A5086984955- Pluripotent Stem Cells Research
- CRISPR and Genetic Engineering
- Neuroscience and Neural Engineering
- Parkinson's Disease Mechanisms and Treatments
- DNA Repair Mechanisms
- 3D Printing in Biomedical Research
- Genomics and Chromatin Dynamics
- Genetics and Neurodevelopmental Disorders
- RNA Interference and Gene Delivery
- Virus-based gene therapy research
- Genomics, phytochemicals, and oxidative stress
- Sulfur-Based Synthesis Techniques
- Nuclear Receptors and Signaling
- Glioma Diagnosis and Treatment
- Nitric Oxide and Endothelin Effects
- Inflammatory mediators and NSAID effects
- Nematode management and characterization studies
- Neurological disorders and treatments
- Nerve injury and regeneration
- Neurogenesis and neuroplasticity mechanisms
- Eicosanoids and Hypertension Pharmacology
- Tissue Engineering and Regenerative Medicine
NHS Tayside
2024
Salk Institute for Biological Studies
2018-2023
Lund University
2013-2019
National Cancer Institute
1987
Cellular reprogramming is a new and rapidly emerging field in which somatic cells can be turned into pluripotent stem or other cell types simply by the expression of specific combinations genes. By viral neural fate determinants, it possible to directly reprogram mouse human fibroblasts functional neurons, also known as induced neurons. The resulting are nonproliferating present an alternative for obtaining patient- disease-specific neurons used disease modeling development therapy. In...
The possibility of directly converting non-neuronal cells into neurons in situ the brain would open therapeutic avenues aimed at repairing after injury or degenerative disease. We have developed an adeno-associated virus (AAV)-based reporter system that allows selective GFP labeling reprogrammed neurons. In this system, is turned on only where it stable and maintained for long time periods, allowing histological functional characterization mature When combined with a modified rabies...
Abstract Direct conversion of human fibroblasts into mature and functional neurons, termed induced neurons ( iN s), was achieved for the first time 6 years ago. This technology offers a promising shortcut obtaining patient‐ disease‐specific disease modeling, drug screening, other biomedical applications. However, from adult donors do not reprogram as easily fetal donors, no current reprogramming approach is sufficiently efficient to allow use this using patient‐derived material large‐scale...
DNA repair within neurons Humans have only a limited capacity to generate new neurons. These cells thus need errors in the genome. To better understand this process, Reid et al. developed Repair-seq, method locate genome of stem cell–derived hotspots (DRHs) were more likely occur specific genomic features such as gene bodies well formations, open chromatin, and active regulatory regions. This showed that was enriched at sites involved neuronal function identity. Furthermore, proteomic data...
Several mutations that cause Parkinson's disease (PD) have been identified over the past decade. These account for 15-25% of PD cases; rest cases are considered sporadic. Currently, it is accepted not a single monolithic but rather constellation diseases with some common phenotypes. While rodent models exist PD-causing mutations, research on sporadic forms lagging due to lack cellular models. In our study, we differentiated patient-derived dopaminergic (DA) neurons from induced pluripotent...
Induced neurons (iNs) offer a novel source of human that can be explored for applications disease modelling, diagnostics, drug screening and cell replacement therapy. Here we present protocol highly efficient generation functional iNs from fetal fibroblasts also demonstrate the ability these converted (hiNs) to survive transplantation maintain their phenotype in adult rat brain. The encompasses delay transgene activation after viral transduction resulted significant increase conversion...
Recent findings show that human fibroblasts can be directly programmed into functional neurons without passing via a proliferative stem cell intermediate. These open up the possibility of generating subtype-specific origin for therapeutic use from fetal cell, patients themselves, or matched donors. In this study, we present an improved system direct neural conversion fibroblasts. The reprogramming genes are regulated by neuron-specific microRNA, miR-124, such each turns off expression once...
Abstract Complex genetic predispositions accelerate the chronic degeneration of midbrain substantia nigra neurons in Parkinson’s disease (PD). Deciphering human molecular makeup PD pathophysiology can guide discovery therapeutics to slow progression. However, insights from postmortem brain studies only portray latter stages PD, and there is a lack data surrounding events preceding neuronal loss patients. We address this gap by identifying gene dysregulation live reprogrammed vitro skin cells...
Direct neuronal reprogramming can be achieved using different approaches: by expressing transcription factors or microRNAs; and knocking down repressive elements. However, there still exists a high variability in terms of the quality maturity induced neurons obtained, depending on strategy employed. Here, we evaluate long‐term culture conditions study effect neuronal‐specific microRNAs, miR124 miR9/9*, while with forced expression Ascl1 , Brn2 knockdown repressor REST. We show that addition...
Homogenates from rat renal papillae, a rich source of the prostaglandin (PG) H synthase system (PHS), metabolized [14C]2-bromohydroquinone, in presence arachidonic acid, to products which are covalently bound protein. The co-oxidation 2-bromohydroquinone caused concentration-dependent stimulation 6-keto-PGF1 alpha, thromboxane B2, PGF2 PGE2, and PGD2 formation. Glutathione (1 mM) decrease formation inhibited acid-supported covalent binding [14C]2-bromohydroquinone with concomitant...
Abstract Several mutations that cause Parkinson’s disease (PD) have been identified over the past decade. These account for 15-25% of PD cases; rest cases are considered sporadic. Currently, it is accepted not a single monolithic but rather constellation diseases with some common phenotypes. While rodent models exist PD-causing mutations, research on sporadic forms lagging due to lack cellular models. In our study, we differentiated patient-derived dopaminergic (DA) neurons from induced...
Abstract BACKGROUND Molecular glioblastoma (mGBM), without classical histological features, was defined in the 2021 WHO classification based on select criteria (EGFR amplification, TERT promoter mutation (pTERT), chromosome 7+/10-). Subsequent validation relied retrospective patient re-diagnosis and/or historical GBMs (hGBMs) controls. Whether pTERT only mGBMs also have a poor prognosis remains uncertain. We comprehensively characterised compared to concurrently diagnosed hGBMs. MATERIAL AND...
Abstract Human aging is the main risk factor for Parkinson’s disease (PD). To better understand age-related PD pathogenesis, we modeled with directly reprogrammed dopaminergic neurons (iDA) which preserve donor signatures. By transcriptome analysis and immunohistochemistry on postmortem tissues, identified a sulfurtransferase, TSTD1, to be upregulated in aged diseased individuals. TSTD1 catalyzes sulfur transfer from thiosulfate glutathione (GSH). GSH cysteine were significantly decreased...
Abstract Neurons are the longest-living cells in our bodies, becoming post-mitotic early development upon terminal differentiation. Their lack of DNA replication makes them reliant on repair mechanisms to maintain genome fidelity. These decline with age, potentially giving rise genomic dysfunction that may influence cognitive and neurodegenerative diseases. Despite this challenge, knowledge how instability emerges what neurons other long-lived have evolved protect their integrity over human...