A5059235004- Computational Drug Discovery Methods
- Nerve injury and regeneration
- Protein Degradation and Inhibitors
- Bioinformatics and Genomic Networks
- Renal Diseases and Glomerulopathies
- Neurogenesis and neuroplasticity mechanisms
- Lipid metabolism and biosynthesis
- Pancreatic and Hepatic Oncology Research
- Photosynthetic Processes and Mechanisms
- Cell Image Analysis Techniques
- Signaling Pathways in Disease
- Diabetes Treatment and Management
- Pancreatic function and diabetes
- Axon Guidance and Neuronal Signaling
- Spinal Cord Injury Research
- interferon and immune responses
- 14-3-3 protein interactions
- ATP Synthase and ATPases Research
- Renal cell carcinoma treatment
- Ovarian cancer diagnosis and treatment
- Lipid metabolism and disorders
- Biomedical Text Mining and Ontologies
- Histone Deacetylase Inhibitors Research
- Retinal Development and Disorders
- Genetics, Bioinformatics, and Biomedical Research
University of Miami
2016-2025
Sylvester Comprehensive Cancer Center
2017-2024
National Space Science and Technology Center
2024
University of Miami Health System
2024
Neurological Surgery
2017-2023
University of Economics and Management
2022
University Health Network
2012-2014
University of Toronto
2012-2014
Toronto General Hospital
2014
University of Padua
2010
Protein kinases are highly tractable targets for drug discovery. However, the biological function and therapeutic potential of majority 500+ human protein remains unknown. We have developed physical virtual collections small molecule inhibitors, which we call chemogenomic sets, that designed to inhibit catalytic almost half kinases. In this manuscript share our progress towards generation a comprehensive kinase set (KCGS), release kinome profiling data large inhibitor (Published Kinase...
We describe the assembly and annotation of a chemogenomic set protein kinase inhibitors as an open science resource for studying biology. The only includes that show potent inhibition narrow spectrum activity when screened across large panel biochemical assays. Currently, contains 187 cover 215 human kinases. (KCGS), current Version 1.0, is most highly annotated selective available to researchers use in cell-based screens.
Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are anti-hyperglycemic agents that prevent glucose reabsorption in proximal tubular cells. SGLT2i improves renal outcomes both diabetic and non-diabetic patients, indicating it may have beneficial effects beyond glycemic control. Here, we demonstrate affects energy metabolism podocyte lipotoxicity experimental Alport syndrome (AS). In vitro, found the SGLT2 protein was expressed human mouse podocytes to a similar extent Newly established...
Schwann cell-derived extracellular vesicles (SCEVs) have demonstrated favorable effects in spinal cord, peripheral nerve, and brain injuries. Herein, a scalable, standardized, efficient isolation methodology of SCEVs obtaining high yield with consistent composition as measured by proteomic, lipidomic, miRNA analysis their content is described for future clinical use. Human cells were obtained ethically from nine donors cultured defined growth medium optimized proliferation. At confluency,...
The mammalian target of rapamycin (mTOR) positively regulates axon growth in the central nervous system (CNS). Although regeneration and functional recovery from CNS injuries are typically limited, knockdown or deletion PTEN, a negative regulator mTOR, increases mTOR activity induces robust regeneration. It has been suggested that inhibition S6 kinase 1 (S6K1, gene symbol: RPS6KB1), prominent target, would blunt mTOR's positive effect on growth. In contrast to this expectation, we...
Mammalian central nervous system (CNS) neurons regrow their axons poorly following injury, resulting in irreversible functional losses. Identifying therapeutics that encourage CNS axon repair has been difficult, part because multiple etiologies underlie this regenerative failure. This suggests a particular need for drugs engage molecular targets. Although multitarget are generally more effective than highly selective alternatives, we lack systematic methods discovering such drugs....
Histone deacetylase (HDAC) inhibitors may have therapeutic utility in multiple neurological and psychiatric disorders, but the underlying mechanisms remain unclear. Here, we identify BRD4, a BET bromodomain reader of acetyl-lysine histones, as an essential component involved potentiated expression brain-derived neurotrophic factor (BDNF) memory following HDAC inhibition. In vitro studies, reveal that pharmacological inhibition BRD4 reversed increase BDNF mRNA induced by class I/IIb inhibitor...
A precision medicine approach is appealing for use in AML due to ease of access tumor samples and the significant variability patients' response treatment. Attempts establish a platform AML, however, have been unsuccessful, at least part small compound panels having relatively slow turn over rates, which restricts scope treatment delays its onset. For this pilot study, we evaluated cohort 12 patients with refractory using an ex vivo drug sensitivity testing (DST) platform. Purified blasts...
BackgroundDiscoidin domain receptor 1 (DDR1) is a tyrosine kinase that activated by collagens involved in the pathogenesis of fibrotic disorders. Interestingly, de novo production collagen type I (Col I) has been observed Col4a3 knockout mice, mouse model Alport Syndrome (AS mice). Deletion DDR1 AS mice was shown to improve survival and renal function. However, mechanisms driving DDR1-dependent fibrosis remain largely unknown.MethodsPodocyte pDDR1 levels, Collagen cluster differentiation 36...
Copper is an essential cofactor of two mitochondrial enzymes: cytochrome c oxidase (COX) and Cu-Zn superoxide dismutase (Sod1p). incorporation into these enzymes facilitated by metallochaperone proteins which probably use copper from a matrix-localized pool. Here we describe novel conserved metallochaperone-like protein, Cmc1p, whose function affects both COX Sod1p. In Saccharomyces cerevisiae, Cmc1p localizes to the inner membrane facing intermembrane space. for full expression respiration,...
Tissue damage after spinal cord injury (SCI) elicits a robust inflammatory cascade that fails to resolve in timely manner, resulting impaired wound healing and cellular regeneration. This response is partly mediated by infiltrating immune cells, including macrophages. As professional phagocytes, macrophages initially play an important role debris clearance at the site, which would be necessary for proper tissue After SCI, most become filled with lipid droplets due excessive uptake of debris,...
Dysregulation of lipid homeostasis is associated with a wide range pathologies encompassing neurological, metabolic, cardiovascular, oncological, and renal disorders. We previously showed that droplet (LD) accumulation in podocytes contributes to the progression diabetic kidney disease (DKD) reducing LDs preserves podocyte function prevents albuminuria. Here, we sought identify compounds treat pathological LD accumulation. developed phenotypic assay using human deployed it screen...
A fundamental impediment to functional recovery from spinal cord injury (SCI) and traumatic brain is the lack of sufficient axonal regeneration in adult central nervous system. There thus a need develop agents that can stimulate axon growth re-establish severed connections. Given critical role played by protein kinases regulating potential for pharmacological intervention, small molecule kinase inhibitors present promising therapeutic strategy. Here, we report robust cell-based phenotypic...
Cumulative scientific and technological advances over the past two centuries have transformed drug discovery from a largely serendipitous process into high tech pipelines of today.
Axon injury is a hallmark of many neurodegenerative diseases, often resulting in neuronal cell death and functional impairment. Dual leucine zipper kinase (DLK) has emerged as key mediator this process. However, while DLK inhibition robustly protective wide range disease models, it also inhibits axonal regeneration. Indeed, there are no genetic perturbations that known to both improve long-term survival promote To identify such neuroprotective target, we conducted set complementary...
Mitochondrial copper metabolism and delivery to cytochrome c oxidase mitochondrially localized CuZn-superoxide dismutase (Sod1) requires a growing number of intermembrane space proteins containing twin Cx(9)C motif. Among them, Cmc1 was recently identified by our group. Here we describe another conserved mitochondrial metallochaperone-like protein, Cmc2, close homologue Cmc1, whose function affects both Sod1. In the yeast Saccharomyces cerevisiae, Cmc2 localizes inner membrane facing space....
Solid pseudopapillary tumors (SPT) are rare, generally low grade pancreatic neoplasms that occasionally display malignant behavior.To analyze the clinical and pathological features associated with increased risk of recurrence SPT.Cohort study patients SPT who underwent resection primary tumor in selected cases metastatic disease from 1999-2013 at a single tertiary care Hepatopancreatobiliary center. Risk factors for were statistically analyzed.There 32 patients. The mean age was 35.65 years...
After spinal cord injury (SCI), infiltrating macrophages undergo excessive phagocytosis of myelin and cellular debris, forming lipid-laden foamy macrophages. To understand their role in the pathology SCI, investigation macrophage phenotype vitro revealed a pro-inflammatory profile, increased reactive oxygen species (ROS) production, mitochondrial dysfunction. Bioinformatic analysis identified PI3K as regulator inflammation macrophages, inhibition this pathway decreased lipid content,...