A5032497568- SARS-CoV-2 and COVID-19 Research
- COVID-19 Clinical Research Studies
- Liver physiology and pathology
- Antibiotic Resistance in Bacteria
- Long-Term Effects of COVID-19
- 3D Printing in Biomedical Research
- Tuberculosis Research and Epidemiology
- Neonatal Respiratory Health Research
- Single-cell and spatial transcriptomics
- Peripheral Neuropathies and Disorders
- Drug-Induced Hepatotoxicity and Protection
- Renal and related cancers
- Esophageal Cancer Research and Treatment
- Advanced biosensing and bioanalysis techniques
- Complement system in diseases
- Congenital Diaphragmatic Hernia Studies
- Cell Image Analysis Techniques
- Nanoparticle-Based Drug Delivery
- Digestive system and related health
- Computational Drug Discovery Methods
- Pharmacogenetics and Drug Metabolism
- Pancreatic function and diabetes
- RNA Interference and Gene Delivery
- PARP inhibition in cancer therapy
- Viral Infections and Immunology Research
University of Michigan
2020-2024
Western University of Health Sciences
2018-2021
Michigan Medicine
2021
Significance Since its emergence in China December 2019, SARS-CoV-2 has caused a global pandemic. Repurposing of FDA-approved drugs is promising strategy for identifying rapidly deployable treatments COVID-19. Herein, we developed pipeline quantitative, high-throughput, image-based screening infection human cells that led to the identification several and clinical candidates with vitro antiviral activity.
Patients with coronavirus disease 2019 (COVID-19) present a wide range of acute clinical manifestations affecting the lungs, liver, kidneys and gut. Angiotensin converting enzyme (ACE) 2, best-characterized entry receptor for disease-causing virus SARS-CoV-2, is highly expressed in aforementioned tissues. However, pathways that underlie are still poorly understood. Here, we unexpectedly found complement system was one intracellular most induced by SARS-CoV-2 infection lung epithelial cells....
Drug-induced liver injury (DILI), both intrinsic and idiosyncratic, causes frequent morbidity, mortality, clinical trial failures post-approval withdrawal. This suggests an unmet need for improved in vitro models DILI risk prediction that can account diverse host genetics other factors. In this study, we evaluated the utility of human organoids (HLOs) high-throughput organ-on-chip system.
The global spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and associated disease COVID-19, requires therapeutic interventions that can be rapidly identified translated to clinical care. Traditional drug discovery methods have a >90% failure rate take 10-15 years from target identification use. In contrast, repurposing significantly accelerate translation. We developed quantitative high-throughput screen identify efficacious agents against SARS-CoV-2. From library...
Dbait is a small double-stranded DNA molecule that has been utilized as radiosensitizer to enhance the sensitivity of glioma radiotherapy (RT). However, there no effective drug delivery system effectively overcome blood-brain barrier (BBB). The aim this study was develop gene by using BBB and dual-targeting microenvironment-responsive micelles (ch-Kn(s-s)R8-An) deliver into for RT. Angiopep-2 can target low-density lipoprotein receptor-related protein-1 (LRP1) overexpressed on brain...
Although the COVID-19 pandemic began over three years ago, virus responsible for disease, SARS-CoV-2, continues to infect people across globe. As such, there remains a critical need development of novel therapeutics against SARS-CoV-2. One technology that has remained relatively unexplored in is use antisense oligonucleotides (ASOs)—short single-stranded nucleic acids bind target RNA transcripts modulate their expression. In this study, ASOs targeted SARS-CoV-2 genome and host entry factors,...
Epithelial organoids derived from intestinal tissue, called enteroids, recapitulate many aspects of the organ in vitro and can be used for biological discovery, personalized medicine, drug development. Here, we interrogated cell signaling environment within developing human intestine to identify niche cues that may important epithelial development homeostasis. We identified an EGF family member, EPIREGULIN (EREG), which is robustly expressed crypt. Enteroids generated grown standard culture...
The global rise of metallo-β-lactamases (MBLs) is problematic due to their ability inactivate most β-lactam antibiotics. MBL inhibitors that could be coadministered with and restore the efficacy β-lactams are highly sought after. In this study, we employ virtual screening candidate without thiols or carboxylates avoid off-target effects using Avalanche software package, followed by experimental validation selected compounds. As target enzymes, chose clinically relevant B1 MBLs NDM-1, IMP-1,...
Alveolar type 2 (AT2) cells function as stem in the adult lung and aid repair after injury. The current study aimed to understand signaling events that control differentiation of this therapeutically relevant cell during human development. Using explant organoid models, we identified opposing effects TGFβ- BMP-signaling, where inhibition activation BMP-signaling context high WNT- FGF-signaling efficiently differentiated early progenitors into AT2-like vitro. manner exhibit surfactant...
Early in the COVID-19 pandemic, data suggested that males had a higher risk of developing severe disease and androgen deprivation therapy might be associated with protection. Combined fact
Drug-induced liver injury (DILI) is a major failure mode in pharmaceutical development. This study aims to address the limitations of existing preclinical models by assessing high-throughput, microfluidic liver-on-a-chip system, termed "Curio Barrier Liver Chips," and its capacity recapitulate effects chronic hepatotoxic drug treatment through metabolic phenotypic characterization.
Abstract Patients with coronavirus disease 2019 (COVID-19) present a wide range of acute clinical manifestations affecting the lungs, liver, kidneys, and gut. Angiotensin-converting enzyme 2 (ACE2), best-characterized entry receptor for disease-causing virus SARS-CoV-2, is highly expressed in aforementioned tissues. However, pathways that underlie are still poorly understood. Here, we unexpectedly found complement system was one intracellular most induced by SARS-CoV-2 infection lung...
Disease progression during SARS-CoV-2 infection is tightly linked to the fate of lung epithelial cells, with severe cases COVID-19 characterized by direct injury alveolar epithelium and an impairment in its regeneration from progenitor cells. The molecular pathways that govern respiratory cell death proliferation infection, however, remain unclear. We now report a high-throughput CRISPR screen for host genetic modifiers survival SARS-CoV-2-infected Calu-3 top four genes identified our encode...
ABSTRACT Many esophageal diseases can arise during development or throughout life. Therefore, well-characterized in vitro models and detailed methods are essential for studying human development, homeostasis disease. Here, we (1) create an atlas of the cell types observed normal adult esophagus; (2) establish ancestrally diverse biobank esophagus tissue to interrogate injury; (3) benchmark using atlas. We created a single-cell RNA sequencing reference fresh biopsies continuously expanding...
(1) Background: Metallo-β-lactamases (MBLs) have raised concerns due to their ability inactivate carbapenems and newer generation cephalosporins the absence of clinically available MBL inhibitors. Their genes are often transferred horizontally, number variants has grown exponentially, with many showing enhanced enzyme activity or stability. In this study, we investigated a closely related group from IMP family that all contain combination mutations S115T S119G relative IMP-1. (2) Methods:...
Nonsynonymous mutations are well documented in TEM β-lactamases. The resulting amino acid changes often alter the conferred phenotype from broad spectrum (2b) by TEM-1 to extended (2be), inhibitor resistant (2br), or both and (2ber). encoding blaTEM genes also deviate numerous synonymous mutations, which not understood. blaTEM-3 blaTEM-33 blaTEM-109 (2ber) were studied comparison blaTEM-1blaTEM-33 was chosen for more detailed studies because it deviates blaTEM-1 a single nonsynonymous...
Niclosamide, an FDA-approved oral anthelmintic drug, has broad biological activity including anticancer, antibacterial, and antiviral properties. Niclosamide also been identified as a potent inhibitor of SARS-CoV-2 infection in vitro, generating interest its use for the treatment or prevention COVID-19. Unfortunately, there are several potential issues with using niclosamide COVID-19, low bioavailability, significant polypharmacology, high cellular toxicity, unknown efficacy against emerging...
The rapid advancement of high-content, single-cell technologies like robotic confocal microscopy with multiplexed dyes (morphological profiling) can be leveraged to reveal fundamental biology, ranging from microbial and abiotic stress organ development. Specifically, heterogeneous cell systems perturbed genetically or chemical treatments allow for inference causal mechanisms. An exciting strategy navigate the high-dimensional space possible perturbation type combinations is use generative...
Alveolar type 2 (AT2) cells function as stem in the adult lung and aid repair after injury. The current study aimed to understand signaling events that control differentiation of this therapeutically relevant cell during human development. Using explant organoid models, we identified opposing effects TGFβ- BMP-signaling, where inhibition activation BMP-signaling context high WNT- FGF-signaling efficiently differentiated early progenitors into AT2-like vitro . manner exhibit surfactant...
Abstract Niclosamide, an FDA-approved oral anthelmintic drug, has broad biological activity including anticancer, antibacterial, and antiviral properties. Niclosamide also been identified as a potent inhibitor of SARS-CoV-2 infection in vitro , generating interest its use for the treatment or prevention COVID-19. Unfortunately, there are several potential issues with using niclosamide COVID-19, low bioavailability, significant polypharmacology, high cellular toxicity, unknown efficacy...
Summary European Americans (EA) are more susceptible to esophageal tissue damage and inflammation when exposed gastric acid bile reflux have a higher incidence of adenocarcinoma compared African (AA). Population studies implicated specific genes for these differences; however, the underlying cause differences is not well understood. We describe robust long-term culture system grow primary human esophagus in vitro , use single cell RNA sequencing compare biopsies their counterparts, identify...
ABSTRACT Background and Aims Drug-induced liver injury (DILI), both intrinsic idiosyncratic, causes frequent morbidity, mortality, clinical trial failures post-approval withdrawal. This suggests an unmet need for improved in vitro models DILI risk prediction that can account diverse host genetics other factors. In this study, we evaluated the utility of human organoids (HLOs) high-throughput organ-on-chip system. Methods HLOs were derived from 3 separate iPSC lines benchmarked on two...
1. Abstract Objective Drug-induced liver injury (DILI) is a major failure mode in pharmaceutical development. This study aims to address the limitations of existing preclinical models by introducing high-throughput, microfluidic liver-on-a-chip system, termed as “Curio Barrier Liver Chips,” seeded with human organoids enable metabolic and phenotypic morphologic characterization. Methods Curio chips, fabricated an 8×2 well configuration, were utilized establish 3D organoid cultures....