A5034081739- Immune cells in cancer
- Bacillus and Francisella bacterial research
- Cystic Fibrosis Research Advances
- Neonatal Respiratory Health Research
- SARS-CoV-2 and COVID-19 Research
- Respiratory Support and Mechanisms
- Bacteriophages and microbial interactions
- Bacterial Genetics and Biotechnology
- RNA Interference and Gene Delivery
- Immune responses and vaccinations
- Yersinia bacterium, plague, ectoparasites research
- Phagocytosis and Immune Regulation
- MicroRNA in disease regulation
- interferon and immune responses
- Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
- Immune Response and Inflammation
- Immune Cell Function and Interaction
- Chronic Obstructive Pulmonary Disease (COPD) Research
- Advanced biosensing and bioanalysis techniques
- Influenza Virus Research Studies
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Immunodeficiency and Autoimmune Disorders
- Fibroblast Growth Factor Research
- Nosocomial Infections in ICU
- Immunotherapy and Immune Responses
The Ohio State University
2021-2024
The Ohio State University Wexner Medical Center
2021-2024
Memorial Sloan Kettering Cancer Center
2022
Vita-Salute San Raffaele University
2022
Pulmonary and Critical Care Associates
2022
SleepMed
2022
Sutter Davis Hospital
2021
University of Washington
2015-2020
Washington Center
2020
University of Iowa
2010-2015
Cell-targeted therapies (smart drugs), which selectively control cancer cell progression with limited toxicity to normal cells, have been developed effectively treat some cancers. However, many cancers such as metastatic prostate (PC) yet be treated current smart drug technology. Here, we describe the thorough preclinical characterization of an RNA aptamer (A9g) that functions a for PC by inhibiting enzymatic activity prostate-specific membrane antigen (PSMA). Treatment cells A9g results in...
ABSTRACT Francisella tularensis is capable of rampant intracellular growth and causes a potentially fatal disease in humans. Whereas many mutational studies have been performed with avirulent strains , relatively little has done that cause human disease. We generated near-saturating transposon library the virulent strain Schu S4, which was subjected to high-throughput screening by site hybridization through primary macrophages, negatively selecting 202 genes. Of special note were genes locus...
Abstract A fundamental step in the life cycle of Francisella tularensis is bacterial entry into host cells. F. activates complement, and recent data suggest that classical pathway required for complement factor C3 deposition on surface. Nevertheless, inefficient neither specific serum components necessary activation by nonimmune human nor receptors mediate infection neutrophils have been defined. In this study, neutrophil uptake GFP-expressing strains live vaccine strain Schu S4 was...
Chronic pulmonary bacterial infections and associated inflammation remain a cause of morbidity mortality in people with cystic fibrosis (PwCF) despite new modulator therapies. Therapies targeting host factors that dampen detrimental without suppressing immune responses critical for controlling limited, while the development lung caused by antimicrobial resistant bacteria is an increasing global problem, significant challenge CF. Pharmacological compounds mammalian MAPK proteins MEK1 MEK2,...
Cystic fibrosis (CF) is caused by homozygous mutations in the cystic transmembrane conductance regulator (CFTR) gene, resulting multi-organ dysfunction and decreased lifespan quality of life. A durable cure for CF will likely require a gene therapy approach to correct CFTR. Rapid advancements genome editing technologies such as CRISPR/Cas9 have already resulted successful FDA approval cell-based therapies, providing new therapeutic avenues many rare diseases. However, immune responses...
Objectives/Goals: Novel therapeutics to control Staphylococcus aureus ( S. ) infections are needed for people with cystic fibrosis (CF, PwCF). In this study, our objective is determine if the pharmacologic MEK1/2 inhibitor compound ATR-002 can restrict growth of clinical isolates and modulate infection in a murine model infection. Methods/Study Population: To evaluate anti-inflammatory effects on human macrophages, cells were stimulated TLR2 agonists FSL1 or Pam3CSK4 dose range ATR-002,...
Francisella tularensis is a Gram-negative, facultative intracellular pathogen that replicates in the cytosol of macrophages and causative agent potentially fatal disease tularemia. A characteristic feature F. its limited proinflammatory capacity, but mechanisms underlie diminished host response to this organism are only partially defined. Recently, microRNAs have emerged as important regulators immunity inflammation. In present study we investigated microRNA primary human monocyte-derived...
ABSTRACT Francisella tularensis is a facultative intracellular bacterial pathogen and the causative agent of tularemia. After infection macrophages, organism escapes from its phagosome replicates to high density in cytosol, but factors required for these aspects virulence are incompletely defined. Here, we describe isolation characterization subsp. strain Schu S4 mutants that lack functional iglI , iglJ or pdpC three genes pathogenicity island. Our data demonstrate were defective replication...
Abstract Macrophages have important functional roles in regulating the timely promotion and resolution of inflammation. Although many intracellular signaling pathways involved proinflammatory responses macrophages are well characterized, components that regulate macrophage reparative properties less understood. We identified MEK1/2 pathway as a key regulator properties. Pharmacological inhibition by inhibitor (MEKi) significantly increased expression IL-4/IL-13 (M2)-responsive genes murine...
CFTR modulators decrease some etiologies of CF airway inflammation; however, data indicate that non-resolving infection and inflammation persist in individuals with chronic bacterial infections. Thus, identification therapies diminish without allowing unrestrained growth remains a critical research goal. Novel strategies for combatting deleterious the modulator era require better understanding cellular contributions to disease, how inflammatory cells change after initiation therapy....
Flavocytochrome b(558), the catalytic core of phagocyte NADPH oxidase (NOX2), mediates electron transfer from to molecular oxygen generate superoxide, precursor highly ROS for host defense. b(558) is an integral membrane heterodimer consisting a large glycosylated subunit, gp91(phox), and smaller p22(phox). We recently showed in murine macrophages that flavocytochrome localizes PM Rab11-positive recycling endosomes, whereas primary hMDMs, gp91(phox) p22(phox) reside ER. The antimicrobial...
Inhibition of vascular smooth muscle cell (VSMC) proliferation by drug eluting stents has markedly reduced intimal hyperplasia and subsequent in-stent restenosis. However, the effects antiproliferative drugs on endothelial cells (EC) contribute to delayed re-endothelialization late stent thrombosis. Cell-targeted therapies inhibit VSMC remodeling while maintaining EC health are necessary allow healing preventing We describe an RNA aptamer (Apt 14) that functions as a smart preferentially...
Interferon lambda (IFNλ) signaling is a promising therapeutic target against viral infection in murine models, yet little known about its molecular regulation and cognate receptor, interferon receptor 1 (IFNLR1) human lung. We hypothesized that the IFNλ axis was active lung macrophages. In alveolar macrophages (HAMs), we observed increased IFNLR1 expression robust increase interferon-stimulated gene (ISG) response to ligand. While monocytes express minimal IFNLR1, differentiation of into...
The MEK1/2-ERK1/2 pathway has been implicated in regulating the inflammatory response to lung injury and infection, pharmacologic MEK1/2 inhibitor compounds are reported reduce detrimental inflammation multiple animal models of disease, part through modulation leukocyte responses. However, specific contribution myeloid MEK1 acute (ALI) its resolution remain unknown. Here, role Mek1 was investigated a murine model LPS-induced ALI (LPS-ALI) by genetic deletion using Cre-floxed system (LysMCre...
Optimization of protective immune responses against SARS-CoV-2 remains an urgent worldwide priority. In this regard, type III IFN (IFN-λ) restricts infection in vitro, and treatment with IFN-λ limits infection, inflammation, pathogenesis murine models. Furthermore, has been developed for clinical use to limit COVID-19 severity. However, whether endogenous signaling effect on antiviral immunity long-term protection vivo is unknown. study, we identified a requirement promoting viral clearance...
The Francisella tularensis pathogenicity island (FPI) encodes many proteins that are required for virulence. Expression of these genes depends upon the FevR (PigR) regulator and its interactions with MglA/SspA RNA polymerase transcriptional complex. Experiments to identify how transcription FPI is activated have led identification mutations within migR, trmE, cphA decrease expression. Recent data demonstrated small alarmone ppGpp, produced by RelA SpoT, important stabilizing in Francisella....
The lipopolysaccharide (LPS) and O-antigen polysaccharide capsule structures of Francisella tularensis play significant roles in helping these highly virulent bacteria avoid detection within a host. We previously created pools F. mutants that we screened to identify strains were not reactive monoclonal antibody the capsule. To follow up published work, characterize further seven Schu S4 mutant identified by our screen. These carry following transposon mutations: FTT0846::Tn5, hemH::Tn5,...
<b>This study demonstrates that initiation of the CFTR modulator ivacaftor in people with cystic fibrosis and susceptible <i>CFTR</i> mutations causes an acute reduction blood monocyte sensitivity to key proinflammatory cytokine IFN-γ</b>http://bit.ly/2TeI6LG
Matrix metalloproteinases (MMPs) are transcriptionally regulated proteases that have multiple roles in modifying the extracellular matrix (ECM) and inflammatory response. Our previous work identified Mmp28 as a key regulator of inflammation macrophage polarization during experimental models pulmonary infection, fibrosis, chronic smoke exposure. However, signaling pathways responsible for regulation expression remain undefined. This study utilized murine macrophages obtained from wild type,...
This study was designed to test the therapeutic potential of a MEK1/2 inhibitor (MEKi) in an experimental model Pseudomonas aeruginosa pneumonia. The found that treatment with MEKi reduced alveolar neutrophilic inflammation and led faster recovery weight compared carrier-treated mice, without impairing bacterial clearance. Alveolar macrophages isolated from MEKi-treated mice also had increased M2 gene protein expression, supporting concept modulates vivo macrophage inflammatory responses. In...