A5029484954- RNA modifications and cancer
- RNA Research and Splicing
- Genetics and Neurodevelopmental Disorders
- Pancreatic function and diabetes
- Endoplasmic Reticulum Stress and Disease
- Genetic Neurodegenerative Diseases
- RNA and protein synthesis mechanisms
- Amyotrophic Lateral Sclerosis Research
- Diabetes and associated disorders
- RNA regulation and disease
- Genomics and Rare Diseases
- Genomic variations and chromosomal abnormalities
- Neuroscience and Neuropharmacology Research
- Neuroscience and Neural Engineering
- Neurogenetic and Muscular Disorders Research
- Language Development and Disorders
- Mitochondrial Function and Pathology
- Microtubule and mitosis dynamics
- Autism Spectrum Disorder Research
- Pluripotent Stem Cells Research
- Cellular transport and secretion
- Congenital heart defects research
- Neurogenesis and neuroplasticity mechanisms
- Phagocytosis and Immune Regulation
- Connective tissue disorders research
Case Western Reserve University
2017-2025
University School
2022-2024
University of California, San Diego
2010-2018
Howard Hughes Medical Institute
2012-2018
Children’s Institute
2018
University of California, Irvine
2005-2010
University of Wisconsin–Madison
2010
One major unresolved question in the field of pancreas biology is whether ductal cells have ability to generate insulin-producing β-cells. Conclusive examination this has been limited by lack appropriate tools efficiently and specifically label vivo. We generated Sox9CreER(T2) mice, which, during adulthood, allow for labeling an average 70% pancreatic cells, including terminal duct/centroacinar cells. Fate-mapping studies Sox9(+) domain revealed endocrine acinar cell neogenesis from...
Neurodegenerative diseases can occur so early as to affect neurodevelopment. From a cohort of more than 2,000 consanguineous families with childhood neurological disease, we identified founder mutation in four independent pedigrees cleavage and polyadenylation factor I subunit 1 (CLP1). CLP1 is multifunctional kinase implicated tRNA, mRNA, siRNA maturation. Kinase activity the mutant protein was defective, tRNA endonuclease complex (TSEN) destabilized, resulting impaired pre-tRNA cleavage....
The translation of "next-generation" sequencing directly to the clinic is still being assessed but has potential for genetic diseases reduce costs, advance accuracy, and point unsuspected yet treatable conditions. To study its capability in clinic, we performed whole-exome 118 probands with a diagnosis pediatric-onset neurodevelopmental disease which most known causes had been excluded. Twenty-two genes not previously identified as disease-causing were this (19% cohort), further establishing...
All pancreatic endocrine cell types arise from a common precursor population, yet the molecular mechanisms that establish and maintain unique gene expression programs of each lineage have remained largely elusive. Such knowledge would improve our ability to correctly program or reprogram cells adopt specific fates. Here, we show transcription factor Nkx6.1 is both necessary sufficient specify insulin-producing beta cells. Heritable in precursors mice respecify non-beta towards lineage, while...
Abstract Pancreatic β-cells are prone to endoplasmic reticulum (ER) stress due their role in insulin secretion. They require sustainable and efficient adaptive responses cope with this stress. Whether episodes of chronic directly compromise β-cell identity is unknown. We show here under reversible, conditions undergo transcriptional translational reprogramming associated impaired expression regulators function identity. Upon recovery from stress, regain function, indicating a high degree...
An increased level of phosphorylation eukaryotic translation initiation factor 2 subunit-α (eIF2α, encoded by EIF2S1; eIF2α-p) coupled with decreased guanine nucleotide exchange activity eIF2B is a hallmark the 'canonical' integrated stress response (c-ISR)1. It unclear whether impaired in human diseases including leukodystrophies2, which occurs absence eIF2α-p induction, synonymous c-ISR. Here we describe mechanism triggered activity, distinct from c-ISR, term split ISR (s-ISR). The s-ISR...
Despite much progress in identifying transcriptional regulators that control the specification of different pancreatic endocrine cell types,the spatiotemporal aspects subtype have remained largely elusive. Here, we address mechanism by which transcription factors Nkx6.1 (Nkx6-1) and Nkx6.2 (Nkx6-2) orchestrate development alpha- beta-cell lineages. Specifically, assayed for rescue insulin-producing beta-cells mutant mice upon restoring Nkx6 activity select progenitor populations with...
Cranial sensory neurons largely derive from neurogenic placodes (epibranchial and dorsolateral), which are ectodermal thickenings that form the ganglia associated with cranial nerves, but molecular mechanisms of placodal development unclear. Here, we show pharyngeal endoderm induces epibranchial neurogenesis in zebrafish, BMP signaling plays a crucial role this process. Using her5:egfp transgenic line to follow endodermal movements living embryos, contact between pouches surface ectoderm...
Abstract Wolcott–Rallison syndrome (WRS) and the recently delineated microcephaly with simplified gyration, epilepsy, permanent neonatal diabetes (MEDS) are clinically overlapping autosomal recessive disorders characterized by early onset diabetes, skeletal defects, growth retardation. While liver renal symptoms more severe in WRS, neurodevelopmental characteristics pronounced MEDS patients, which uncontrolled epilepsy uniformly present. Mutations EIF2AK3 gene were described patients WRS...
Recent advances in genetic diagnosis identified variants genes encoding GABA
A number of mutations in genes that encode ubiquitously expressed RNA-binding proteins cause tissue specific disease. Many these diseases are neurological nature revealing critical roles for this class the brain. We recently identified a gene encodes polyadenosine protein, ZC3H14 (Zinc finger CysCysCysHis domain-containing protein 14), nonsyndromic, autosomal recessive form intellectual disability. This finding reveals molecular basis disease and provides evidence is essential proper brain...
The loss or dysfunction of the pancreatic endocrine β-cell results in diabetes. Recent innovative therapeutic approaches for diabetes aim to induce proliferation vivo by pharmacological intervention. Based on finding that overexpression transcription factor Nkx6.1 islets vitro increases while maintaining function, has been proposed as a potential target therapy. However, it is unknown whether elevated levels β-cells have similar effects observed isolated islets. To this end, we sought...
ABSTRACT Vesicle-associated membrane protein-associated protein-B (VAPB) is an ER bound protein. VAPB P56S causes a dominant, familial form of amyotrophic lateral sclerosis (ALS), however, the mechanism through which this mutation motor neuron (MN) disease remains unknown. Using inducible wild type (WT) and expressing iPSC-derived MNs we show that P56S, but not WT, protein decreased neuronal firing mitochondrial-ER contact (MERC) with associated age-dependent decrease in mitochondrial...