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Metabolism Of A Selective Serotonin And Norepinephrine Reuptake Inhibitor Duloxetine In Liver Microsomes And Mice, Xuan Qin, John M Hakenjos, Kevin R Mackenzie, Mercedes Barzi, Hemantkumar Chavan, Pranavanand Nyshadham, Jin Wang, Sung Yun Jung, Joie Z Guner, Si Chen, Lei Guo, Partha Krishnamurthy, Karl-Dimiter Bissig, Stephen Palmer, Martin M Matzuk, Feng Li Feb 2022

Metabolism Of A Selective Serotonin And Norepinephrine Reuptake Inhibitor Duloxetine In Liver Microsomes And Mice, Xuan Qin, John M Hakenjos, Kevin R Mackenzie, Mercedes Barzi, Hemantkumar Chavan, Pranavanand Nyshadham, Jin Wang, Sung Yun Jung, Joie Z Guner, Si Chen, Lei Guo, Partha Krishnamurthy, Karl-Dimiter Bissig, Stephen Palmer, Martin M Matzuk, Feng Li

Faculty, Staff and Students Publications

Duloxetine (DLX) is a dual serotonin and norepinephrine reuptake inhibitor, widely used for the treatment of major depressive disorder. Although DLX has shown good efficacy and safety, serious adverse effects (e.g., liver injury) have been reported. The mechanisms associated with DLX-induced toxicity remain elusive. Drug metabolism plays critical roles in drug safety and efficacy. However, the metabolic profile of DLX in mice is not available, although mice serve as commonly used animal models for mechanistic studies of drug-induced adverse effects. Our study revealed 39 DLX metabolites in human/mouse liver microsomes and mice. Of note, 13 metabolites are novel, including five …

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Review Of Gene Therapies For Age-Related Macular Degeneration, Arshad M Khanani, Mathew J Thomas, Aamir A Aziz, Christina Y Weng, Carl J Danzig, Glenn Yiu, Szilárd Kiss, Nadia K Waheed, Peter K Kaiser Feb 2022

Review Of Gene Therapies For Age-Related Macular Degeneration, Arshad M Khanani, Mathew J Thomas, Aamir A Aziz, Christina Y Weng, Carl J Danzig, Glenn Yiu, Szilárd Kiss, Nadia K Waheed, Peter K Kaiser

Faculty, Staff and Students Publications

Gene therapies aim to deliver a therapeutic payload to specified tissues with underlying protein deficiency. Since the 1990s, gene therapies have been explored as potential treatments for chronic conditions requiring lifetime care and medical management. Ocular gene therapies target a range of ocular disorders, but retinal diseases are of particular importance due to the prevalence of retinal disease and the current treatment burden of such diseases on affected patients, as well as the challenge of properly delivering these therapies to the target tissue. The purpose of this review is to provide an update on the most current data available for …

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Δnp63 Regulates A Common Landscape Of Enhancer Associated Genes In Non-Small Cell Lung Cancer, Marco Napoli, Sarah J Wu, Bethanie L Gore, Hussein A Abbas, Kyubum Lee, Rahul Checker, Shilpa Dhar, Kimal Rajapakshe, Aik Choon Tan, Min Gyu Lee, Cristian Coarfa, Elsa R Flores Feb 2022

Δnp63 Regulates A Common Landscape Of Enhancer Associated Genes In Non-Small Cell Lung Cancer, Marco Napoli, Sarah J Wu, Bethanie L Gore, Hussein A Abbas, Kyubum Lee, Rahul Checker, Shilpa Dhar, Kimal Rajapakshe, Aik Choon Tan, Min Gyu Lee, Cristian Coarfa, Elsa R Flores

Faculty, Staff and Students Publications

Distinct lung stem cells give rise to lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC). ΔNp63, the p53 family member and p63 isoform, guides the maturation of these stem cells through the regulation of their self-renewal and terminal differentiation; however, the underlying mechanistic role regulated by ∆Np63 in lung cancer development has remained elusive. By utilizing a ΔNp63-specific conditional knockout mouse model and xenograft models of LUAD and LUSC, we found that ∆Np63 promotes non-small cell lung cancer by maintaining the lung stem cells necessary for lung cancer cell initiation and progression in quiescence. ChIP-seq analysis of lung basal cells, …

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Maternal Lactobacillus Reuteri Supplementation Shifts The Intestinal Microbiome In Mice And Provides Protection From Experimental Colitis In Female Offspring, Mahesh Krishna, Melinda Engevik, Karen Queliza, Savini Britto, Rajesh Shah, Wenly Ruan, Hongtao Wang, James Versalovic, Richard Kellermayer Feb 2022

Maternal Lactobacillus Reuteri Supplementation Shifts The Intestinal Microbiome In Mice And Provides Protection From Experimental Colitis In Female Offspring, Mahesh Krishna, Melinda Engevik, Karen Queliza, Savini Britto, Rajesh Shah, Wenly Ruan, Hongtao Wang, James Versalovic, Richard Kellermayer

Faculty, Staff and Students Publications

The purpose of our experiment was to explore how stochastic (inter-individual variation) gut microbiome composition may link to inflammatory bowel disease (IBD) susceptibility and guide the development of a perinatal preventative probiotic. Dextran sodium sulfate (DSS) was introduced to C57BL/BJ mice to induce acute colitis as a model of IBD. Potentially protective bacteria were identified using a discovery-validation cohort approach toward stochastic DSS susceptibility.

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A Crispr Toolbox For Generating Intersectional Genetic Mouse Models For Functional, Molecular, And Anatomical Circuit Mapping, Savannah J Lusk, Andrew Mckinney, Patrick J Hunt, Paul G Fahey, Jay Patel, Andersen Chang, Jenny J Sun, Vena K Martinez, Ping Jun Zhu, Jeremy R Egbert, Genevera Allen, Xiaolong Jiang, Benjamin R Arenkiel, Andreas S Tolias, Mauro Costa-Mattioli, Russell S Ray Jan 2022

A Crispr Toolbox For Generating Intersectional Genetic Mouse Models For Functional, Molecular, And Anatomical Circuit Mapping, Savannah J Lusk, Andrew Mckinney, Patrick J Hunt, Paul G Fahey, Jay Patel, Andersen Chang, Jenny J Sun, Vena K Martinez, Ping Jun Zhu, Jeremy R Egbert, Genevera Allen, Xiaolong Jiang, Benjamin R Arenkiel, Andreas S Tolias, Mauro Costa-Mattioli, Russell S Ray

Faculty, Staff and Students Publications

BACKGROUND: The functional understanding of genetic interaction networks and cellular mechanisms governing health and disease requires the dissection, and multifaceted study, of discrete cell subtypes in developing and adult animal models. Recombinase-driven expression of transgenic effector alleles represents a significant and powerful approach to delineate cell populations for functional, molecular, and anatomical studies. In addition to single recombinase systems, the expression of two recombinases in distinct, but partially overlapping, populations allows for more defined target expression. Although the application of this method is becoming increasingly popular, its experimental implementation has been broadly restricted to manipulations of a limited set of …

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Organoid Models For Infectious Disease, Sarah E Blutt, Mary K Estes Jan 2022

Organoid Models For Infectious Disease, Sarah E Blutt, Mary K Estes

Faculty, Staff and Students Publications

Infectious diseases affect individual health and have widespread societal impacts. New ex vivo models are critical to understand pathogenesis, host response, and features necessary to develop preventive and therapeutic treatments. Pluripotent and tissue stem cell-derived organoids provide new tools for the study of human infections. Organoid models recapitulate many characteristics of in vivo disease and are providing new insights into human respiratory, gastrointestinal, and neuronal host-microbe interactions. Increasing culture complexity by adding the stroma, interorgan communication, and the microbiome will improve the use of organoids as models for infection. Organoid cultures provide a platform with the capability to improve human …

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Characterization Of The Copd Alveolar Niche Using Single-Cell Rna Sequencing, Maor Sauler, John E Mcdonough, Taylor S Adams, Neeharika Kothapalli, Thomas Barnthaler, Rhiannon B Werder, Jonas C Schupp, Jessica Nouws, Matthew J Robertson, Cristian Coarfa, Tao Yang, Maurizio Chioccioli, Norihito Omote, Carlos Cosme, Sergio Poli, Ehab A Ayaub, Sarah G Chu, Klaus H Jensen, Jose L Gomez, Clemente J Britto, Micha Sam B Raredon, Laura E Niklason, Andrew A Wilson, Pascal N Timshel, Naftali Kaminski, Ivan O Rosas Jan 2022

Characterization Of The Copd Alveolar Niche Using Single-Cell Rna Sequencing, Maor Sauler, John E Mcdonough, Taylor S Adams, Neeharika Kothapalli, Thomas Barnthaler, Rhiannon B Werder, Jonas C Schupp, Jessica Nouws, Matthew J Robertson, Cristian Coarfa, Tao Yang, Maurizio Chioccioli, Norihito Omote, Carlos Cosme, Sergio Poli, Ehab A Ayaub, Sarah G Chu, Klaus H Jensen, Jose L Gomez, Clemente J Britto, Micha Sam B Raredon, Laura E Niklason, Andrew A Wilson, Pascal N Timshel, Naftali Kaminski, Ivan O Rosas

Faculty, Staff and Students Publications

Chronic obstructive pulmonary disease (COPD) is a leading cause of death worldwide, however our understanding of cell specific mechanisms underlying COPD pathobiology remains incomplete. Here, we analyze single-cell RNA sequencing profiles of explanted lung tissue from subjects with advanced COPD or control lungs, and we validate findings using single-cell RNA sequencing of lungs from mice exposed to 10 months of cigarette smoke, RNA sequencing of isolated human alveolar epithelial cells, functional in vitro models, and in situ hybridization and immunostaining of human lung tissue samples. We identify a subpopulation of alveolar epithelial type II cells with transcriptional evidence for aberrant …

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An Estrogen-Sensitive Hypothalamus-Midbrain Neural Circuit Controls Thermogenesis And Physical Activity, Hui Ye, Bing Feng, Chunmei Wang, Kenji Saito, Yongjie Yang, Lucas Ibrahimi, Sarah Schaul, Nirali Patel, Leslie Saenz, Pei Luo, Penghua Lai, Valeria Torres, Maya Kota, Devin Dixit, Xing Cai, Na Qu, Ilirjana Hyseni, Kaifan Yu, Yuwei Jiang, Qingchun Tong, Zheng Sun, Benjamin R Arenkiel, Yanlin He, Pingwen Xu, Yong Xu Jan 2022

An Estrogen-Sensitive Hypothalamus-Midbrain Neural Circuit Controls Thermogenesis And Physical Activity, Hui Ye, Bing Feng, Chunmei Wang, Kenji Saito, Yongjie Yang, Lucas Ibrahimi, Sarah Schaul, Nirali Patel, Leslie Saenz, Pei Luo, Penghua Lai, Valeria Torres, Maya Kota, Devin Dixit, Xing Cai, Na Qu, Ilirjana Hyseni, Kaifan Yu, Yuwei Jiang, Qingchun Tong, Zheng Sun, Benjamin R Arenkiel, Yanlin He, Pingwen Xu, Yong Xu

Faculty, Staff and Students Publications

Estrogen receptor–α (ERα) expressed by neurons in the ventrolateral subdivision of the ventromedial hypothalamic nucleus (ERαvlVMH) regulates body weight in females, but the downstream neural circuits mediating this biology remain largely unknown. Here we identified a neural circuit mediating the metabolic effects of ERαvlVMH neurons. We found that selective activation of ERαvlVMH neurons stimulated brown adipose tissue (BAT) thermogenesis, physical activity, and core temperature and that ERαvlVMH neurons provide monosynaptic glutamatergic inputs to 5-hydroxytryptamine (5-HT) neurons in the dorsal raphe nucleus (DRN). Notably, the ERαvlVMH → DRN circuit responds to changes in ambient temperature and nutritional states. We further showed …

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Using Cryo-Et To Distinguish Platelets During Pre-Acute Myeloid Leukemia From Steady State Hematopoiesis, Yuewei Wang, Tong Huo, Yu-Jung Tseng, Lan Dang, Zhili Yu, Wenjuan Yu, Zachary Foulks, Rebecca L Murdaugh, Steven J Ludtke, Daisuke Nakada, Zhao Wang Jan 2022

Using Cryo-Et To Distinguish Platelets During Pre-Acute Myeloid Leukemia From Steady State Hematopoiesis, Yuewei Wang, Tong Huo, Yu-Jung Tseng, Lan Dang, Zhili Yu, Wenjuan Yu, Zachary Foulks, Rebecca L Murdaugh, Steven J Ludtke, Daisuke Nakada, Zhao Wang

Faculty, Staff and Students Publications

Early diagnosis of acute myeloid leukemia (AML) in the pre-leukemic stage remains a clinical challenge, as pre-leukemic patients show no symptoms, lacking any known morphological or numerical abnormalities in blood cells. Here, we demonstrate that platelets with structurally abnormal mitochondria emerge at the pre-leukemic phase of AML, preceding detectable changes in blood cell counts or detection of leukemic blasts in blood. We visualized frozen-hydrated platelets from mice at different time points during AML development in situ using electron cryo-tomography (cryo-ET) and identified intracellular organelles through an unbiased semi-automatic process followed by quantitative measurement. A large proportion of platelets exhibited changes …

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Rspo2 And Rankl Signal Through Lgr4 To Regulate Osteoclastic Premetastatic Niche Formation And Bone Metastasis, Zhiying Yue, Xin Niu, Zengjin Yuan, Qin Qin, Wenhao Jiang, Liang He, Jingduo Gao, Yi Ding, Yanxi Liu, Ziwei Xu, Zhenxi Li, Zhengfeng Yang, Rong Li, Xiwen Xue, Yankun Gao, Fei Yue, Xiang H-F Zhang, Guohong Hu, Yi Wang, Yi Li, Geng Chen, Stefan Siwko, Alison Gartland, Ning Wang, Jianru Xiao, Mingyao Liu, Jian Luo Jan 2022

Rspo2 And Rankl Signal Through Lgr4 To Regulate Osteoclastic Premetastatic Niche Formation And Bone Metastasis, Zhiying Yue, Xin Niu, Zengjin Yuan, Qin Qin, Wenhao Jiang, Liang He, Jingduo Gao, Yi Ding, Yanxi Liu, Ziwei Xu, Zhenxi Li, Zhengfeng Yang, Rong Li, Xiwen Xue, Yankun Gao, Fei Yue, Xiang H-F Zhang, Guohong Hu, Yi Wang, Yi Li, Geng Chen, Stefan Siwko, Alison Gartland, Ning Wang, Jianru Xiao, Mingyao Liu, Jian Luo

Faculty, Staff and Students Publications

Therapeutics targeting osteoclasts are commonly used treatments for bone metastasis; however, whether and how osteoclasts regulate premetastatic niche and bone tropism are largely unknown. In this study, we report that osteoclast precursors (OPs) can function as a premetastatic niche component that facilitates breast cancer (BCa) bone metastasis at early stages. At the molecular level, unbiased GPCR ligand/agonist screening in BCa cells suggested that R-spondin 2 (RSPO2) and RANKL, through interaction with their receptor LGR4, promoted osteoclastic premetastatic niche formation and enhanced BCa bone metastasis. This was achieved by RSPO2/RANKL-LGR4 signal modulating the WNT inhibitor DKK1 through Gαq and β-catenin signaling. …

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Clonal Hematopoiesis Mutations In Patients With Lung Cancer Are Associated With Lung Cancer Risk Factors, Wei Hong, Ang Li, Yanhong Liu, Xiangjun Xiao, David C Christiani, Rayjean J Hung, James Mckay, John Field, Christopher I Amos, Chao Cheng Jan 2022

Clonal Hematopoiesis Mutations In Patients With Lung Cancer Are Associated With Lung Cancer Risk Factors, Wei Hong, Ang Li, Yanhong Liu, Xiangjun Xiao, David C Christiani, Rayjean J Hung, James Mckay, John Field, Christopher I Amos, Chao Cheng

Faculty, Staff and Students Publications

Clonal hematopoiesis (CH) is a phenomenon caused by expansion of white blood cells descended from a single hematopoietic stem cell. While CH can be associated with leukemia and some solid tumors, the relationship between CH and lung cancer remains largely unknown. To help clarify this relationship, we analyzed whole-exome sequencing (WES) data from 1,958 lung cancer cases and controls. Potential CH mutations were identified by a set of hierarchical filtering criteria in different exonic regions, and the associations between the number of CH mutations and clinical traits were investigated. Family history of lung cancer (FHLC) may exert diverse influences on …

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Glynac (Glycine And N-Acetylcysteine) Supplementation Improves Impaired Mitochondrial Fuel Oxidation And Lowers Insulin Resistance In Patients With Type 2 Diabetes: Results Of A Pilot Study, Rajagopal V Sekhar Jan 2022

Glynac (Glycine And N-Acetylcysteine) Supplementation Improves Impaired Mitochondrial Fuel Oxidation And Lowers Insulin Resistance In Patients With Type 2 Diabetes: Results Of A Pilot Study, Rajagopal V Sekhar

Faculty, Staff and Students Publications

Patients with type 2 diabetes (T2D) are known to have mitochondrial dysfunction and increased insulin resistance (IR), but the underlying mechanisms are not well understood. We reported previously that (a) adequacy of the antioxidant glutathione (GSH) is necessary for optimal mitochondrial fatty-acid oxidation (MFO); (b) supplementing the GSH precursors glycine and N-acetylcysteine (GlyNAC) in mice corrected GSH deficiency, reversed impaired MFO, and lowered oxidative stress (OxS) and IR; and (c) supplementing GlyNAC in patients with T2D improved GSH synthesis and concentrations, and lowered OxS. However, the effect of GlyNAC on MFO, MGO (mitochondrial glucose oxidation), IR and plasma FFA …

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Mapk4 Promotes Triple Negative Breast Cancer Growth And Reduces Tumor Sensitivity To Pi3k Blockade, Wei Wang, Dong Han, Qinbo Cai, Tao Shen, Bingning Dong, Michael T Lewis, Runsheng Wang, Yanling Meng, Wolong Zhou, Ping Yi, Chad J Creighton, David D Moore, Feng Yang Jan 2022

Mapk4 Promotes Triple Negative Breast Cancer Growth And Reduces Tumor Sensitivity To Pi3k Blockade, Wei Wang, Dong Han, Qinbo Cai, Tao Shen, Bingning Dong, Michael T Lewis, Runsheng Wang, Yanling Meng, Wolong Zhou, Ping Yi, Chad J Creighton, David D Moore, Feng Yang

Faculty, Staff and Students Publications

About 15-20% of breast cancer (BCa) is triple-negative BCa (TNBC), a devastating disease with limited therapeutic options. Aberrations in the PI3K/PTEN signaling pathway are common in TNBC. However, the therapeutic impact of PI3K inhibitors in TNBC has been limited and the mechanism(s) underlying this lack of efficacy remain elusive. Here, we demonstrate that a large subset of TNBC expresses significant levels of MAPK4, and this expression is critical for driving AKT activation independent of PI3K and promoting TNBC cell and xenograft growth. The ability of MAPK4 to bypass PI3K for AKT activation potentially provides a direct mechanism regulating tumor sensitivity …

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Mutations In Hcfc1 And Ronin Result In An Inborn Error Of Cobalamin Metabolism And Ribosomopathy, Tiffany Chern, Annita Achilleos, Xuefei Tong, Matthew C Hill, Alexander B Saltzman, Lucas C Reineke, Arindam Chaudhury, Swapan K Dasgupta, Yushi Redhead, David Watkins, Joel R Neilson, Perumal Thiagarajan, Jeremy B A Green, Anna Malovannaya, James F Martin, David S Rosenblatt, Ross A Poché Jan 2022

Mutations In Hcfc1 And Ronin Result In An Inborn Error Of Cobalamin Metabolism And Ribosomopathy, Tiffany Chern, Annita Achilleos, Xuefei Tong, Matthew C Hill, Alexander B Saltzman, Lucas C Reineke, Arindam Chaudhury, Swapan K Dasgupta, Yushi Redhead, David Watkins, Joel R Neilson, Perumal Thiagarajan, Jeremy B A Green, Anna Malovannaya, James F Martin, David S Rosenblatt, Ross A Poché

Faculty, Staff and Students Publications

Combined methylmalonic acidemia and homocystinuria (cblC) is the most common inborn error of intracellular cobalamin metabolism and due to mutations in Methylmalonic Aciduria type C and Homocystinuria (MMACHC). Recently, mutations in the transcriptional regulators HCFC1 and RONIN (THAP11) were shown to result in cellular phenocopies of cblC. Since HCFC1/RONIN jointly regulate MMACHC, patients with mutations in these factors suffer from reduced MMACHC expression and exhibit a cblC-like disease. However, additional de-regulated genes and the resulting pathophysiology is unknown. Therefore, we have generated mouse models of this disease. In addition to exhibiting loss of Mmachc, metabolic perturbations, and developmental defects previously …

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Secretogranin Iii Stringently Regulates Pathological But Not Physiological Angiogenesis In Oxygen-Induced Retinopathy, Chang Dai, Prabuddha Waduge, Liyang Ji, Chengchi Huang, Ye He, Hong Tian, Elizabeth Zuniga-Sanchez, Amit Bhatt, Iok-Hou Pang, Guanfang Su, Keith A Webster, Wei Li Jan 2022

Secretogranin Iii Stringently Regulates Pathological But Not Physiological Angiogenesis In Oxygen-Induced Retinopathy, Chang Dai, Prabuddha Waduge, Liyang Ji, Chengchi Huang, Ye He, Hong Tian, Elizabeth Zuniga-Sanchez, Amit Bhatt, Iok-Hou Pang, Guanfang Su, Keith A Webster, Wei Li

Faculty, Staff and Students Publications

Conventional angiogenic factors, such as vascular endothelial growth factor (VEGF), regulate both pathological and physiological angiogenesis indiscriminately, and their inhibitors may elicit adverse side effects. Secretogranin III (Scg3) was recently reported to be a diabetes-restricted VEGF-independent angiogenic factor, but the disease selectivity of Scg3 in retinopathy of prematurity (ROP), a retinal disease in preterm infants with concurrent pathological and physiological angiogenesis, was not defined. Here, using oxygen-induced retinopathy (OIR) mice, a surrogate model of ROP, we quantified an exclusive binding of Scg3 to diseased versus healthy developing neovessels that contrasted sharply with the ubiquitous binding of VEGF. Functional immunohistochemistry visualized …

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Aav5 Delivery Of Crispr-Cas9 Supports Effective Genome Editing In Mouse Lung Airway, Shun-Qing Liang, Christopher J Walkey, Alexa E Martinez, Qin Su, Mary E Dickinson, Dan Wang, William R Lagor, Jason D Heaney, Guangping Gao, Wen Xue Jan 2022

Aav5 Delivery Of Crispr-Cas9 Supports Effective Genome Editing In Mouse Lung Airway, Shun-Qing Liang, Christopher J Walkey, Alexa E Martinez, Qin Su, Mary E Dickinson, Dan Wang, William R Lagor, Jason D Heaney, Guangping Gao, Wen Xue

Faculty, Staff and Students Publications

Genome editing in the lung has the potential to provide long-term expression of therapeutic protein to treat lung genetic diseases. Yet efficient delivery of CRISPR to the lung remains a challenge. The NIH Somatic Cell Genome Editing (SCGE) Consortium is developing safe and effective methods for genome editing in disease tissues. Methods developed by consortium members are independently validated by the SCGE small animal testing center to establish rigor and reproducibility. We have developed and validated a dual adeno-associated virus (AAV) CRISPR platform that supports effective editing of a lox-stop-lox-Tomato reporter in mouse lung airway. After intratracheal injection of the …

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Autophagosomes Fuse To Phagosomes And Facilitate The Degradation Of Apoptotic Cells In Caenorhabditis Elegans, Omar Peña-Ramos, Lucia Chiao, Xianghua Liu, Xiaomeng Yu, Tianyou Yao, Henry He, Zheng Zhou Jan 2022

Autophagosomes Fuse To Phagosomes And Facilitate The Degradation Of Apoptotic Cells In Caenorhabditis Elegans, Omar Peña-Ramos, Lucia Chiao, Xianghua Liu, Xiaomeng Yu, Tianyou Yao, Henry He, Zheng Zhou

Faculty, Staff and Students Publications

Autophagosomes are double-membrane intracellular vesicles that degrade protein aggregates, intracellular organelles, and other cellular components. During the development of the nematode Caenorhabditis elegans, many somatic and germ cells undergo apoptosis. These cells are engulfed and degraded by their neighboring cells. We discovered a novel role of autophagosomes in facilitating the degradation of apoptotic cells using a real-time imaging technique. Specifically, the double-membrane autophagosomes in engulfing cells are recruited to the surfaces of phagosomes containing apoptotic cells and subsequently fuse to phagosomes, allowing the inner vesicle to enter the phagosomal lumen. Mutants defective in the production of autophagosomes display significant …

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Cathepsin S Is A Novel Target For Age-Related Dry Eye, Zhiyuan Yu, Jinmiao Li, Gowthaman Govindarajan, Sarah F Hamm-Alvarez, Jehan Alam, De-Quan Li, Cintia S De Paiva Jan 2022

Cathepsin S Is A Novel Target For Age-Related Dry Eye, Zhiyuan Yu, Jinmiao Li, Gowthaman Govindarajan, Sarah F Hamm-Alvarez, Jehan Alam, De-Quan Li, Cintia S De Paiva

Faculty, Staff and Students Publications

Cathepsin S (CTSS) is a protease that is proinflammatory on epithelial cells. The purpose of this study was to investigate the role of CTSS in age-related dry eye disease. Ctss−/− mice [in a C57BL/6 (B6) background] of different ages were compared to B6 mice. CTSS activity in tears and lacrimal gland (LG) lysates was measured. The corneal barrier function was investigated in naïve mice or after topical administration of CTSS eye drops 5X/day for two days. Eyes were collected, and conjunctival goblet cell density was measured in PAS-stained sections. Immunoreactivity of the tight junction proteins, ZO-1 and occludin, was …

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Crispr/Cas9-Mediated Genome Editing Reveals 12 Testis-Enriched Genes Dispensable For Male Fertility In Mice, Yuki Oyama, Haruhiko Miyata, Keisuke Shimada, Yoshitaka Fujihara, Keizo Tokuhiro, Thomas X Garcia, Martin M Matzuk, Masahito Ikawa Jan 2022

Crispr/Cas9-Mediated Genome Editing Reveals 12 Testis-Enriched Genes Dispensable For Male Fertility In Mice, Yuki Oyama, Haruhiko Miyata, Keisuke Shimada, Yoshitaka Fujihara, Keizo Tokuhiro, Thomas X Garcia, Martin M Matzuk, Masahito Ikawa

Faculty, Staff and Students Publications

Gene expression analyses suggest that more than 1000-2000 genes are expressed predominantly in mouse and human testes. Although functional analyses of hundreds of these genes have been performed, there are still many testis-enriched genes whose functions remain unexplored. Analyzing gene function using knockout (KO) mice is a powerful tool to discern if the gene of interest is essential for sperm formation, function, and male fertility in vivo. In this study, we generated KO mice for 12 testis-enriched genes, 1700057G04Rik, 4921539E11Rik, 4930558C23Rik, Cby2, Ldhal6b, Rasef, Slc25a2, Slc25a41, Smim8, Smim9, Tmem210, and Tomm20l, using the clustered regularly interspaced short palindromic repeats /CRISPR-associated …

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Clonal Hematopoiesis Analyses In Clinical, Epidemiologic, And Genetic Aging Studies To Unravel Underlying Mechanisms Of Age-Related Dysfunction In Humans, Kenneth Walsh, Nalini Raghavachari, Candace Kerr, Alexander G Bick, Steven R Cummings, Todd Druley, Cynthia E Dunbar, Giulio Genovese, Margaret A Goodell, Siddhartha Jaiswal, Jaroslaw Maciejewski, Pradeep Natarajan, Anastasia V Shindyapina, Alan R Shuldiner, Erik B Van Den Akker, Jan Vijg Jan 2022

Clonal Hematopoiesis Analyses In Clinical, Epidemiologic, And Genetic Aging Studies To Unravel Underlying Mechanisms Of Age-Related Dysfunction In Humans, Kenneth Walsh, Nalini Raghavachari, Candace Kerr, Alexander G Bick, Steven R Cummings, Todd Druley, Cynthia E Dunbar, Giulio Genovese, Margaret A Goodell, Siddhartha Jaiswal, Jaroslaw Maciejewski, Pradeep Natarajan, Anastasia V Shindyapina, Alan R Shuldiner, Erik B Van Den Akker, Jan Vijg

Faculty, Staff and Students Publications

Aging is characterized by increased mortality, functional decline, and exponential increases in the incidence of diseases such as cancer, stroke, cardiovascular disease, neurological disease, respiratory disease, etc. Though the role of aging in these diseases is widely accepted and considered to be a common denominator, the underlying mechanisms are largely unknown. A significant age-related feature observed in many population cohorts is somatic mosaicism, the detectable accumulation of somatic mutations in multiple cell types and tissues, particularly those with high rates of cell turnover (e.g., skin, liver, and hematopoietic cells). Somatic mosaicism can lead to the development of cellular clones that …

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Sr9009 Improves Heart Function After Pressure Overload Independent Of Cardiac Rev-Erb, Hui Li, Shiyang Song, Chih-Liang Tien, Lei Qi, Andrea Graves, Eleni Nasiotis, Thomas P Burris, Yuanbiao Zhao, Zheng Sun, Lilei Zhang Jan 2022

Sr9009 Improves Heart Function After Pressure Overload Independent Of Cardiac Rev-Erb, Hui Li, Shiyang Song, Chih-Liang Tien, Lei Qi, Andrea Graves, Eleni Nasiotis, Thomas P Burris, Yuanbiao Zhao, Zheng Sun, Lilei Zhang

Faculty, Staff and Students Publications

The core clock component REV-ERB is essential for heart function. Previous studies show that REV-ERB agonist SR9009 ameliorates heart remodeling in the pressure overload model with transverse aortic constriction (TAC). However, it is unknown whether SR9009 indeed works through cardiac REV-ERB, given that SR9009 might target other proteins and that REV-ERB in non-cardiac tissues might regulate cardiac functions indirectly. To address this question, we generated the REV-ERBα/β cardiac-specific double knockout mice (cDKO). We found that REV-ERB cardiac deficiency leads to profound dilated cardiac myopathy after TAC compared to wild-type (WT) control mice, confirming the critical role of REV-ERB in protecting …

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Rotavirus-Induced Lipid Droplet Biogenesis Is Critical For Virus Replication, Jeanette M Criglar, Mary K Estes, Sue E Crawford Jan 2022

Rotavirus-Induced Lipid Droplet Biogenesis Is Critical For Virus Replication, Jeanette M Criglar, Mary K Estes, Sue E Crawford

Faculty, Staff and Students Publications

A variety of pathogens, including viruses, bacteria and parasites, target cellular lipid droplets for their replication. Rotaviruses (RVs) infect the villous epithelium of the small intestine and are a major cause of acute gastroenteritis in infants and young children worldwide. RVs induce and require lipid droplets for the formation of viroplasms, sites of virus genome replication, and nascent particle assembly. Here we review the role of lipid droplets in RV replication. Inhibitors of fatty acid synthesis or chemicals that interfere with lipid droplet homeostasis decrease the number and size of viroplasms and the yield of infectious virus. We used a …

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Paraventricular Vitamin D Receptors Are Required For Glucose Tolerance In Males But Not Females, Jessie Beck, Silvania Da Silva Teixeira, Keisha Harrison, Gabrielle Phillips, Yanlin He, Stephanie Sisley Jan 2022

Paraventricular Vitamin D Receptors Are Required For Glucose Tolerance In Males But Not Females, Jessie Beck, Silvania Da Silva Teixeira, Keisha Harrison, Gabrielle Phillips, Yanlin He, Stephanie Sisley

Faculty, Staff and Students Publications

When delivered directly into the brain, vitamin D, can improve glucose levels in male mice. Additionally, the loss of the vitamin D receptor (VDR) in male mice's paraventricular hypothalamus (PVH) results in impaired glucose tolerance. Data in humans shows that low vitamin D levels are detrimental to glucose homeostasis, an effect that may be more prominent in men. However, it is unknown if vitamin D action in the brain is required for normal glucose regulation in female mice. This study shows that in both viral and genetic models, male mice with obesity and PVH VDR loss have impaired glucose tolerance …

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Embryonic Hypotaurine Levels Contribute To Strain-Dependent Susceptibility In Mouse Models Of Valproate-Induced Neural Tube Defects, John W Steele, Ying Linda Lin, Nellie Chen, Bogdan J Wlodarczyk, Qiuying Chen, Nabeel Attarwala, Madhu Venkatesalu, Robert M Cabrera, Steven S Gross, Richard H Finnell Jan 2022

Embryonic Hypotaurine Levels Contribute To Strain-Dependent Susceptibility In Mouse Models Of Valproate-Induced Neural Tube Defects, John W Steele, Ying Linda Lin, Nellie Chen, Bogdan J Wlodarczyk, Qiuying Chen, Nabeel Attarwala, Madhu Venkatesalu, Robert M Cabrera, Steven S Gross, Richard H Finnell

Faculty, Staff and Students Publications

Valproic acid (VPA, valproate, Depakote) is a commonly used anti-seizure medication (ASM) in the treatment of epilepsy and a variety of other neurological disorders. While VPA and other ASMs are efficacious for management of seizures, they also increase the risk for adverse pregnancy outcomes, including neural tube defects (NTDs). Thus, the utility of these drugs during pregnancy and in women of childbearing potential presents a continuing public health challenge. Elucidating the underlying genetic or metabolic risk factors for VPA-affected pregnancies may lead to development of non-teratogenic ASMs, novel prevention strategies, or more targeted methods for managing epileptic pregnancies. To address …

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Common Genomic Aberrations In Mouse And Human Breast Cancers With Concurrent P53 Deficiency And Activated Pten-Pi3k-Akt Pathway, Jarrod D Martinez, Qianxing Mo, Yixiang Xu, Li Qin, Yi Li, Jianming Xu Jan 2022

Common Genomic Aberrations In Mouse And Human Breast Cancers With Concurrent P53 Deficiency And Activated Pten-Pi3k-Akt Pathway, Jarrod D Martinez, Qianxing Mo, Yixiang Xu, Li Qin, Yi Li, Jianming Xu

Faculty, Staff and Students Publications

Simultaneous P53 loss and activation of the PTEN-restricted PI3K-AKT pathway frequently occur in aggressive breast cancers. P53 loss causes genome instability, while PTEN loss and/or activating mutations of PIK3CA and AKT promote cancer cell proliferation that also increases incidences of genomic aberrations. However, the genomic alterations associated with P53 loss and activated PTEN-PI3K-AKT signaling in breast cancer have not been defined. Spatiotemporally controlled breast cancer models with inactivation of both P53 and Pten in adult mice have not been established for studying genomic alterations. Herein, we deleted both floxed Pten and Tp53 genes in the mammary gland epithelial cells in …

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Decidualization Of Human Endometrial Stromal Cells Requires Steroid Receptor Coactivator-3, Vineet K Maurya, Maria M Szwarc, David M Lonard, William E Gibbons, San-Pin Wu, Bert W O'Malley, Francesco J Demayo, John P Lydon Jan 2022

Decidualization Of Human Endometrial Stromal Cells Requires Steroid Receptor Coactivator-3, Vineet K Maurya, Maria M Szwarc, David M Lonard, William E Gibbons, San-Pin Wu, Bert W O'Malley, Francesco J Demayo, John P Lydon

Faculty, Staff and Students Publications

Steroid receptor coactivator-3 (SRC-3; also known as NCOA3 or AIB1) is a member of the multifunctional p160/SRC family of coactivators, which also includes SRC-1 and SRC-2. Clinical and cell-based studies as well as investigations on mice have demonstrated pivotal roles for each SRC in numerous physiological and pathophysiological contexts, underscoring their functional pleiotropy. We previously demonstrated the critical involvement of SRC-2 in murine embryo implantation as well as in human endometrial stromal cell (HESC) decidualization, a cellular transformation process required for trophoblast invasion and ultimately placentation. We show here that, like SRC-2, SRC-3 is expressed in the epithelial and stromal …

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Nuclear Progesterone Receptor Expressed By The Cortical Thymic Epithelial Cells Dictates Thymus Involution In Murine Pregnancy, Soo Hyun Ahn, Sean L Nguyen, Tae Hoon Kim, Jae-Wook Jeong, Ripla Arora, John P Lydon, Margaret G Petroff Jan 2022

Nuclear Progesterone Receptor Expressed By The Cortical Thymic Epithelial Cells Dictates Thymus Involution In Murine Pregnancy, Soo Hyun Ahn, Sean L Nguyen, Tae Hoon Kim, Jae-Wook Jeong, Ripla Arora, John P Lydon, Margaret G Petroff

Faculty, Staff and Students Publications

Progesterone is a gonadal pro-gestational hormone that is absolutely necessary for the success of pregnancy. Most notable actions of progesterone are observed in the female reproductive organs, the uterus and the ovary. Acting through the nuclear progesterone receptor (PGR), progesterone prepares the endometrium for implantation of the embryo. Interestingly, the maternal thymus also is a known expressor of Pgr; its absence is associated with murine pregnancy complications. However, the localization of its expression and its functional importance were not known. Here, we used a transgenic dual fluorescent reporter mouse model and genetic deletion of Pgr in Foxn1+ thymic epithelial …

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Pathologic Inflammation In Malnutrition Is Driven By Proinflammatory Intestinal Microbiota, Large Intestine Barrier Dysfunction, And Translocation Of Bacterial Lipopolysaccharide, Grace T Patterson, Elvia Y Osorio, Alex Peniche, Sara M Dann, Erika Cordova, Geoffrey A Preidis, Ji Ho Suh, Ichiaki Ito, Omar A Saldarriaga, Michael Loeffelholz, Nadim J Ajami, Bruno L Travi, Peter C Melby Jan 2022

Pathologic Inflammation In Malnutrition Is Driven By Proinflammatory Intestinal Microbiota, Large Intestine Barrier Dysfunction, And Translocation Of Bacterial Lipopolysaccharide, Grace T Patterson, Elvia Y Osorio, Alex Peniche, Sara M Dann, Erika Cordova, Geoffrey A Preidis, Ji Ho Suh, Ichiaki Ito, Omar A Saldarriaga, Michael Loeffelholz, Nadim J Ajami, Bruno L Travi, Peter C Melby

Faculty, Staff and Students Publications

Acute malnutrition, or wasting, is implicated in over half of all deaths in children under five and increases risk of infectious disease. Studies in humans and preclinical models have demonstrated that malnutrition is linked to an immature intestinal microbiota characterized by increased prevalence of Enterobacteriaceae. Observational studies in children with moderate acute malnutrition (MAM) have also observed heightened systemic inflammation and increased circulating bacterial lipopolysaccharides (LPS; endotoxin). However, the mechanisms that underpin the systemic inflammatory state and endotoxemia, and their pathophysiological consequences, remain uncertain. Understanding these pathophysiological mechanisms is necessary to design targeted treatments that will improve the unacceptable rate …

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Hepatic Pparα Is Destabilized By Sirt1 Deacetylase In Undernourished Male Mice, Ji Ho Suh, Kang Ho Kim, Margaret E Conner, David D Moore, Geoffrey A Preidis Jan 2022

Hepatic Pparα Is Destabilized By Sirt1 Deacetylase In Undernourished Male Mice, Ji Ho Suh, Kang Ho Kim, Margaret E Conner, David D Moore, Geoffrey A Preidis

Faculty, Staff and Students Publications

The nutrient sensing nuclear receptor peroxisome proliferator-activated receptor-α (PPARα) regulates the host response to short-term fasting by inducing hepatic transcriptional programming of ketogenesis, fatty acid oxidation and transport, and autophagy. This adaptation is ineffective in chronically undernourished individuals, among whom dyslipidemia and hepatic steatosis are common. We recently reported that hepatic PPARα protein is profoundly depleted in male mice undernourished by a low-protein, low-fat diet. Here, we identify PPARα as a deacetylation target of the NAD-dependent deacetylase sirtuin-1 (SIRT1) and link this to the decrease in PPARα protein levels in undernourished liver. Livers from undernourished male mice expressed high levels …

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Pcsk9 Inhibitors In The Management Of Cardiovascular Risk: A Practical Guidance, Xiaoming Jia, Mahmoud Al Rifai, Anum Saeed, Christie M Ballantyne, Salim S Virani Jan 2022

Pcsk9 Inhibitors In The Management Of Cardiovascular Risk: A Practical Guidance, Xiaoming Jia, Mahmoud Al Rifai, Anum Saeed, Christie M Ballantyne, Salim S Virani

Faculty, Staff and Students Publications

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are potent medications in the toolkit for treatment of atherosclerotic cardiovascular disease. These agents have been well studied in clinical trials supporting their efficacy in dramatically reducing low-density lipoprotein cholesterol (LDL-C) and impact on cardiovascular outcomes. Since the approval of commercial use for PCSK9 inhibitors in 2015, we have also gained significant experience in the use of these therapeutics in the real-world setting. In this article, we review current guideline recommendations, clinical trial evidence on efficacy and safety as well as data on cost-effectiveness, prescription and adherence. We focus primarily on the monoclonal …

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