A5027284944- RNA Interference and Gene Delivery
- Alzheimer's disease research and treatments
- Neuroinflammation and Neurodegeneration Mechanisms
- Virus-based gene therapy research
- Protein Tyrosine Phosphatases
- Genetic Neurodegenerative Diseases
- Endoplasmic Reticulum Stress and Disease
- Prion Diseases and Protein Misfolding
- Mitochondrial Function and Pathology
- Biotin and Related Studies
- Glycosylation and Glycoproteins Research
- Alcoholism and Thiamine Deficiency
- S100 Proteins and Annexins
- Muscle Physiology and Disorders
- Nicotinic Acetylcholine Receptors Study
- Nerve injury and regeneration
- Cholinesterase and Neurodegenerative Diseases
- RNA regulation and disease
- Neurogenesis and neuroplasticity mechanisms
- Endometriosis Research and Treatment
- Phosphodiesterase function and regulation
- Gastroesophageal reflux and treatments
- Genetics and Neurodevelopmental Disorders
- Neuroscience and Neuropharmacology Research
- Perfectionism, Procrastination, Anxiety Studies
Evotec (Germany)
2015-2022
Yale University
2010-2016
Evotec (United States)
2014
University of South Florida
2006-2013
USF Health Byrd Alzheimer's Institute
2013
Florida College
2008-2013
Wellcome Centre for Ethics and Humanities
2011
University of Oxford
2011
Alzheimer's disease (AD) is a progressive and incurable neurodegenerative disorder. Early in the pathophysiology of AD, synaptic function disrupted by soluble Aβ oligomers, possibly through Aβ-mediated internalization NMDA receptors. Striatal-enriched phosphatase (STEP) tyrosine that regulates Recent work shows STEP elevated prefrontal cortex human AD patients animal models AD. Here, we use genetic manipulations to reduce activity triple transgenic mouse model show decrease levels reverses...
A major question for gene therapy in brain concerns methods to administer therapeutic genes a uniform manner over portions of the brain. second neuroimmunology extent which monocytes migrate CNS degenerative disorders. Here we show that CD11b+ cells (largely monocytes) isolated from bone marrow GFP (green fluorescent protein)-expressing donors spontaneously home compacted amyloid plaques Injections these as single pulse rapid clearance circulation (90 min half-life) and tissue residence...
Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the huntingtin gene. Major pathological hallmarks of HD include inclusions mutant (mHTT) protein, loss neurons predominantly caudate nucleus, and atrophy multiple brain regions. However, early sequence histological events that manifest region- cell-specific manner has not been well characterized. Here we use high-content approach to precisely monitor changes HTT...
ATP-dependent P2X3 receptors play a crucial role in the sensitization of nerve fibers and pathological pain pathways. They are also involved pathways triggering cough may contribute to pathophysiology endometriosis overactive bladder. However, despite strong therapeutic rationale for targeting receptors, preliminary antagonists have been hampered by off-target effects, including severe taste disturbances associated with blocking P2X2/3 receptor heterotrimer. Here we present antagonist,...
Glutamatergic signaling through N-methyl-D-aspartate receptors (NMDARs) is required for synaptic plasticity. Disruptions in glutamatergic are proposed to contribute the behavioral and cognitive deficits observed schizophrenia (SZ). One possible source of compromised function SZ decreased surface expression GluN2B-containing NMDARs. STEP61 a brain-enriched protein tyrosine phosphatase that dephosphorylates regulatory on GluN2B, thereby promoting its internalization. Here, we report levels...
Abstract Introduction The neuronal mechanism driving Alzheimer's disease (AD) is incompletely understood. Methods Immunohistochemistry, pharmacology, biochemistry, and behavioral testing are employed in two pathological contexts—AD a transgenic mouse model—to investigate T14, 14mer peptide, as key signaling molecule the neuropathology. Results T14 increases AD brains progresses conspicuous 5XFAD mice, where its immunoreactivity corresponds to that seen AD: neurons immunoreactive for...
Reduction of Aβ deposition is a major therapeutic strategy in Alzheimer's disease (AD). The concentration the brain modulated not only by production but also its degradation. One proteases involved degradation peptides endothelin-converting enzyme (ECE). In this study, we investigated effects an intracranial administration seroptype 5 recombinant adeno-associated viral vector (rAAV) containing ECE-1 synthetic gene on amyloid precursor protein (APP) plus presenilin-1 (PS1) transgenic mice....
The brain-specific tyrosine phosphatase, STEP (STriatal-Enriched protein Phosphatase) is an important regulator of synaptic function. normally opposes strengthening by increasing N-methyl D-aspartate glutamate receptor (NMDAR) internalization through dephosphorylation GluN2B and inactivation the kinases extracellular signal–regulated kinase 1/2 Fyn. Here we show that STEP61 elevated in cortex Nrg1+/− knockout mouse model schizophrenia (SZ). Genetic reduction or pharmacological inhibition...
The accumulation of β-amyloid peptides in the brain has been recognized as an essential factor Alzheimer's disease pathology. Several proteases, including Neprilysin (NEP), endothelin converting enzyme (ECE), and insulin degrading (IDE), have shown to cleave (Aβ). We previously reported reductions amyloid APP+PS1 mice with increased expression ECE. In this study we compared vector-induced NEP IDE. used recombinant adeno-associated viral vectors expressing either native forms (NEP-n) or IDE...
Abstract Background Antibodies against the Aß peptide clear deposits when injected intracranially. Deglycosylated antibodies have reduced effector functions compared to their intact counterparts, potentially avoiding immune activation. Methods or C-terminal specific high affinity anti-Aβ antibody (2H6) were intracranially into right frontal cortex and hippocampus of amyloid precursor protein (APP) transgenic mice. The untreated left hemisphere was used normalize for extent deposition present...
<h3>Background</h3> Huntington’s disease (HD) is a debilitating neurodegenerative marked by trinucleotide repeat expansion in the huntingtin gene (HTT) that might lead to production of pathogenic mutant protein (mHTT). Recent evidence suggests alterations neurotrophin tyrosine kinase receptor signalling pathways contribute HD pathophysiology. Brain-derived neurotrophic factor (BDNF)-mediated activation B (TrkB) critical component involved survival, differentiation and synaptic plasticity...
Aβ deposition is one of the major neuropathological hallmarks Alzheimer's disease (AD); so reducing amyloid burden may present a possible therapeutic strategy. One proteases involved in degradation peptides neprilysin (Nep). In this study, we investigated long-term effects an intracranial administration recombinant adeno-associated viral vector (rAAV) expressing Nep constructs on APP/PS1 transgenic mice. Three were expressed under control chicken beta-actin promoter with rAAV serotype 9...
Recombinant Adeno-associated viral (rAAV) vectors are an effective means of gene delivery and transfer to the central nervous system hold promise for treatment several types degenerative brain diseases. One disadvantage typical intracranial injections into parenchyma is a limited distribution rAAV macromolecules all regions where therapies may be needed. Convection enhanced (CED) method delivering clinically relevant volumes therapeutic agents significantly larger areas in direct injection...
<h3>Background</h3> Huntington's disease (HD) is a progressive neurodegenerative caused by polyglutamine repeat expansion in the huntingtin (HTT) protein with no effective disease-modifying therapies available. Mutant HTT toxicity, associated misfolding of expanded repeat-containing protein, affects several intracellular pathways and leads to widespread neurodegeneration. In addition, mutant forms aggregates, which contribute pathogenesis. One promising strategy develop HD modifying aim...
The neurotropic B vitamins such as thiamine (B1), pyridoxine (B6), and cobalamin (B12) play a pivotal role in the maintenance of neuronal viability contribute essentially to healthy nervous system. Furthermore, it is well recognised that deficiencies can lead variety neurological conditions peripheral neuropathies. However, date, effect vitamin depletion on modulation genes cellular pathways has not been fully assessed. In this current study we used RNA sequencing transcriptomic analysis...