A5071526419- Cellular transport and secretion
- Endoplasmic Reticulum Stress and Disease
- Chemokine receptors and signaling
- Cancer, Lipids, and Metabolism
- Cancer, Stress, Anesthesia, and Immune Response
- Ubiquitin and proteasome pathways
- Histone Deacetylase Inhibitors Research
- Computational Drug Discovery Methods
- Lysosomal Storage Disorders Research
- Epigenetics and DNA Methylation
- Autophagy in Disease and Therapy
- Cancer-related gene regulation
- Immune cells in cancer
- Pancreatic function and diabetes
- Peptidase Inhibition and Analysis
- Genetics and Neurodevelopmental Disorders
- Immune Response and Inflammation
- Carbohydrate Chemistry and Synthesis
- Calcium signaling and nucleotide metabolism
- Cancer Genomics and Diagnostics
- Protein Degradation and Inhibitors
- Cystic Fibrosis Research Advances
- Genetic Neurodegenerative Diseases
- Pregnancy-related medical research
- Neuroscience and Neuropharmacology Research
National Center for Advancing Translational Sciences
2016-2025
National Institutes of Health
2015-2024
Humboldt State University
2023
United States Geological Survey
2023
National Institute on Drug Abuse
2012-2018
Johns Hopkins Medicine
2010-2014
Johns Hopkins University
2008-2014
Children's Hospital of Philadelphia
2005
University of Pennsylvania
2005
Center for Veterinary Medicine
1997
Cyclic GMP-AMP (cGAMP) synthase (cGAS) stimulator of interferon genes (STING) senses pathogen-derived or abnormal self-DNA in the cytosol and triggers an innate immune defense against microbial infection cancer. STING agonists induce both adaptive responses are a new class cancer immunotherapy agents tested multiple clinical trials. However, is commonly silenced cells via unclear mechanisms, limiting application these agonists. Here, we report that expression epigenetically suppressed by...
Retention of critical endoplasmic reticulum (ER) luminal proteins needed to carry out diverse functions (e.g., protein synthesis and folding, lipid metabolism) is mediated through a carboxy-terminal ER retention sequence (ERS) its interaction with KDEL receptors. Here, we demonstrate that depleting calcium causes mass departure ERS-containing from cells by overwhelming In addition, provide evidence KDELR2 KDELR3, but not KDELR1, are unfolded response (UPR) genes upregulated as an adaptive...
Abstract Assessment of the interactions between a drug and its protein target in physiologically relevant cellular environment constitutes major challenge pre-clinical discovery space. The Cellular Thermal Shift Assay (CETSA) enables such an assessment by quantifying changes thermal stability proteins upon ligand binding intact cells. Here, we present development validation homogeneous, standardized, target-independent, high-throughput (384- 1536-well formats) CETSA platform that uses split...
Understanding the SARS-CoV-2 virus' pathways of infection, virus–host–protein interactions, and mechanisms virus-induced cytopathic effects will greatly aid in discovery design new therapeutics to treat COVID-19. Chloroquine hydroxychloroquine, extensively explored as clinical agents for COVID-19, have multiple cellular including alkalizing lysosomes blocking autophagy well exhibiting dose-limiting toxicities patients. Therefore, we evaluated additional lysosomotropic compounds identify an...
Ipomoeassin F is a potent natural cytotoxin that inhibits growth of many tumor cell lines with single-digit nanomolar potency. However, its biological and pharmacological properties have remained largely unexplored. Building upon our earlier achievements in total synthesis medicinal chemistry, we used chemical proteomics to identify Sec61α (protein transport protein Sec61 subunit alpha isoform 1), the pore-forming translocon, as direct binding partner ipomoeassin living cells. The...
Relapse to maladaptive eating habits during dieting is often provoked by stress. Recently, we identified a role of dorsal medial prefrontal cortex (mPFC) neurons in stress-induced reinstatement palatable food seeking male rats. It unknown whether endogenous neural activity mPFC drives female Here, used an optogenetic approach, which rats received bilateral microinjections viral constructs coding light-sensitive eNpHR3.0–eYFP or control eYFP protein and intracranial fiber optic implants. Rats...
A series of quinazolin-4-one based hydroxamic acids was rationally designed and synthesized as novel dual PI3K/HDAC inhibitors by incorporating an HDAC pharmacophore into a PI3K inhibitor (Idelalisib) via optimized linker. Several these were highly potent (IC50 < 10 nM) selective against PI3Kγ, δ HDAC6 enzymes exhibited good antiproliferative activity multiple cancer cell lines. The lead compound 48c, induced necrosis in several mutant FLT3-resistant AML lines primary blasts from patients,...
Endoplasmic reticulum calcium homeostasis is critical for cellular functions and disrupted in diverse pathologies including neurodegeneration cardiovascular disease. Owing to the high concentration of within ER, studying this subcellular compartment requires tools that are optimized these conditions. To develop a single-fluorophore genetically encoded indicator organelle, we targeted low affinity variant GCaMP3 ER lumen (GCaMPer (10.19)). A set viral vectors was constructed express GCaMPer...
Abstract Isocitrate dehydrogenase 1 and 2 (IDH1 IDH2) are key metabolic enzymes that mutated in a variety of cancers to confer gain-of-function activity resulting the accumulation an oncometabolite, D-2-hydroxyglutarate (2-HG). Accumulation 2-HG can result epigenetic dysregulation block cellular differentiation, suggesting these mutations play role neoplasia. Based on its potential as cancer target, number small molecule inhibitors have been developed specifically inhibit mutant forms IDH...
Endoplasmic reticulum (ER) calcium homeostasis is disrupted in diverse pathologies, including neurodegeneration, cardiovascular diseases, and diabetes. Temporally defining dysregulation during disease progression, however, has been challenging. Here we describe secreted ER calcium-monitoring proteins (SERCaMPs), which allow for longitudinal monitoring of homeostasis. We identified a carboxy-terminal modification that sufficient to confer release protein specifically response depletion. A...
Significance Podocyte injury is the hallmark of nephrotic syndrome (NS), a leading cause chronic kidney disease affecting approximately 500 million people. We demonstrate that podocyte endoplasmic reticulum (ER) calcium release channel, type 2 ryanodine receptor (RyR2), undergoes phosphorylation during ER stress. The accelerated efflux due to leaky RyR2 activates cytosolic protease calpain 2, injury. Most importantly, we have identified chemical compound, K201, and biotherapeutic protein,...
Thermal shift assays (TSAs) can reveal changes in protein structure, due to a resultant change thermal stability. Since proteins are often stabilized upon binding of ligand molecules, these provide readout for target engagement. TSA has traditionally been applied using purified and more recently extended study engagement cellular environments with the emergence (CETSAs). The utility CETSA confirming molecular interaction targets native context, desire apply this technique broadly, fueled...
Lactate dehydrogenase (LDH) catalyzes the conversion of pyruvate to lactate, with concomitant oxidation reduced nicotinamide adenine dinucleotide as final step in glycolytic pathway. Glycolysis plays an important role metabolic plasticity cancer cells and has long been recognized a potential therapeutic target. Thus, potent, selective inhibitors LDH represent attractive approach. However, date, pharmacological agents have failed achieve significant target engagement vivo, possibly because...
Wolfram syndrome is a rare genetic disorder largely caused by pathogenic variants in the WFS1 gene and manifested diabetes mellitus, optic nerve atrophy, progressive neurodegeneration. Recent clinical findings have revealed as spectrum disorder. Therefore, genotype-phenotype correlation analysis needed for diagnosis therapeutic development. Here, we focus on c.1672C>T, p.R558C variant, which highly prevalent Ashkenazi Jewish population. Clinical investigation indicated that patients carrying...
NADPH oxidases (NOX's), and the reactive oxygen species (ROS) they produce, play an important role in host defense, thyroid hormone synthesis, apoptosis, gene regulation, angiogenesis other processes. However, overproduction of ROS by these enzymes is associated with cardiovascular disease, fibrosis, traumatic brain injury (TBI) diseases. Structural similarities between NOX's have complicated development specific inhibitors. Here, we report NCATS-SM7270, a small molecule optimized from...
Abstract Brain metastasis occurs in about 50% of all women with metastatic HER2+ breast cancer and confers poor prognosis for patients. Despite effective HER2-targeted treatments peripheral trastuzumab HER2 inhibitors, limited brain permeability renders these inefficient (BCBM). The scarcity suitable patient-derived vivo models BCBM has curtailed the study molecular mechanisms that promote growth therapeutic resistance metastasis. Here, we generated characterized a luminal B cell model...
Tumor necrosis factor alpha (TNF-alpha) is an important mediator of inflammation, apoptosis, and the development secondary lymphoid structures. Multiple polymorphic microsatellites have been identified in around gene, there are also multiple single-base pair biallelic polymorphisms introns promoter. The TNF-alpha -308 promoter polymorphism a G-to-A transition which has statistically associated with various autoimmune disorders. Some studies found that it may directly mediate increased...
Over 170 different mutations in the gene encoding SOD1 all cause amyotrophic lateral sclerosis (ALS). Available studies have been primarily focused on mechanisms underlying mutant cytotoxicity. How cells defend against cytotoxicity remains largely unknown. Here, we show that misfolding of ALS-linked mutants and wild-type (wt) exposes a normally buried nuclear export signal (NES)-like sequence. The carrier protein CRM1 recognizes this NES-like sequence exports misfolded to cytoplasm....
Abstract UBA1 is the primary E1 ubiquitin-activating enzyme responsible for generation of activated ubiquitin required ubiquitination, a process that regulates stability and function numerous proteins. Decreased or insufficient ubiquitination can cause drive aging many diseases. Therefore, small-molecule enhancing activity could have broad therapeutic potential. Here we report auranofin, drug approved treatment rheumatoid arthritis, potent enhancer. Auranofin binds to UBA1’s fold domain...
Arylsulfatase synthesis was shown to occur in Salmonella typhimurium LT2. The enzyme had a molecular weight of approximately 50,000 and separated into five forms by isoelectrofocusing. optimal pH for substrate hydrolysis 6.7, with Michaelis constants nitrocatechol sulfate nitrophenyl being 4.1 7.9 mM, respectively. Enzyme strongly influenced the presence tyramine growth medium. uptake [14C]tyramine arylsulfatase were initiated during second phase diauxie response, when organism cultured...
Natural products and their derivatives continue to be wellsprings of nascent therapeutic potential. However, many laboratories have limited resources for biological evaluation, leaving previously isolated or synthesized compounds largely completely untested. To address this issue, the Canvass library natural was assembled, in collaboration with academic industry researchers, quantitative high-throughput screening (qHTS) across a diverse set cell-based biochemical assays. Characterization...