their markers, and the biological context in which each subset presents with a tumor-promoting or a tumor-restraining function. In this timely review, we discuss recent advances in CAF biology in the context of emerging areas of interest …

Cancer-Induced Nerve Injury Promotes Resistance To Anti-Pd-1 Therapy, Erez N Baruch, Frederico O Gleber-Netto, Priyadharsini Nagarajan, Xiayu Rao, Shamima Akhter, Tuany Eichwald, Tongxin Xie, Mohammad Balood, Adebayo Adewale, Shorook Naara, Hinduja N Sathishkumar, Shajedul Islam, William Mccarthy, Brandi J Mattson, Renata Ferrarotto, Michael K Wong, Michael A Davies, Sonali Jindal, Sreyashi Basu, Karine Roversi, Amin Reza Nikpoor, Maryam Ahmadi, Ali Ahmadi, Catherine Harwood, Irene Leigh, Dennis Gong, Paulino Tallón De Lara, Derrick L Tao, Tara M Davidson, Nadim J Ajami, Andrew Futreal, Kunal Rai, Veena Kochat, Micah Castillo, Preethi Gunaratne, Ryan P Goepfert, Sharia D Hernandez, Nikhil I Khushalani, Jing Wang, Stephanie S Watowich, George A Calin, Michael R Migden, Mona Yuan, Naijiang Liu, Yi Ye, William L Hwang, Paola D Vermeer, Nisha J D'Silva, Yuri L Bunimovich, Dan Yaniv, Jared K Burks, Javier Gomez, Patrick M Dougherty, Kenneth Y Tsai, James P Allison, Padmanee Sharma, Jennifer A Wargo, Jeffrey N Myers, Sebastien Talbot, Neil D Gross, Moran Amit

Faculty, Staff and Student Publications

Perineural invasion (PNI) is a well-established factor of poor prognosis in multiple cancer types1, yet its mechanism remains unclear. Here we provide clinical and mechanistic insights into the role of PNI and cancer-induced nerve injury (CINI) in resistance to anti-PD-1 therapy. Our study demonstrates that PNI and CINI of tumour-associated nerves are associated with poor response to anti-PD-1 therapy among patients with cutaneous squamous cell carcinoma, melanoma and gastric cancer. Electron microscopy and electrical conduction analyses reveal that cancer cells degrade the nerve fibre myelin sheets. The injured neurons respond by autonomously initiating IL-6- and type I interferon-mediated …

Pka-Driven Spp1 Activation As A Novel Mechanism Connecting The Bone Microenvironment To Prostate Cancer Progression, Pablo Sanchis, Agustina Sabater, Julia Lechuga, Jimena Rada, Rocio Seniuk, Gaston Pascual, Mora Gatti, Juan Bizzotto, Peter D A Shepherd, Jun Yang, Javier Cotignola, Elba Vazquez, Joaquin Mateo, Pia Valacco, Estefania Labanca, Christopher Logothetis, Geraldine Gueron, Nicolas Anselmino

Faculty, Staff and Student Publications

Prostate cancer (PCa) bone metastasis (BM) poses a significant clinical challenge due to the heterogeneity of treatment responses and patient outcomes. In this study, we examined the role of Protein Kinase A (PKA) signaling in modulating the expression of osteopontin (SPP1/OPN), a protein associated with poor prognosis, within a subset of PCa BM patients. By integrating multi-omics results we identified a novel mechanism in which bone-derived type-I collagen (Col1a1) and fibronectin (Fn1) stimulate SPP1 expression in PCa cells through the activation of PKA signaling. This bone-induced regulation of SPP1 was confirmed both in vitro, using PCa-bone co-culture systems (PC3 or …

From Nociception In Aneural Animals To Human Suffering: Toward A Comparative Biology Of Pain, Edgar T Walters

Faculty, Staff and Student Publications

Pain is a core feature of human life, but systematic comparisons of this biological trait across taxa have been rare. A broadly accepted definition based on human experience emphasizes dual features of pain: a sensory (discriminative) component for sensing and monitoring tissue injury, and an affective (emotional) component to motivate avoidance of tissue distress. Conscious pain is coupled to unconscious nociception (detection of incipient or existing injury). This Review considers nociception and pain across phyla within a comparative framework, addressing basic questions about evolutionary origins, mechanisms and functions of pain. The occurrence of adaptive cellular responses to injury in virtually …

Dynamic Rewiring Of Microrna Networks In The Brainstem Autonomic Control Circuits During Hypertension Development In The Female Spontaneously Hypertensive Rat, Alison Moss, Ankita Srivastava, Lakshmi Kuttippurathu, James S. Schwaber, Rajanikanth Vadigepalli

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

We describe global microRNA (miRNA) changes in the central autonomic control circuits during the development of neurogenic hypertension. Using the female spontaneously hypertensive rat (SHR) and the normotensive Wistar Kyoto (WKY), we analyzed the dynamic miRNA expression changes in three brainstem regions-the nucleus of the solitary tract, caudal ventrolateral medulla, and rostral ventrolateral medulla-as a time series beginning at 8 wk of age before hypertension onset through to extended chronic hypertension. Our analysis yielded nine miRNAs that were significantly differentially regulated in all three regions between SHR and WKY over time. We collated computationally predicted gene targets of these nine …

Peritoneal Immunosurgery: Immunotherapy Augmented Surgery For The Treatment Of Peritoneal Cancers, Ada I Ozcan, Arianexys Aquino López, Mary K Mckenna, Malcolm K Brenner, Alastair M Thompson

Faculty, Staff and Students Publications

Peritoneal malignancy often indicates disruptions in multiple physiological systems resulting from widespread cancer. The heterogenous origin and dynamic nature of peritoneal cancer make it difficult to treat with standard approaches that fit into guidelines. We describe how successful treatment should address the underlying pathology, the systemic response to surgical treatments and target the immune perturbations that facilitate the establishment and propagation of this multifaceted disease.

Adeno-Associated Virus-Mediated Silencing Of Sox4 Leads To Long-Term Amelioration Of Liver Phenotypes In Mouse Models Of Alagille Syndrome, Duncan Fox, Jun Xie, Jennifer L Burwinkel, Josh M Adams, Kashish Chetal, Marzieh Keivandarian, Yaniv Faingelernt, Sanjay Subramanian, Mario F Lopez, Anna L Peters, Nathan Salomonis, Neda Zarrin-Khameh, Guangping Gao, Stacey S Huppert, Hamed Jafar-Nejad

Faculty, Staff and Students Publications

Background & aims: In patients with Alagille syndrome (ALGS), bile duct paucity often leads to severe cholestatic phenotypes for which liver transplantation remains the only definitive treatment. No Food and Drug Administration-approved mechanism-based strategies exist to enhance biliary development in ALGS or other diseases with bile duct paucity. We aimed to identify a therapeutic target to address this unmet need.

Methods: Preclinical ALGS mouse models lacking 1 copy of Jag1 with or without conditional deletion of 1 or both copies of Sox9 were used. Sox4 levels were reduced genetically or with adeno-associated virus 8 (AAV8) vectors driving a Sox4-silencing sequence. …

Protein Kinase Rock1 Activates Mitochondrial Fission Linking To Oxidative Stress And Muscle Atrophy, Meijun Si, Jihong Chen, Rizhen Yu, Hongchun Lin, Feng Li, Sungyun Jung, Sandhya S Thomas, Farhard R Danesh, Yanlin Wang, Hui Peng, Zhaoyong Hu

Faculty, Staff and Students Publications

Introduction: Chronic kidney disease (CKD) is associated with protein-energy wasting, characterized by a reduction in muscle mass and strength. Although mitochondrial dysfunction and oxidative stress are implicated in the pathogenesis of muscle wasting, underlying mechanisms remain unclear.

Methods: Here, we used transcriptomic analysis, metabolomics analyses, and mouse gene manipulation to investigate the effects of mitochondrial plasticity and oxidative stress on muscle wasting the subtotal nephrectomy mouse models of CKD. The mice with CKD were age- and sex-matched to sham-operated controls.

Results: Through these approaches, Rho-associated kinase ROCK1 emerged as a key molecule responsible for the observed mitochondrial fission and oxidative …

Lac-Phe Induces Hypophagia By Inhibiting Agrp Neurons In Mice, Hailan Liu, Veronica L Li, Qingzhuo Liu, Yao Liu, Cunjin Su, Hueyxian Wong, Na Yin, Hesong Liu, Xing Fang, Kristine M Mcdermott, Hueyzhong Wong, Meng Yu, Longlong Tu, Jonathan C Bean, Yongxiang Li, Mengjie Wang, Yue Deng, Yuhan Shi, Olivia Z Ginnard, Yuxue Yang, Junying Han, Megan E Burt, Sanika V Jossy, Chunmei Wang, Yongjie Yang, Benjamin R Arenkiel, Dong Kong, Yang He, Jonathan Z Long, Yong Xu

Faculty, Staff and Students Publications

Lactate-derived N-lactoyl-phenylalanine (Lac-Phe) was recently identified as an lactate-derived circulating metabolite that reduces feeding and obesity, but mechanisms that underlie the metabolic benefits of Lac-Phe remain unknown. Here we demonstrated that Lac-Phe directly inhibits hypothalamic neurons that express Agouti-related protein (AgRP), resulting in an indirect activation of anorexigenic neurons in the paraventricular nucleus of the hypothalamus (PVH). We also found that both AgRP inhibition and PVH activation are required to mediate Lac-Phe-induced hypophagia. Further, we show that Lac-Phe inhibits AgRP neurons via activating the ATP-sensitive potassium (KATP) channel, and inhibition of the KATP channel blunts effects of Lac-Phe to suppress …

Corneal Sensory Nerve Regulation Of Tear Production Through Stimulation Of Transient Receptor Potential Melastatin 8 (Trpm8) Channel: A Potential New Approach For Treating Dry Eye Disease, Juana Gallar, Stephen Pflugfelder, Anat Galor, Preeya K Gupta, Pedram Hamrah

Faculty, Staff and Students Publications

The lacrimal functional unit (LFU) tightly controls the secretion of all tear components, thus playing a critical role in maintaining ocular surface homeostasis. Forming an exquisitely sensitive neural network across the ocular surface, corneal sensory nerves detect environmental stimuli (e.g., temperature, chemicals, and mechanical pressure) through transient receptor potential (TRP) ion channels. Among these, TRP melastatin 8 (TRPM8) is a key regulator of basal tear production. Stimulated by the small temperature reductions and tear film osmolarity increases that arise due to evaporative cooling, TRPM8 activates the LFU, leading to increased basal tear production. Here, we focus on reviewing the topical …

Endoglin-Directed Car T Cells Comprehensively Target Tumors In Advanced Sarcomas, Harrison R Berger, Malina Maharana, Jeneffer Mirabal, Lyazat Kurenbekova, Alberto Delaidelli, Atreyi Dasgupta, Ahmed Z Gad, Mohamed F Sheha, Sybrina S Kerr, Ada I Ozcan, Jessica S Morris, Angela M Major, M John Hicks, Mary K Mckenna, Ben K Seon, Matthew L Baker, Poul H Sorensen, Meenakshi Hegde, Jason T Yustein, Nabil Ahmed, Sujith K Joseph

Faculty, Staff and Students Publications

There are limited therapeutic options for patients with advanced sarcomas, which leads to dismal outcomes for children and adults. Although chimeric antigen receptor (CAR) T cells hold promise for treating advanced sarcomas, this approach is constrained by a paucity of effective targets. Our previous clinical study identified endoglin (ENG/CD105), a TGFβ coreceptor, as a target of the endogenous immune response in a patient with sarcoma who exhibited an exceptional response to HER2-targeted CAR T-cell therapy. ENG is expressed on various sarcomas, cancer-associated fibroblasts, and neoangiogenic vessels and therefore offers comprehensive tumor targeting. Furthermore, ENG knockout in sarcoma cells reduces their …

Fructose And Glucose From Sugary Drinks Enhance Colorectal Cancer Metastasis Via Sord, Tianshi Feng, Qin Luo, Yanlin Liu, Zeyu Jin, David Skwarchuk, Rumi Lee, Miso Nam, John M Asara, Daya R Adye, Philip L Lorenzi, Lin Tan, Guangsheng Pei, Zhongming Zhao, Neda Zarrin-Khameh, Adriana Paulucci-Holthauzen, Brian W Simons, Ju-Seog Lee, Scott Kopetz, Jihye Yun

Faculty, Staff and Students Publications

The consumption of sugar-sweetened beverages (SSBs), which contain high levels of fructose and glucose, has been causally and mechanistically linked to an increased risk of colorectal cancer (CRC). However, the effects of SSB consumption on advanced stages of disease progression, including metastasis, remain poorly understood. Here we show that exposure of CRC cells to a glucose and fructose formulation-reflecting the composition of both high-fructose corn syrup and sucrose found in SSBs-enhances cellular motility and metastatic potential compared to glucose alone. Given that CRC cells grow poorly in fructose alone, and cells in vivo are not physiologically exposed to fructose without …

Exploring The Transformative Effects Of Calorie Restriction On The Lacrimal Gland In Adult Mice, Olivier Mauduit, Prashant Kumar, Kaitlin K Scholand, Emre Aksan, Laura Schaefer, Anmar Abu-Romman, Vanessa Delcroix, Zhiyuan Yu, Aude I Sindikubwabo, Ron Korstanje, Helen P Makarenkova, Cintia S De Paiva

Faculty, Staff and Students Publications

Advanced age is one of the most recognizable risk factors for dry eye. Dry eye disease affects millions worldwide and can result from age-related lacrimal gland dysfunction, which correlates with a decline in lacrimal gland secretory cell function and chronic inflammation. This study investigated the potential of calorie restriction to maintain lacrimal gland and ocular surface health. Adult female C57BL/6 J mice were subjected to a 40% calorie restriction for 4 months, starting at 6-7 months and continuing until 10-11 months. These mice were compared to controls fed ad libitum. Bulk RNA sequencing of lacrimal glands, conjunctiva, and cornea subjected …

Nrf2 Hyperactivation As A Driver Of Radiotherapy Resistance And Suppressed Antitumor Immunity In Head And Neck Squamous Cell Carcinoma, Rutulkumar Patel, Kalil Saab, Lixia Luo, Yan Ma, Rashid Abdullah Osman, Nerissa T Williams, Jeffrey Everitt, Maciej J Zelazowski, Patricia Castro, William K Decker, William H Hudson, Jeffrey N Myers, Vlad C Sandulache, Mitchell J Frederick, Yvonne M Mowery, David G Kirsch

Faculty, Staff and Students Publications

Purpose: Alterations in the KEAP1/NFE2L2 (NRF2)/CUL3 pathway occur in ∼20% of human head and neck squamous cell carcinomas (HNSCC) and are associated with resistance to standard-of-care therapy. However, this pathway's role in radiotherapy resistance in HNSCC has not been well studied.

Experimental design: We generated genetically engineered mouse models and developed primary murine cancer cell lines harboring mutations commonly observed in human HNSCC, including inducible activation of PIK3CA and deletion of Trp53, with or without Keap1 loss. Primary tumors were initiated via 4-hydroxytamoxifen injection ± the tobacco carcinogen benzo[a]pyrene (BAP) into the oral buccal mucosa. Tumors were analyzed by Western …

Inhibition Of Ros1 Activity With Lorlatinib Reversibly Suppresses Fertility In Male Mice, Yuki Oyama, Kentaro Shimada, Haruhiko Miyata, Rie Iida-Norita, Chihiro Emori, Maki Kamoshita, Seiya Oura, Ryohei Katayama, Martin M Matzuk, Masahito Ikawa

Faculty, Staff and Students Publications

Background: Inhibition of sperm maturation in the epididymis is a promising post-testicular strategy for short-acting male contraceptives. It has been shown that ROS1, a receptor tyrosine kinase expressed in the epididymis, is essential for epididymal differentiation, sperm maturation, and male fertility in mice. However, it is unknown if inhibition of ROS1 suppresses male fertility reversibly.

Objectives: Our study aimed to investigate the effects of ROS1 inhibitor administration in male mice on sperm function and fertility.

Materials and methods: We used lorlatinib, an anti-cancer drug that inhibits ROS1. We treated 10-week-old sexually mature male mice with lorlatinib for 3 weeks and …

Phosphorylation At Serine 214 Correlates With Tau Seeding Activity In An Age-Dependent Manner In Two Mouse Models For Tauopathies And Is Required For Tau Transsynaptic Propagation, Pablo Martinez, Nur Jury-Garfe, Henika Patel, Yanwen You, Abigail Perkins, Yingjian You, Audrey Lee-Gosselin, Ruben Vidal, Cristian A Lasagna-Reeves

Faculty, Staff and Students Publications

Background

Tau aggregation and propagation are hallmark features of Alzheimer's disease and related tauopathies. The molecular identity and post-translational modifications that contribute to tau seeding activity remain incompletely understood.

Objective

To characterize the temporal dynamics of tau seeding activity and identify specific phosphorylated tau species associated with tau propagation in vivo.

Methods

We profiled tau seeding activity using a FRET-based biosensor cell line and correlated it with the abundance of phospho- and conformational tau species in two transgenic mouse models of tauopathy (P301S-1N4R and P301S-0N4R). Immunohistochemistry and subcellular fractionation were used to examine the spatial distribution of tau species. Functional …

Systematic Targeting Of Gd2-Positive Neuroblastoma Tumors With A Photooncolytic Phage Nanovector Platform, Suleman Khan Zadran, Nicola Facchinello, Piergiuseppe De Rosa, Roberto Saporetti, Paolo Emidio Costantini, Luca Ulfo, Michela Nigro, Annapaola Petrosino, Lucia Pappagallo, Sara Aloisi, Giorgio Milazzo, Zainul Abe Din, Alberto Rigamonti, Leonardo Flora, Martina Santulli, Leonardo Cimadom, Giampaolo Zuccheri, Mattia Zangoli, Manuele Di Sante, Matteo Di Giosia, Francesca Di Maria, Roberto Bernardoni, Eveline Barbieri, Matteo Calvaresi, Alberto Danielli, Giovanni Perini

Faculty, Staff and Students Publications

Disialoganglioside-GD2 is a key molecular target for Neuroblastoma (NB) immunotherapy based on the employment of GD2-targeting antibodies. However, about 50% of treated patients can experience tumor relapse due to limited immune-mediated cytotoxicity and poor antibody penetration into tumors. To address this problem, a tumor-penetrating photo-oncolytic phage nanovector platform is genetically and chemically developed that selectively targets GD2-expressing NB cells. The phage bioconjugates, functionalized with different photosensitizers, result in specific and selective oncolysis of GD2-positive NB cells upon light irradiation, without affecting GD2-negative ones. The photo-oncolytic phage vectors are shown to deeply penetrate into GD2-positive tumor spheroids in vitro, and to …

Alternative Polyadenylation Contributes To Fibroblast Senescence In Pulmonary Fibrosis, Jingjing Huang, Maria Jose Gacha-Garay, Yu Wang, Scott D Collum, Rene A Girard, Hydia Puente, Seung-Hee Yoo, Rahat Hussain, Jayeshkumar Patel, Manish Patel, Eric J Wagner, Hari Krishnayalamanchili, Harry Karmouty-Quintana, Zheng Chen, Tingting Mills

Faculty, Staff and Students Publications

Idiopathic pulmonary fibrosis (IPF) is a prevalent and deadly age-related disease characterized by chronic, progressive, and irreversible fibrosis. A key effector cell population in the fibroproliferative response is the fibroblasts. Fibroblast cell senescence gradually worsens during aging, and the acquisition of a senescence-associated secretory phenotype (SASP) turns senescent fibroblasts into pro-inflammatory cells. However, the mechanism promoting senescence in IPF, especially at the post-transcriptional level, is poorly understood. We recently discovered that Nudix Hydrolase 21 (NUDT21, also named CFIm25), an RNA-binding protein, plays a critical role in regulating the expression of SASP factors through alternative polyadenylation (APA). APA allows adding poly(A) …

Hydrogen Sulfide Inhibits Recruitment Of Monocyte-Derived Tumor Associated Macrophages In Glioblastoma By Downregulating Cxcl12, Joseph Camarano, Morgan Roque, Gabrielle Gahn, Stephen Garrett Whipple, Danielle Terrell, Charles Ronkon, Jamie Toms, Anthony Sin, Bharat Guthikonda, Khatri Latha, Yuhui Yang, Xinggui Shen, Christopher G Kevil, Ganesh Rao, Sungho Lee

Faculty, Staff and Students Publications

Tumor associated macrophages (TAMs) directly contribute to the dismal prognosis of glioblastoma by preventing anti-tumor immunity and promoting tumor invasion and angiogenesis. Inhibiting TAM infiltration is a potential therapeutic strategy in glioblastoma, with several chemokine antagonists in early clinical development. Hydrogen sulfide, a gasotransmitter that regulates microglial accumulation in a wide range of CNS diseases, may be a novel therapeutic target to prevent TAM recruitment in glioblastoma. In this study, hydrogen sulfide concentrations were directly measured from 14 isocitrate dehydrogenase (IDH)-wildtype glioblastoma surgical samples and compared against overall survival as well as expression of TAM markers and chemokines. Effects of …

Carbonic Anhydrase Inhibition Sensitizes Group 3 Medulloblastoma To Radiotherapy, Cory M Richman, Alexandra Rasnitsyn, Borja L Holgado, Maria Vladoiu, Namal Abeysundara, Sandra Majo, Sara Chabi, Lucie J Taunay, Hiromichi Suzuki, Ichiyo Shibahara, Joonas Haapasalo, Jonelle G Pallotta, Tajana Douglas, Kaitlin Kharas, Kyle Juraschka, Oliver Ocsenas, Sachin A Kumar, Kristiina Nordfors, Ana Guerreiro Stücklin, Raul A Suarez, Jiao Zhang, Xiaochong Wu, Craig Daniels, Livia Garzia, Jüri Reimand, Olivier Saulnier, Thomas E Merchant, Celio Pouponnot, David R Raleigh, Michael D Taylor, Pasqualino De Antonellis

Faculty, Staff and Students Publications

Group 3 (G3) medulloblastoma constitutes the most aggressive molecular subgroup, and nearly all patients present with metastases upon recurrence. Treatment for newly diagnosed medulloblastoma relies on a combination of maximal safe surgical resection, followed by chemotherapy and ionizing radiation, and no therapies have been shown to confer a survival benefit at the time of recurrence. Given the limited therapeutic options available for patients with medulloblastoma, especially at recurrence, and the incomplete understanding of the molecular mechanisms underlying resistance to treatment, we sought to uncover actionable targets and biomarkers that could help refine patient selection and treatment of newly diagnosed medulloblastoma …

Aging Affects Lipid Homeostasis In Lacrimal Glands By Upregulating Lipogenesis And Changing Its Specificity, Seher Yuksel, Prashant Kumar, Sydney E Krenz, Kaitlin K Scholand, Zhiyuan Yu, Anastasiia Ivanova, Helen P Makarenkova, Sarah F Hamm-Alvarez, Igor A Butovich, Cintia S De Paiva

Faculty, Staff and Students Publications

Purpose: The lacrimal gland (LG) develops age-related alterations. This study investigated the lipid content of the accumulated secretions within the murine aged LG.

Methods: C57BL/6J animals of different ages (3 months, 12 months, and 20-26 months) were used. Published data of bulk RNA sequencing of aged LGs were used to investigate lipid pathways. Exorbital LGs were excised for histology or PCR. Histologic sections were stained with standard histochemical stains or immunostained using anti-adiponectin, anti-perilipin 2 antibodies, and BODIPY dye. LG lipidomes were investigated using unbiased, untargeted high-resolution liquid chromatography/mass spectrometry (LC/MS), and the data were processed using unbiased, untargeted principal …

Dominant Negative Atp5f1a Variants Disrupt Oxidative Phosphorylation Causing Neurological Disorders, Sara M Fielder, Marisa W Friederich, Daniella H Hock, Jessie R Zhang, Liana M Valin, Jill A Rosenfeld, Kevin T A Booth, Natasha J Brown, Rocio Rius, Tanavi Sharma, Liana N Semcesen, Kim C Worley, Lindsay C Burrage, Kayla Treat, Tara Samson, Sarah Govert, Sara Dacunha, Weimin Yuan, Jian Chen, Jacob Lesinski, Hieu Hoang, Stephanie A Morrison, Farah A Ladha, Roxanne A Van Hove, Cole R Michel, Richard Reisdorph, Eric Tycksen, Dustin Baldridge, Gary A Silverman, Claudia Soler-Alfonso, Erin Conboy, Francesco Vetrini, Lisa Emrick, William J Craigen, Undiagnosed Diseases Network, Stephen M Sykes, David A Stroud, Johan L K Van Hove, Tim Schedl, Stephen C Pak

Faculty, Staff and Students Publications

ATP5F1A encodes the α-subunit of complex V of the respiratory chain, which is responsible for mitochondrial ATP synthesis. We describe 6 probands with heterozygous de novo missense ATP5F1A variants that presented with developmental delay, intellectual disability, and movement disorders. All variants were located at the contact points between the α- and β-subunits. Functional studies in C. elegans revealed that the variants were damaging via a dominant negative genetic mechanism. Biochemical and proteomics studies of proband-derived cells showed a marked reduction in complex V abundance and activity. Mitochondrial physiology studies revealed increased oxygen consumption, yet decreased mitochondrial membrane potential and ATP …

Tigit Affects Car Nk-Cell Effector Function In The Solid Tumor Microenvironment By Modulating Immune Synapse Strength, Ishwar Navin, Matthew Dysthe, Prashant S Menon, Corrine Baumgartner, Tim Sauer, Navin Varadarajan, Robin Parihar

Faculty, Staff and Students Publications

Therapies using NK cells that express chimeric antigen receptors (CAR-NK) have been successfully employed against hematologic malignancies. However, solid tumors resist CAR-NKs partly by enriching tumor microenvironments with ligands for NK cell inhibitory receptors. Although the NK inhibitory receptor T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) has been implicated in impaired antitumor activity of endogenous NK cells, the consequences of TIGIT expression on engineered CAR-NKs have not been explored. To address this gap, we compared TIGIT-expressing and TIGIT-deleted human CAR-NKs targeting the GD2 solid tumor antigen in tumor immune microenvironment co-cultures and in vivo tumor immune …

Normal Urinary Oxalate Excretion In 4-Hydroxy-2-Oxo-Glutarate Aldolase 1 (Hoga1) Deficient Mice With Agt Expression In Peroxisomes And Not In Mitochondria, Iolanda Boffa, Rosa Ferriero, Mariarosaria Cancelliere, Edoardo Nusco, Leonardo Gatticchi, Donna Palmer, Philip Ng, Pasquale Piccolo, Barbara Cellini, Kyle Wood, John Knight, Nicola Brunetti-Pierri

Faculty, Staff and Students Publications

Primary hyperoxaluria type 3 (PH3) is caused by mutations in Hoga1 gene. PH3 individuals develop nephrolithiasis, but the mechanism underlying hyperoxaluria is unclear and a mouse model recapitulating the human disease can provide insights into the pathogenesis of PH3. Hoga1−/− mice do not have increased urinary oxalate excretion, probably due to the murine mitochondrial alanine-glioxylate-aminotransferase (AGT) activity, which in humans is only expressed in peroxisomes. However, Hoga1−/−/Agxt−/− mice with AGT installed on peroxisome and not on mitochondria did not show increased urinary oxalate, suggesting that AGT expression in both cellular compartments is not an explanation for …

Repeated Withdrawal Of A Glpr Agonist Induces Hyperleptinemia And Deteriorates Metabolic Health In Obese Aging Um-Het3 Mice, Nisi Jiang, Jiyuan Yin, Noah Lawrence, Jieyi Meng, Laurence T Maeyens, Ziying Xu, Xin Li, Mbolle Ekane, Ariana Chaudhary, Pengju Cao, Guannan Li, Carolina Solis-Herrera, Yi Zhu, Shangang Zhao

Children’s Nutrition Research Center Staff Publications

GLP-1-based therapy is highly effective in combating aging-associated metabolic diseases. However, the metabolic effects of frequent withdrawal from this therapy in aged, obese mice have not been previously studied. In this study, aged obese UM-HET3 mice were assigned to three groups: Group 1 received no liraglutide treatment (Lira OFF); Group 2 underwent 3 cycles of treatment followed by withdrawal (Lira ON/OFF); and Group 3 remained on continuous treatment (Lira ON). As expected, mice in Group 3 showed reduced body weight and food intake, along with improved metabolic health. In contrast, mice in Group 2 developed hyperleptinemia and visceral fat expansion, …

Enhanced Control Of Liposomal Drug Release By Drug-Aptamer Complexes, Xiangang Huang, Yang Li, Matthew Torre, Rachelle Shao, Wei Zhang, Zihan Wang, Daniel S Kohane, Christopher B Weldon

Duncan NRI Faculty and Staff Publications

Conventional diffusion-controlled drug delivery systems (DDS) can have undesirable initial burst release, leading to potential systemic toxicity, and the rate of basal release can deplete content, shortening the duration of effect. Here, it is hypothesized that conventional drug delivery systems-using liposomes as an example-can be enhanced by incorporation of an aptamer that binds specifically to the encapsulated drug. Affinity of the aptamer to the drug within liposomes (Lipo-Apt) would slow release. It is demonstrated that this approach works with a range of relatively small and hydrophilic molecules, including tetrodotoxin (TTX), serotonin (Ser), and kanamycin (Kan). The in vivo utility of …

Picalm Alzheimer’S Risk Allele Causes Aberrant Lipid Droplets In Microglia, Alena Kozlova, Siwei Zhang, Ari Sudwarts, Hanwen Zhang, Stanislau Smirnou, Seul Kee Byeon, Christina Thapa, Xiaotong Sun, Kimberley Stephenson, Xiaojie Zhao, Brendan Jamison, Moorthi Ponnusamy, Xin He, Julie A Schneider, Akhilesh Pandey, David A Bennett, Zhiping P Pang, Alan R Sanders, Hugo J Bellen, Gopal Thinakaran, Jubao Duan

Faculty, Staff and Students Publications

Despite genome-wide association studies (GWAS) of late-onset Alzheimer’s disease (LOAD) having identified many genetic risk loci1–3, the underlying disease mechanisms remain largely unclear. Determining causal disease variants and their LOAD-relevant cellular phenotypes has been a challenge. Here, using our approach for identifying functional GWAS risk variants showing allele-specific open chromatin, we systematically identified putative causal LOAD-risk variants in human induced pluripotent stem (iPS)-cell-derived neurons, astrocytes and microglia, and linked a PICALM LOAD-risk allele to a microglial-specific role of PICALM in lipid droplet (LD) accumulation. Allele-specific open-chromatin mapping revealed functional risk variants for 26 LOAD-risk loci, mostly …

Dominant Negative Atp5f1a Variants Disrupt Oxidative Phosphorylation Causing Neurological Disorders, Sara M Fielder, Jessie R Zhang, Liana M Valin, Tara Samson, Sarah Govert, Sara Dacunha, Weimin Yuan, Jian Chen, Jacob Lesinski, Hieu Hoang, Stephanie A Morrison, Eric Tycksen, Dustin Baldridge, Gary A Silverman, Lisa Emrick, William J Craigen, Stephen M Sykes, Tim Schedl, Stephen C Pak, Et Al.

2020-Current year OA Pubs

ATP5F1A encodes the α-subunit of complex V of the respiratory chain, which is responsible for mitochondrial ATP synthesis. We describe 6 probands with heterozygous de novo missense ATP5F1A variants that presented with developmental delay, intellectual disability, and movement disorders. All variants were located at the contact points between the α- and β-subunits. Functional studies in C. elegans revealed that the variants were damaging via a dominant negative genetic mechanism. Biochemical and proteomics studies of proband-derived cells showed a marked reduction in complex V abundance and activity. Mitochondrial physiology studies revealed increased oxygen consumption, yet decreased mitochondrial membrane potential and ATP …