A5080251578- Cancer-related Molecular Pathways
- Glycogen Storage Diseases and Myoclonus
- Cancer, Hypoxia, and Metabolism
- SARS-CoV-2 and COVID-19 Research
- Hepatocellular Carcinoma Treatment and Prognosis
- Genetics and Neurodevelopmental Disorders
- Wnt/β-catenin signaling in development and cancer
- Peptidase Inhibition and Analysis
- Cardiac tumors and thrombi
- Sarcoma Diagnosis and Treatment
- Epigenetics and DNA Methylation
- Virus-based gene therapy research
- COVID-19 Clinical Research Studies
- Amino Acid Enzymes and Metabolism
- Cancer, Lipids, and Metabolism
- Phosphodiesterase function and regulation
- interferon and immune responses
- Cytomegalovirus and herpesvirus research
- Glycosylation and Glycoproteins Research
- Neuroendocrine Tumor Research Advances
- Bone Tumor Diagnosis and Treatments
- Hedgehog Signaling Pathway Studies
- RNA modifications and cancer
- Hearing, Cochlea, Tinnitus, Genetics
- Dermatological diseases and infestations
National Institutes of Health
2015-2024
Office of Research Services
2014-2024
Office of the Director
2009-2024
Eunice Kennedy Shriver National Institute of Child Health and Human Development
2012
National Heart Lung and Blood Institute
2004-2011
Foundation for the National Institutes of Health
2010
National Institute of Allergy and Infectious Diseases
2008
University of Maryland, Baltimore County
2008
United States Department of Health and Human Services
2007
National Cancer Institute
2004-2006
Mutations in the key enzyme of sialic acid biosynthesis, uridine diphospho–N-acetylglucosamine 2-epimerase/N-acetylmannosamine (ManNAc) kinase (GNE/MNK), result hereditary inclusion body myopathy (HIBM), an adult-onset, progressive neuromuscular disorder. We created knockin mice harboring M712T Gne/Mnk mutation. Homozygous mutant (GneM712T/M712T) did not survive beyond P3. At P2, significantly decreased Gne-epimerase activity was observed GneM712T/M712T muscle, but no myopathic features were...
The S1P(2) receptor is a member of family G protein-coupled receptors that bind the extracellular sphingolipid metabolite sphingosine 1-phosphate with high affinity. widely expressed and linked to multiple protein signaling pathways, but its physiological function has remained elusive. Here we have demonstrated expression essential for proper functioning auditory vestibular systems. Auditory brainstem response analysis revealed receptor-null mice were deaf by one month age. These null...
Acute lymphoblastic leukemia (ALL) is a clonal disease that evolves through the accrual of genetic rearrangements and/or mutations within dominant clone. The TEL-AML1 (ETV6-RUNX1) fusion in precursor-B (pre-B) ALL most common rearrangement childhood cancer; however, cellular origin and molecular pathogenesis TEL-AML1-induced have not been identified. To study ALL, we generated transgenic zebrafish expressing either ubiquitously or lymphoid progenitors. expression all lineages, but...
Here we describe and characterize a small serine/threonine kinase (SSTK) which consists solely of the N- C-lobes protein catalytic domain. SSTK is highly conserved among mammals, no close homologues were found in genomes nonmammalian organisms. specifically interacts with HSP90-1beta, HSC70, HSP70 proteins, this association appears to be required for activity. The transcript was most abundant human mouse testes but also detected all tissues tested. In testis, localized heads elongating...
MicroRNAs (miRNAs) act in post-transcriptional gene silencing and are proposed to function a wide spectrum of pathologies, including cancers viral diseases. Currently, our knowledge, no detailed mechanistic characterization small molecules that interrupt miRNA pathways have been reported. In screening chemical library, we identified compounds suppress RNA interference activity cultured cells. Two were characterized; one impaired Dicer while the other blocked RNA-loading into an Argonaute 2...
A critical question in understanding the immunity to SARS-COV-2 is whether recovered patients are protected against re-challenge and transmission upon second exposure. We developed a Syrian hamster model which intranasal inoculation of just 100 TCID 50 virus caused viral pneumonia. Aged hamsters more severe disease even succumbed SARS-CoV-2 infection, representing first lethal using genetically unmodified laboratory animals. After initial clearance, were re-challenged with 10 5 displayed...
Xanthine oxidoreductase (XOR) is the enzyme responsible for final step in purine degradation resulting generation of uric acid. Here we have generated mice deficient XOR. As expected, these animals lack tissue XOR activity and low to undetectable serum levels Although normal at birth, XOR-/- fail thrive after 10 14 days, most die within first month. The cause death appears be a form severe renal dysplasia, phenotype that closely resembles what has been observed previously cyclooxygenase-2...
A series of ring expanded nucleoside (REN) analogues were synthesized and screened for inhibition cellular RNA helicase activity human immunodeficiency virus type 1 (HIV-1) replication. We identified two compounds, 2, that inhibited the ATP dependent DDX3. Compounds 2 also suppressed HIV-1 replication in T cells monocyte-derived macrophages. Neither compound at therapeutic doses was significantly toxic ex vivo cell culture or mice. Our findings provide proof-of-concept a factor, an helicase,...
The Cell Division-Cycle-14 gene encodes a dual-specificity phosphatase necessary in yeast for exit from mitosis. Numerous disparate roles of vertebrate (CDC14A) have been proposed largely based on studies cultured cancer cells vitro. vivo functions CDC14A are unknown. We generated and analyzed mutations zebrafish mouse CDC14A, developed computational structural model human protein report four novel truncating three missense alleles families segregating progressive, moderate-to-profound...
Li-Fraumeni syndrome (LFS) is a cancer predisposition disorder caused by germline mutations in TP53 that can lead to increased mitochondrial metabolism patients. However, the implications of altered function for tumorigenesis LFS are unclear. Here, we have reported genetic or pharmacologic disruption respiration improves cancer-free survival mouse model expresses mutant p53. Mechanistically, inhibition autophagy and decreased aberrant proliferation signaling In pilot study, patients treated...
CD154-specific antibody therapy prevents allograft rejection in many experimental transplant models. However, initial clinical trials with anti-CD154 have been disappointing suggesting the need for as of yet undetermined adjuvant therapy. In rodents, donor antigen (e.g., a blood transfusion), or mTOR inhibition sirolimus), enhances anti-CD154's efficacy. We performed renal transplants major histocompatibility complex-(MHC) mismatched rhesus monkeys and treated recipients combinations...
Eosinophilic crystalline pneumonia is an idiopathic disease that occurs in many strains and stocks of mice, more commonly on a C57BL/6 background. The sporadically most mice varies from mild subclinical to severe fulminating, sometimes resulting respiratory distress death. In this study, 94 aged male female 129S4/SvJae were evaluated for eosinophilic lesions. There was 87% incidence, with females overrepresented. Histologically, there multifocal coalescing inflammatory infiltrates composed...
PRKAR1A inactivation leads to dysregulated cAMP signaling and Carney complex (CNC) in humans, a syndrome associated with skin, endocrine other tumors. The CNC phenotype is not easily explained by the ubiquitous defect; furthermore, Prkar1a(+/-) mice did develop skin To identify whether Prkar1a defect truly generic but weak tumorigenic signal that depends on tissue-specific or factors, we investigated when bred within Rb1(+/-) Trp53(+/-) backgrounds, treated two-step carcinogenesis protocol....
Congenital heart valve defects in humans occur approximately 2% of live births and are a major source compromised cardiac function. In this study we demonstrate that normal development function dependent upon Galnt1, the gene encodes member family glycosyltransferases (GalNAc-Ts) responsible for initiation mucin-type O-glycosylation. adult mouse, mimics human congenital disease, including aortic pulmonary stenosis regurgitation; altered ejection fraction; dilation, was observed Galnt1 null...
The rapid emergence of several variants concern SARS-CoV-2 calls for evaluations viral fitness and pathogenicity in animal models order to understand the mechanism enhanced transmission possible increases morbidity mortality rates. Here, we demonstrated that immunity naturally acquired through a prior infection with first-wave variant does confer nearly complete protection against B.1.1.7 Syrian hamsters upon reexposure.
Detection of secretory antibodies in the airway is highly desirable when evaluating mucosal protection by vaccines against a respiratory virus, such as severe acute syndrome coronavirus 2 (SARS-CoV-2). We show that intranasal delivery an attenuated SARS-CoV-2 (Nsp1-K164A/H165A) induces both and systemic IgA IgG male Syrian hamsters. Interestingly, either direct immunization or airborne transmission-mediated Nsp1-K164A/H165A hamsters offers heterologous challenge with variants concern (VOCs)...
Mutations of the lamin B receptor (LBR) have been shown to cause HEM dysplasia in humans and ichthyosis mice. LBR is a bifunctional protein with both binding sterol Delta(14)-reductase domain. It previously has proposed that primary are inborn errors cholesterol synthesis. However, DHCR14 also encodes could provide enzymatic redundancy respect To test hypothesis function as Delta(14)-reductases, we obtained mice (Lbr(-/-)) disrupted Dhcr14. Heterozygous Lbr Dhcr14 were intercrossed for...
Hepatocyte growth factor (HGF) is a multifunctional protein that signals through the MET receptor. HGF stimulates cell proliferation, dispersion, neuronal survival, and wound healing. In inner ear, levels of must be fine-tuned for normal hearing. mice, deficiency expression limited to auditory system, or an overexpression HGF, causes neurosensory deafness. humans, noncoding variants in are associated with nonsyndromic deafness DFNB39 . However, mechanism by which these was unknown. Here, we...
Eukaryotic initiation factor 5A (eIF5A)†,‡ is an essential protein that requires a unique amino acid, hypusine, for its activity. Hypusine formed exclusively in eIF5A post-translationally via two enzymes, deoxyhypusine synthase (DHPS) and hydroxylase. Each of the genes encoding these proteins, Eif5a, Dhps, Dohh, required mouse embryonic development. Variants EIF5A or DHPS were recently identified as genetic basis underlying certain rare neurodevelopmental disorders humans. To investigate...
Abstract Few live attenuated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines are in pre-clinical or clinical development. We seek to attenuate SARS-CoV-2 (isolate WA1/2020) by removing the polybasic insert within spike protein and open reading frames (ORFs) 6–8, introducing mutations that abolish non-structural 1 (Nsp1)-mediated toxicity. The derived virus (WA1-ΔPRRA-ΔORF6-8-Nsp1 K164A/H165A ) replicates 100- 1000-fold-lower titers than ancestral induces little lung...
Abstract Short telomeres are a defining feature of telomere biology disorders (TBDs), including dyskeratosis congenita (DC), for which there is no effective general cure. Patients with TBDs often experience bone marrow failure. NAD, an essential metabolic coenzyme, decreased in models DC. Herein, using telomerase reverse transcriptase null ( Tert −/− ) mice critically short telomeres, we investigated the effect NAD supplementation precursor, nicotinamide riboside (NR), on features health...
The current study was designed to evaluate the effects of oral administration citrus coumarin, isopimpinellin, on skin tumor initiation by topically applied benzo[a]pyrene (B[a]P) and 7,12-dimethylbenz[a]anthracene (DMBA). To orally administered isopimpinellin B[a]P DMBA, its DNA adduct formation were first evaluated. Female SENCAR mice pre-treated twice with corn oil, or (70 mg/kg body wt per os) at 24 h 2 prior topical treatment DMBA. Another imperatorin, also included in these experiments...