A5030274577- Pluripotent Stem Cells Research
- CRISPR and Genetic Engineering
- Genetic Neurodegenerative Diseases
- 3D Printing in Biomedical Research
- Neuroscience and Neuropharmacology Research
- Metabolism, Diabetes, and Cancer
- Neuroscience and Neural Engineering
- Pharmacological Effects and Toxicity Studies
- Mitochondrial Function and Pathology
- Renal and related cancers
- Neurogenesis and neuroplasticity mechanisms
- Genetics and Neurodevelopmental Disorders
- DNA Repair Mechanisms
- Epigenetics and DNA Methylation
- Single-cell and spatial transcriptomics
- Ion channel regulation and function
- Retinoids in leukemia and cellular processes
- Virus-based gene therapy research
- Parkinson's Disease Mechanisms and Treatments
- Nuclear Receptors and Signaling
- Histone Deacetylase Inhibitors Research
- Fibroblast Growth Factor Research
- Cardiac electrophysiology and arrhythmias
- Genetics, Aging, and Longevity in Model Organisms
- RNA and protein synthesis mechanisms
University of Michigan–Ann Arbor
2015-2024
Michigan United
2024
Calvin University
2006-2018
Vanderbilt University Medical Center
2012-2017
Vanderbilt University
2016-2017
Vanderbilt Health
2016
Ann Arbor VA Medical Center
2015
Allen Institute for Brain Science
2012-2014
John F. Kennedy Center for the Performing Arts
2012-2013
Abstract Missense variants in the SCN8A voltage-gated sodium channel gene are linked to early-infantile epileptic encephalopathy type 13, also known as SCN8A-related epilepsy. These patients exhibit a wide spectrum of intractable seizure types, severe developmental delay, movement disorders, and elevated risk sudden unexpected death The mechanisms by which lead epilepsy poorly understood, although heterologous expression systems mouse models have demonstrated altered current properties. To...
Brain organoid methods are complicated by multiple rosette structures and morphological variability. We have developed a human brain technique that generates self-organizing, single-rosette cortical organoids (SOSR-COs) with reproducible size structure at early timepoints. Rather than patterning 3-dimensional embryoid body, we initiate formation from 2-dimensional monolayer of pluripotent stem cells patterned small molecules into neuroepithelium differentiated to the developing dorsal...
Recent successes in deriving human-induced pluripotent stem cells (hiPSCs) allow for the possibility of studying human neurons derived from patients with neurological diseases. Concomitant inhibition BMP and TGF-β1 branches TGF-β signaling pathways by endogenous antagonist, Noggin, small molecule SB431542, respectively, induces efficient neuralization hiPSCs, a method known as dual-SMAD inhibition. The use inhibitors instead their counterparts has several advantages including lower cost,...
The essential micronutrient manganese is enriched in brain, especially the basal ganglia. We sought to identify neuronal signaling pathways responsive neurologically relevant levels, as previous data suggested that alterations striatal handling occur Huntington's disease (HD) models. found p53 phosphorylation at serine 15 most cell event exposure (of 18 tested) human neuroprogenitors and a mouse line. Manganese-dependent activation of was severely diminished HD cells. Inhibitors ataxia...
Specifically ablating genes in human induced pluripotent stem cells (iPSCs) allows for studies of gene function as well disease mechanisms disorders caused by loss-of-function (LOF) mutations. While techniques exist engineering such lines, we have developed and rigorously validated a method simultaneous iPSC reprogramming while generating CRISPR/Cas9-dependent insertions/deletions (indels). This approach the efficient rapid formation genetic LOF cell models with isogenic controls. The rate...
Alterations in DNA damage response and repair have been observed Huntington's disease (HD). We generated induced pluripotent stem cells (iPSC) from primary dermal fibroblasts of 5 patients with HD control subjects. A significant fraction the iPSC lines had genomic abnormalities as assessed by karyotype analysis, while none our detectable abnormalities. demonstrate a statistically increase instability during reprogramming. also report association repeat length severity this instability. Our...
Neural tube defects (NTDs), including anencephaly and spina bifida, are common major malformations of fetal development resulting from incomplete closure the neural tube. These conditions lead to either universal death (anencephaly) or severe lifelong complications (spina bifida). Despite hundreds genetic mouse models defect phenotypes, genetics human NTDs poorly understood. Furthermore, pharmaceuticals, such as antiseizure medications, have been found clinically increase risk when...
Huntington's disease (HD) is caused by a mutation in the huntingtin gene (HTT), resulting profound striatal neurodegeneration through an unknown mechanism. Perturbations urea cycle have been reported HD models and patient blood brain. In neurons, arginase central enzyme, metal manganese (Mn) essential cofactor. Deficient biological responses to Mn, reduced Mn accumulation observed mouse cell models. Here we report vivo ex evidence of metabolic phenotype prodromal model. Further, either or...
ABSTRACT The field of brain organoid research is complicated by morphological variability with multiple neural rosette structures per organoid. We have developed a new human technique that generates self-organizing, single-rosette spheroids (SOSRS) reproducible size, cortical-like lamination, and cell diversity. Rather than patterning 3-dimensional embryoid body, we initiate formation from 2-dimensional monolayer pluripotent stem cells (hPSCs) patterned small molecules into neuroepithelium...
Neurodevelopmental disorders often impair multiple cognitive domains. For instance, a genetic epilepsy syndrome might cause seizures due to cortical hyperexcitability and present with memory impairments arising from hippocampal dysfunction. This study examines how single disorder differentially affects distinct brain regions by using human patient iPSC-derived cortical- hippocampal-ganglionic eminence assembloids model Developmental Epileptic Encephalopathy 13 (DEE-13), condition...
Many neuropsychiatric disorders are thought to result from subtle changes in neural circuit formation. We used human embryonic stem cells and induced pluripotent (hiPSCs) model mature, post-mitotic excitatory neurons examine effects of fibroblast growth factor 2 (FGF2). FGF2 gene expression is known be altered brain regions major depressive disorder (MDD) patients has anti-depressive animal models depression. generated stable inducible (siNeurons) conditionally expressing neurogenin-2...
Introduction Protocadherin-19 ( PCDH19 )-Clustering Epilepsy (PCE) is a developmental and epileptic encephalopathy caused by loss-of-function variants of the gene on X-chromosome. PCE affects females mosaic males while male carriers are largely spared. Mosaic expression cell adhesion molecule due to random X-chromosome inactivation thought impair cell–cell interactions between mutant wild type -expressing cells produce disease. Progress has been made in understanding using rodent models or...
For both disease and basic science research, loss-of-function (LOF) mutations are vitally important. Herein, we provide a simple stream-lined protocol for generating LOF iPSC lines that circumvents the technical challenges of traditional gene-editing cloning established by combining introduction CRISPR vector concurrently with episomal reprogramming plasmids into fibroblasts. Our experiments have produced nearly even numbers all 3 genotypes in autosomal genes. In addition, detailed approach...
Neural tube defects (NTDs) including anencephaly and spina bifida are common major malformations of fetal development resulting from incomplete closure the neural tube. These conditions lead to either universal death (anencephaly) or life-long severe complications (spina bifida). Despite hundreds genetic mouse models having defect phenotypes, genetics human NTDs poorly understood. Furthermore, pharmaceuticals such as antiseizure medications have been found clinically increase risk when...
Induced pluripotent stem cells (iPSCs) are becoming mainstream tools to study mechanisms of development and disease. They have a broad range applications in understanding disease processes, vitro testing novel therapies, potential utility regenerative medicine. Although the techniques for generating iPSCs more straightforward, scientists can expend considerable resources time establish this technology. A major hurdle is accurate determination valid iPSC-like colonies that be selected further...