A5074217980- Lysosomal Storage Disorders Research
- Cholesterol and Lipid Metabolism
- Peroxisome Proliferator-Activated Receptors
- Calcium signaling and nucleotide metabolism
- Lipid metabolism and biosynthesis
- Neonatal and fetal brain pathology
- Cytomegalovirus and herpesvirus research
- Carbohydrate Chemistry and Synthesis
- Adenosine and Purinergic Signaling
- Autoimmune and Inflammatory Disorders Research
- Genetics and Neurodevelopmental Disorders
- RNA and protein synthesis mechanisms
- Cellular transport and secretion
- Congenital heart defects research
- Adrenal and Paraganglionic Tumors
- Glycogen Storage Diseases and Myoclonus
- Pituitary Gland Disorders and Treatments
- Cerebral Palsy and Movement Disorders
- Neuroinflammation and Neurodegeneration Mechanisms
- Hormonal Regulation and Hypertension
- RNA regulation and disease
- Nuclear Receptors and Signaling
- Metabolism and Genetic Disorders
- Hedgehog Signaling Pathway Studies
- Immune Cell Function and Interaction
Eunice Kennedy Shriver National Institute of Child Health and Human Development
2015-2024
National Institutes of Health
2015-2024
University of Oxford
2014-2017
National Heart Lung and Blood Institute
2016
University of Pennsylvania
2016
Kennedy Krieger Institute
2014
Johns Hopkins University
2014
National Human Genome Research Institute
2014
George Washington University
2014
Penn State Milton S. Hershey Medical Center
2014
ABSTRACT We investigated the function of Lhx2, a LIM homeobox gene expressed in developing B-cells, forebrain and neural retina, by analyzing embryos deficient functional Lhx2 protein. mutant are anophthalmic, have malformations cerebral cortex, die utero due to severe anemia. In Lhx2−/− specification optic vesicle occurs; however, development eye arrests prior formation an cup. Deficient cellular proliferation results hypoplasia neocortex aplasia hippocampal anlagen. addition central...
Oxysterols are biomarkers for diagnosis and drug treatment in Niemann-Pick C1 disease.
Context:Pituitary adenomas and pheochromocytomas/paragangliomas (pheo/PGL) can occur in the same patient or family. Coexistence of two diseases could be due to either a common pathogenic mechanism coincidence.
Background: Mutations in the subunits B, C, and D of succinate dehydrogenase (SDH) mitochondrial complex II have been associated with development paragangliomas (PGL), gastrointestinal stromal tumors, papillary thyroid renal carcinoma (SDHB), testicular seminoma (SDHD). Aim: Our aim was to examine possible causative link between SDHD inactivation somatotropinoma. Patients Methods: A 37-yr-old male presented acromegaly hypertension. Other family members were found PGL. Elevated plasma urinary...
Context:Germline mutations in genes coding succinate dehydrogenase (SDH) subunits A, B, C, and D have been identified familial paragangliomas (PGLs)/pheochromocytomas (PHEOs) other tumors. We described a GH-secreting pituitary adenoma (PA) caused by SDHD mutation patient with PGLs. Additional patients PAs SDHx defects since reported.
This article describes a rapid UPLC-MS/MS method to quantitate novel bile acids in biological fluids and the evaluation of their diagnostic potential Niemann-Pick C (NPC). Two new compounds, NPCBA1 (3β-hydroxy,7β-N-acetylglucosaminyl-5-cholenoic acid) NPCBA2 (probably 3β,5α,6β-trihydroxycholanoyl-glycine), were observed accumulate preferentially NPC patients: median plasma concentrations 40- 10-fold higher patients than controls. However, normal some because they carried common mutation...
The RSH/Smith–Lemli–Opitz syndrome (RSH/SLOS) is a human autosomal recessive characterized by multiple malformations, distinct behavioral phenotype with autistic features and mental retardation. RSH/SLOS due to an inborn error of cholesterol biosynthesis caused mutation the 3β-hydroxysterol Δ7-reductase gene. To further our understanding developmental neurological processes that underlie pathophysiology this disorder, we have developed mouse model disruption Here provide biochemical,...
Cholesterol plays a key role in many cellular processes, and is generated by cells through de novo biosynthesis or acquired from exogenous sources the uptake of low-density lipoproteins. complex, multienzyme-catalyzed pathway involving series sequentially acting enzymes. Inherited defects genes encoding cholesterol biosynthetic enzymes other regulators homeostasis result severe metabolic diseases, which are rare general population currently without effective therapy. Historically, these...
Niemann–Pick disease type C (NPC) is a lysosomal storage disorder characterized by liver and progressive neurodegeneration. Deficiency of either NPC1 or NPC2 leads to the accumulation cholesterol glycosphingolipids in late endosomes early lysosomes. In order identify pathological mechanisms underlying NPC uncover potential biomarkers, we gene expression changes an Npc1 mouse model at six ages spanning progression disease. We identified altered all ages, including asymptomatic, 1-week-old...
The drug 2-hydroxypropyl-β-cyclodextrin (HPβCD) reduces lysosomal cholesterol accumulation in Niemann-Pick disease, type C (NPC) and has been advanced to human clinical trials. However, its mechanism of action for reducing NPC cells is uncertain molecular target unknown. We found that methyl-β-cyclodextrin (MβCD), a potent analog HPβCD, restored impaired macroautophagy/autophagy flux C1 (NPC1) cells. This effect was mediated by direct activation AMP-activated protein kinase (AMPK), an...
Lysosomal storage disorders (LSDs) occur at a frequency of 1 in every 5,000 live births and are common cause pediatric neurodegenerative disease. The relatively small number patients with LSDs lack validated biomarkers substantial challenges for clinical trial design. Here, we evaluated the use commercially available fluorescent probe, Lysotracker, that can be used to measure relative acidic compartment volume circulating B cells as potentially universal biomarker LSDs. We this metric mouse...
Introduction: Smith–Lemli–Opitz syndrome (SLOS) is a malformation inherited in an autosomal recessive fashion. It due to metabolic defect the conversion of 7-dehydrocholesterol cholesterol, which leads accumulation and frequently deficiency cholesterol. The characterized by typical dysmorphic facial features, multiple malformations, intellectual disability.Areas covered: In this paper we provide overview clinical phenotype discuss how manifestations vary depending on age patients. We then...
Niemann-Pick disease, type C1 (NPC1) is a neurodegenerative disorder with limited treatment options. NPC1 associated neuroinflammation; however, attempts to therapeutically target neuroinflammation in have had mixed success. We show here that characterized by an atypical microglia activation phenotype. Specifically, Npc1-/- demonstrated altered morphology, reduced levels of lineage markers and shift toward glycolytic metabolism. Treatment 2-hydroxypropyl-β-cyclodextrin (HPβCD), drug...
Vertebrate limb development is controlled by three signaling centers that regulate patterning and growth along the proximodistal (PD), anteroposterior (AP) dorsoventral (DV) axes. Coordination of these axes achieved interactions feedback loops involving secreted molecules mediate activities centers. However, it unknown how are processed in responding cells. We have found distinct LIM homeodomain transcription factors, encoded homeobox (LIM-HD) genes Lhx2, Lhx9 Lmx1b integrate events link...
Cholesterol is an abundant lipid in eukaryotic membranes, implicated numerous structural and functional capacities. Here, we have investigated the mechanism by which cholesterol affects secretory granule biogenesis vivo using Dhcr7(-/-) Sc5d(-/-) mouse models of human diseases, Smith-Lemli-Opitz syndrome (SLOS) lathosterolosis. These homozygous-recessive multiple-malformation disorders are characterized absence one last two enzymes biosynthetic pathway, resulting accumulation precursors....
Niemann-Pick disease, type C1 (NPC1) is a fatal, neurodegenerative disorder for which there no definitive therapy. In NPC1, pathological cascade including neuroinflammation, oxidative stress and neuronal apoptosis likely contribute to the clinical phenotype. While genetic cause of NPC1 known, we sought gain further understanding into pathophysiology by identifying differentially expressed proteins in Npc1 mutant mouse cerebella. Using two-dimensional gel electrophoresis mass spectrometry, 77...
Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive inborn error of cholesterol metabolism with neurocognitive manifestations. SLOS the result mutations in gene encoding 7-dehydrocholesterol reductase, which results elevation precursor (7-DHC). Previous reports indicate that intellectual disability, behavioral disturbances, and autism symptoms are frequently part phenotype. In current study, we characterize developmental history behavior 33 individuals aged 4 to 23 years report on...
Abstract Niemann–Pick disease, type C1 (NPC1) is a neurodegenerative, lysosomal storage disorder due to mutation of the NPC1 gene. The phenotype characterized by progressive neuronal dysfunction, including cerebellar ataxia and dementia. There histological evidence neuroinflammation loss, with Purkinje cells particularly vulnerable loss function. Necroptosis was evaluated as mechanism loss. Receptor-interacting protein kinase 1 (RIP1) RIP3 are key components necrosomal complex that regulates...