A5001783135- Genetic Neurodegenerative Diseases
- Nerve injury and regeneration
- Mitochondrial Function and Pathology
- Neuroscience and Neuropharmacology Research
- Neurogenesis and neuroplasticity mechanisms
- Neuroinflammation and Neurodegeneration Mechanisms
- SARS-CoV-2 and COVID-19 Research
- Neuroscience and Neural Engineering
- Muscle Physiology and Disorders
- Ion channel regulation and function
- CRISPR and Genetic Engineering
- Endoplasmic Reticulum Stress and Disease
- Computational Drug Discovery Methods
- Neurological disorders and treatments
- Autophagy in Disease and Therapy
- COVID-19 Clinical Research Studies
- Virus-based gene therapy research
- Cell Image Analysis Techniques
- RNA Interference and Gene Delivery
- Receptor Mechanisms and Signaling
- Ferroptosis and cancer prognosis
- Axon Guidance and Neuronal Signaling
- Glioma Diagnosis and Treatment
- Fungal and yeast genetics research
- Retinal Development and Disorders
National Center for Advancing Translational Sciences
2019-2025
National Institutes of Health
2019-2023
Duke University
2011-2020
Duke University Hospital
2010-2020
Duke Medical Center
2010-2020
Institute of Neurobiology
2002
Howard Hughes Medical Institute
1999
Ludwig Cancer Research
1992-1994
University College London
1993-1994
Ludwig Cancer Research
1992
Ferrostatin-1 (Fer-1) inhibits ferroptosis, a form of regulated, oxidative, nonapoptotic cell death. We found that Fer-1 inhibited death in cellular models Huntington's disease (HD), periventricular leukomalacia (PVL), and kidney dysfunction; lipid peroxidation, but not mitochondrial reactive oxygen species formation or lysosomal membrane permeability. developed mechanistic model to explain the activity Fer-1, which guided development ferrostatins with improved properties. These studies...
Expansion of the polyglutamine repeat within protein Huntingtin (Htt) causes Huntington's disease, a neurodegenerative disease associated with aging and accumulation mutant Htt in diseased neurons. Understanding mechanisms that influence cellular degradation may target treatments designed to activate clearance pathways. We find is phosphorylated by inflammatory kinase IKK, enhancing its normal proteasome lysosome. Phosphorylation regulates additional post-translational modifications,...
MDM2 and MDMX, negative regulators of the tumor suppressor p53, can work separately as a heteromeric complex to restrain p53's functions. also has pro-oncogenic roles in cells, tissues, animals that are independent p53. There is less information available about p53-independent MDMX or MDM2–MDMX complex. We found facilitate ferroptosis cells with without Using small molecules, RNA interference reagents, mutant forms we likely working part complex, normally ferroptotic death. observed alter...
Recent studies suggest that maintenance of the differentiated state requires continuous regulation. Limb regeneration in urodele amphibians provides a context which to address this issue, as limb may involve dedifferentiation multinucleate myotubes yield mononucleate blastemal cells, then proliferate and contribute regenerate tissues. To evaluate possibility, cultured newt were selectively microinjected with lineage tracer rhodamine-dextran introduced into regenerating limbs. In culture,...
DYRKs (dual specificity, tyrosine phosphorylation regulated kinases) and CLKs (cdc2-like are implicated in the onset development of Alzheimer's disease Down syndrome. The marine sponge alkaloid leucettamine B was recently identified as an inhibitor DYRKs/CLKs. Synthesis analogues (leucettines) led to optimized product, leucettine L41. Leucettines were cocrystallized with DYRK1A, DYRK2, CLK3, PIM1, GSK-3β. selectivity L41 studied by activity interaction assays recombinant kinases affinity...
Abstract Huntington’s Disease (HD) is a neurodegenerative disease caused by poly-glutamine expansion in the Htt protein, resulting misfolding and cell death. Expression of cellular protein folding pro-survival machinery heat shock transcription factor 1 (HSF1) ameliorates biochemical neurobiological defects misfolding. We report that HSF1 degraded cells mice expressing mutant Htt, medium spiny neurons derived from human HD iPSCs brain samples patients with HD. Mutant increases CK2α′ kinase...
Significance The aggregation of mutant proteins is pathologically implicated in a large number neuropathies, including Huntington disease and ALS. Although the appearance protein aggregates known to sequester other proteins, how this results gain-of-function toxicity these diseases unclear. Here, we show that disease-associated causes reversible collapse clathrin-mediated endocytosis (CME) inhibits internalization membrane receptors affect neuronal function. CME inhibition occurs through...
Significance Chronic neuroinflammation and oxidative stress are likely complicit in driving disease progression Huntington's (HD). Here, we describe the mechanism of action a unique chemical scaffold that is highly selective for activation NRF2, master transcriptional regulator cellular antiinflammatory antioxidant defense genes. The use this revealed NRF2 responses were muted HD patient-derived neural stem cells, suggesting increased susceptibility critical renewable cell population to...
The National Center for Advancing Translational Sciences (NCATS) has developed an online open science data portal its COVID-19 drug repurposing campaign - named OpenData with the goal of making across a range SARS-CoV-2 related assays available in real-time. cover wide spectrum life cycle, including both viral and human (host) targets. In total, over 10,000 compounds are being tested full concentration-response ranges from multiple annotated small molecule libraries, approved drug,...
Protein disulfide isomerase (PDI) is a chaperone protein in the endoplasmic reticulum that up-regulated mouse models of, and brains of patients with, neurodegenerative diseases involving misfolding. PDI's role these diseases, however, not fully understood. Here, we report discovery reversible, neuroprotective lead optimized compound (LOC)14, acts as modulator PDI. LOC14 was identified using high-throughput screen ∼10,000 lead-optimized compounds for potent rescue viability PC12 cells...