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Our research is directed toward identifying, understanding and reversing the consequences of gene mutations on protein and cell function in inherited human disease. Cell biological and molecular genetic approaches are used in conjunction with clinical studies to obtain a better understanding of gene expression and the molecular pathophysiology underlying selected Mendelian and complex trait diseases. To accomplish this objective, we study gene variation and function in unique human genetic isolates, inbred animal models and families with inherited developmental disorders. Research projects reflect a “bench to bedside” approach, combining efforts from interdisciplinary investigations on humans and animal models. Current study areas include the link between Gaucher disease and parkinsonism, development of novel gene and replacement therapies for Gaucher disease, and the genetics of selected psychiatric disorders, including bipolar affective disorder in the Old Order Amish and obsessive compulsive disorder in domestic animals. 

Gaucher Disease Therapy

This research area focusus on the development of new oral biologics for treating Gaucher Disease. Gaucher Disease a lysosomal storage disorder caused by inherited deficiencies of the enzyme glucocerebrosidase (GBA). Decreases in functioning GBA levels lead to lipid accumulation in the spleen, liver, brain and bone marrow that cause a wide range of clinical manifestations. There are 3 different types of this disease based on the presence or absence of early onset brain involvement. Type 1 is the most common form of Gaucher disease with no neuropathic phenotypes and accounts for more than 90% of all cases. Type 2 is rare and involves severe neurological (brain stem) abnormalities. It is usually fatal within the first 2 years, and it is currently untreatable because of the severe, irreversible brain damage. Type 3 shows similar symptoms as type 1 as well as neurological involvement.

Currently, available treatments for Gaucher disease include enzyme replacement (ERT) and substrate reduction therapies. ERT involves receiving intravenous (IV) infusions about every 2 weeks and can cost up to $200,000 or more each year.

This research will use orally administered glucan particles containing DNA to produce increased levels of functioning GBA. Success of the treatments will be determined by following GBA levels and biomarkers in various tissues of the mice during treatment. An increase in GBA should also lead to a decrease in the lipid glucocerebroside (GL1) and glucosylsphingosine (lyso-GL1).

Gaucher Disease Linked Parkinsons

We are using mouse models of Gaucher disesase to (i) identify novel molecular abnormalities impacting pathophysiology of  Gaucher related PD and sporadic PD, (ii) carry out longitudinal studies of PD progression and biomarker discovery, and (iii) enable testing of novel strategies for treatment, intervention, and potentially even prevention of Gaucher disease and Parkinsons.

Recent clinical, epidemiological and experimental studies have confirmed a strong connection between Parkinson’s disease (PD) and individuals carrying a glucocerebrosidase gene (GBA) Gaucher mutation.  We are building upon our published in-vivo findings of altered nigrostriatal pathway dopaminergic neurotransmission in the conduritol-beta-epoxide (CBE) pharmacological Gaucher mouse model of reduced GBA enzyme activity.  This is the first description in an animal model to recapitulate the synaptic dysfunction reported in human striatal imaging studies of Gaucher mutation carriers asymptomatic for Parkinsonism.  CBE administration produced markedly reduced evoked dopamine release and post-synaptic density size.  These synaptic abnormalities were accompanied by robust elevation of neuroinflammatory markers and alpha-synuclein (a-syn) in nigrostriatal tissue.  To further address the unmet need for better understanding and treatment of bone and brain involvement in Gaucher disease, and more specifically as models for the study of Gaucher-related Parkinsonism and sporadic Parkinson’s disease, we are using two long-lived transgenic mouse models of Gaucher disease bearing the L444P or the R463C point mutations frequently found in Gaucher patients.  These aged homozygous Gaucher transgenic mutant mice have a lifespan of from 1-2 years and show abnormal a-syn accumulation and astroglial activation in the striatum.


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Development of an Osteoprotegerin Gene Therapy to Increase Bone Density

An orally administered gene therapy using macrophage targeted yeast cell wall particles containing DNA encoding human osteoprotegerin, OPG, is being developed to increase bone density and quality by reducing the extent of osteoclast mediated bone resorption. Low bone mass such as osteoporosis is a major health risk for millions of women and men, predisposing individuals to bone fractures, as well as sequelae including stroke and an accelerated decrease in quality of life. Administration of OPG improves the clinical manifestations of bone loss, but current formulations of OPG proteins must be recombinantly produced and intravenously administered. It is anticipated that the improved delivery of OPG to macrophages and osteoclasts in bone by this gene therapy approach will produce increased bone density as a result of reduced bone resorption. The proposed studies will assess the in-vivo impact of this therapeutic approach to improve the skeletal manifestations of low bone density and excessive bone resorption.

Development of an Orally Administered Gene Therapy for Gaucher Disease

An orally administered gene therapy is being been developed as a next generation therapeutic to restore normal enzymatic activity in Gaucher disease, the most common lysosomal storage disorder. This approach uses yeast cell wall particles containing DNA or RNA encoding human glucocerebrosidase to restore normal enzyme in-vivo in Gaucher mice. The skeletal and central nervous system complications of Gaucher disease still present an enormous challenge for current enzyme and gene replacement therapies. Despite the successes of gene therapy strategies in animal models, the clinical trials conducted to date have generally resulted in low levels of gene expression. Studies will determine the extent of improvement in enzyme levels in macrophages and tissues of treated Gaucher mice, the extent of reversal of lipid storage and tissue pathology and impact on survival. We anticipate that this approach will provide improved delivery of human glucocerebrosidase to many tissues, including bone. If macrophages containing human glucocerebrosidase migrate into brain, the resulting increased enzyme levels could provide clinical benefit for the neurological manifestations of Gaucher disease. The successful development of this therapeutic strategy should provide a safer, more efficient and cost effective treatment for patients with Gaucher disease, as well as providing a prototype of therapy to benefit those having a wide range of other lysosomal diseases.

Identification of Gene Mutations Causing Human Disease

Genetic studies are carried out to obtain a better understanding of the molecular basis of human diseases by identifying correlations between molecular variations and clinical manifestations. Examples of clinical research projects with molecular components include: psychiatric disorders (manic-depressive illness; schizophrenia); Gaucher disease and other inherited metabolic disorders; and, Ellis van-Creveld dwarfism.

Summary Clinical management of patients with Gaucher disease and Fabry disease; translational research on lysosomal disorders; development of novel gene and replacement therapies for Gaucher disease; studies on the link between Gaucher disease and parkinsonism;
One or more keywords matched the following items that are connected to Ginns, Edward
Item TypeName
Academic Article A genome-wide search for chromosomal loci linked to bipolar affective disorder in the Old Order Amish.
Academic Article Structure and organization of the human metaxin gene (MTX) and pseudogene.
Academic Article The inheritance of bipolar affective disorder: abundant genes coming together.
Academic Article Splenectomy in Gaucher disease: new management dilemmas.
Academic Article A triplet repeat on 17q accounts for most expansions detected by the repeat-expansion-detection technique.
Academic Article Genotype D399N/R463C in a patient with type 3 Gaucher disease previously assigned genotype N370S/R463C.
Academic Article Monitoring the CNS pathology in aspartylglucosaminuria mice.
Academic Article Targeted reduction of oxytocin expression provides insights into its physiological roles.
Academic Article Detection of polyglutamine expansion in a new acidic protein: a candidate for childhood onset schizophrenia?
Academic Article Apolipoprotein E alleles in childhood-onset schizophrenia.
Academic Article Trypsin bound to sephadex beads. A tool for neuronal cell dissociation.
Academic Article Cells isolated from trypsin-treated brain contain trypsin.
Academic Article Update on the search for DNA markers linked to manic-depressive illness in the Old Order Amish.
Academic Article Deficiency in mouse oxytocin prevents milk ejection, but not fertility or parturition.
Academic Article Glucosylsphingosine accumulation in mice and patients with type 2 Gaucher disease begins early in gestation.
Academic Article Identification of three additional genes contiguous to the glucocerebrosidase locus on chromosome 1q21: implications for Gaucher disease.
Academic Article Mice with an aspartylglucosaminuria mutation similar to humans replicate the pathophysiology in patients.
Academic Article Mice that lack thrombospondin 2 display connective tissue abnormalities that are associated with disordered collagen fibrillogenesis, an increased vascular density, and a bleeding diathesis.
Academic Article Gaucher's disease: the best laid schemes of mice and men.
Academic Article Chromosome 22q11.2 interstitial deletions among childhood-onset schizophrenics and "multidimensionally impaired".
Academic Article Linkage analysis of juvenile parkinsonism to tyrosine hydroxylase gene locus on chromosome 11.
Academic Article Gaucher disease in the neonate: a distinct Gaucher phenotype is analogous to a mouse model created by targeted disruption of the glucocerebrosidase gene.
Academic Article Prolonged ethanol inhalation decreases gamma-aminobutyric acidA receptor alpha subunit mRNAs in the rat cerebral cortex.
Academic Article HLA antigens in childhood onset schizophrenia.
Academic Article Oxytocin and milk removal are required for post-partum mammary-gland development.
Academic Article Association of an X-chromosome dodecamer insertional variant allele with mental retardation.
Academic Article Large CAG/CTG repeats are associated with childhood-onset schizophrenia.
Academic Article Lack of an association between a dopamine-4 receptor polymorphism and attention-deficit/hyperactivity disorder: genetic and brain morphometric analyses.
Academic Article A genome-wide search for chromosomal loci linked to mental health wellness in relatives at high risk for bipolar affective disorder among the Old Order Amish.
Academic Article Anemic Gaucher patients with elevated endogenous erythropoietin levels may not respond to recombinant erythropoietin therapy.
Academic Article Two novel polymorphic sequences in the glucocerebrosidase gene region enhance mutational screening and founder effect studies of patients with Gaucher disease.
Academic Article DNA mutation analysis of Gaucher patients.
Academic Article Genetically altered and defined cell lines for transplantation in animal models of Parkinson's disease.
Academic Article Brain grafts and Parkinson's disease.
Academic Article Cardiovascular fibrosis, hydrocephalus, ophthalmoplegia, and visceral involvement in an American child with Gaucher disease.
Academic Article Childhood-onset schizophrenia/autistic disorder and t(1;7) reciprocal translocation: identification of a BAC contig spanning the translocation breakpoint at 7q21.
Academic Article Absence of a significant linkage between Na(+),K(+)-ATPase subunit (ATP1A3 and ATP1B3) genotypes and bipolar affective disorder in the old-order Amish.
Academic Article Gaucher patients with oculomotor abnormalities do not have a unique genotype.
Academic Article Glutamic acid decarboxylase mRNA in rat brain: regional distribution and effects of intrastriatal kainic acid.
Academic Article Gender-specific reduction of estrogen-sensitive small RNA, miR-30b, in subjects with schizophrenia.
Academic Article Neuron-specific enolase and its mRNA are highly expressed in large congenital nevi: a study using immunocytochemistry, biochemical assay, and in situ hybridization.
Academic Article Re-evaluation of the linkage relationship between chromosome 11p loci and the gene for bipolar affective disorder in the Old Order Amish.
Academic Article Skin ultrastructural findings in type 2 Gaucher disease: diagnostic implications.
Academic Article Human tyrosine hydroxylase (TH) genomic fragment (pHGTH4) identifies a PstI polymorphism.
Academic Article Glucosylsphingosine accumulation in tissues from patients with Gaucher disease: correlation with phenotype and genotype.
Academic Article A new gene, EVC2, is mutated in Ellis-van Creveld syndrome.
Academic Article Rare missense neuronal cadherin gene (CDH2) variants in specific obsessive-compulsive disorder and Tourette disorder phenotypes.
Academic Article The subcellular localization of soluble and membrane-bound lysosomal enzymes in I-cell fibroblasts: a comparative immunocytochemical study.
Academic Article Linkage between the loci for autosomal dominant Charcot-Marie-Tooth neuropathy type 1 and human glucocerebrosidase.
Academic Article Genetic heterogeneity in type 1 Gaucher disease: multiple genotypes in Ashkenazic and non-Ashkenazic individuals.
Academic Article The molecular biology of Gaucher disease and the potential for gene therapy.
Academic Article Retrovirus-mediated transfer of the human glucocerebrosidase gene to Gaucher fibroblasts.
Academic Article Ultrastructural localization of glucocerebrosidase in cultured Gaucher's disease fibroblasts by immunocytochemistry.
Academic Article Gene mapping and leader polypeptide sequence of human glucocerebrosidase: implications for Gaucher disease.
Academic Article GM1 ganglioside concentration in the cerebrospinal fluid of neonates and children.
Academic Article Bone-marrow transplantation in severe Gaucher's disease.
Academic Article A radioassay for GM1 ganglioside concentration in cerebrospinal fluid.
Academic Article Glucocerebroside-beta-glucosidase isozymes.
Academic Article A new group of glucocerebrosidase isozymes found in human white blood cells.
Academic Article Diagnosing Gaucher disease. Early recognition, implications for treatment, and genetic counseling.
Academic Article Responses of the mouse to microwave radiation during estrous cycle and pregnancy.
Academic Article DNA mutational analysis of type 1 and type 3 Gaucher patients: how well do mutations predict phenotype?
Academic Article Consequences of beta-glucocerebrosidase deficiency in epidermis. Ultrastructure and permeability barrier alterations in Gaucher disease.
Academic Article Treatment of Gaucher's disease.
Academic Article DNA targeting of rhinal cortex D2 receptor protein reversibly blocks learning of cues that predict reward.
Academic Article Joint multi-population analysis for genetic linkage of bipolar disorder or "wellness" to chromosome 4p.
Academic Article Mutations in Gaucher's disease detected by MspI.
Academic Article Therapy for Gaucher disease: don't stop thinking about tomorrow.
Academic Article Molecular determinants of dysregulated GABAergic gene expression in the prefrontal cortex of subjects with schizophrenia.
Academic Article Effect of ethacrynic acid on the sodium- and potassium-activated adenosine triphosphatase activity and expression in Old Order Amish bipolar individuals.
Academic Article A canine chromosome 7 locus confers compulsive disorder susceptibility.
Academic Article Regional distribution of the GABAA/benzodiazepine receptor (alpha subunit) mRNA in rat brain.
Academic Article Nucleotide sequence of cDNA containing the complete coding sequence for human lysosomal glucocerebrosidase.
Academic Article Signal sequence and DNA-mediated expression of human lysosomal alpha-galactosidase A.
Academic Article Glucocerebrosidase, a lysosomal enzyme that does not undergo oligosaccharide phosphorylation.
Academic Article Bone marrow transplantation in Gaucher disease.
Academic Article Biosynthesis and maturation of glucocerebrosidase in Gaucher fibroblasts.
Academic Article Molecular weight characterization of beta-D-glucocerebrosidase in mononuclear white blood cells in Gaucher's disease.
Academic Article Mutations of glucocerebrosidase: discrimination of neurologic and non-neurologic phenotypes of Gaucher disease.
Academic Article Prospects for enzyme replacement therapy in Gaucher disease.
Academic Article Structure and organization of the human thrombospondin 3 gene (THBS3).
Academic Article Genetic basis of Gaucher disease.
Academic Article Metaxin, a gene contiguous to both thrombospondin 3 and glucocerebrosidase, is required for embryonic development in the mouse: implications for Gaucher disease.
Academic Article Direct sequencing of trinucleotide repeats from cosmid genomic DNA template.
Academic Article A novel transcript from a pseudogene for human glucocerebrosidase in non-Gaucher disease cells.
Academic Article Isolation, characterization, and proteolysis of human prosaposin, the precursor of saposins (sphingolipid activator proteins).
Concept Tandem Mass Spectrometry
Concept Disease Models, Animal
Concept Nutrition Surveys
Concept Protein Subunits
Concept Sequence Analysis, DNA
Concept Central Nervous System
Concept Supraoptic Nucleus
Concept Genomic Library
Concept Myelin Sheath
Concept Genetic Association Studies
Concept Multigene Family
Concept DiGeorge Syndrome
Concept Photic Stimulation
Concept Sphingolipids
Concept Oncogenes
Concept Rats, Inbred Strains
Concept Splenectomy
Concept Deoxyribonucleases, Type II Site-Specific
Concept Disease Progression
Concept Sensitivity and Specificity
Concept Sodium-Potassium-Exchanging ATPase
Concept Fragile X Syndrome
Concept Genes, Dominant
Concept Amino Acid Substitution
Concept Semen
Concept Genes
Concept Genetic Code
Concept Ellis-Van Creveld Syndrome
Concept Schools
Concept Synaptic Transmission
Concept Statistics as Topic
Concept Amino Acid Sequence
Concept Cohort Studies
Concept Twin Studies as Topic
Concept Tourette Syndrome
Concept Genetic Predisposition to Disease
Concept S100 Proteins
Concept Sphingosine
Concept Nervous System Diseases
Concept Intracellular Signaling Peptides and Proteins
Concept Sodium
Concept Pseudogenes
Concept Cardiovascular Diseases
Concept Statistics, Nonparametric
Concept Charcot-Marie-Tooth Disease
Concept Intercellular Signaling Peptides and Proteins
Concept Conserved Sequence
Concept Transgenes
Concept Saposins
Concept Genes, ras
Concept Communicable Diseases, Emerging
Concept Organ Specificity
Concept Regulatory Sequences, Nucleic Acid
Concept Repetitive Sequences, Nucleic Acid
Concept Species Specificity
Concept Cell Separation
Concept Social Isolation
Concept Signal Transduction
Concept Nucleic Acid Conformation
Concept Schizophrenia, Childhood
Concept Somatostatin
Concept High-Throughput Screening Assays
Concept Schizophrenia
Concept Sphingolipid Activator Proteins
Concept DNA, Recombinant
Concept Synapses
Concept Psychiatric Status Rating Scales
Concept Trinucleotide Repeat Expansion
Concept Lod Score
Concept Sequence Alignment
Concept Alzheimer Disease
Concept Genome, Human
Concept Gene Library
Concept Case-Control Studies
Concept Muscular Atrophy, Spinal
Concept Mice, Inbred Strains
Concept Infant, Newborn, Diseases
Concept Stem Cell Transplantation
Concept Gaucher Disease
Concept Sequence Homology, Amino Acid
Concept Spleen
Concept Substrate Specificity
Concept Genome-Wide Association Study
Concept Protein Sorting Signals
Concept Saccades
Concept Lysosomal Storage Diseases
Concept United States
Concept Sex Characteristics
Concept Corpus Striatum
Concept Parkinson Disease
Concept Skin Neoplasms
Concept Structure-Activity Relationship
Concept In Situ Hybridization, Fluorescence
Concept Substantia Nigra
Concept Skin
Concept alpha-Synuclein
Concept Base Sequence
Concept Alleles
Concept Genes, Recessive
Concept Follow-Up Studies
Concept Dog Diseases
Concept Mice, Mutant Strains
Concept Molecular Sequence Data
Academic Article Phenotypic and genotypic heterogeneity in gaucher disease: Implications for genetic counseling.
Academic Article Neuroinflammation and a-synuclein accumulation in response to glucocerebrosidase deficiency are accompanied by synaptic dysfunction.
Academic Article Disruption of sonic hedgehog signaling in Ellis-van Creveld dwarfism confers protection against bipolar affective disorder.
Academic Article A new glucocerebrosidase-deficient neuronal cell model provides a tool to probe pathophysiology and therapeutics for Gaucher disease.
Academic Article DNA Methylation Signatures of Early Childhood Malnutrition Associated With Impairments in Attention and Cognition.
Academic Article Glucocerebrosidase haploinsufficiency in A53T a-synuclein mice impacts disease onset and course.
Academic Article Cost Effectiveness of Karyotyping, Chromosomal Microarray Analysis, and Targeted Next-Generation Sequencing of Patients with Unexplained Global Developmental Delay or Intellectual Disability.
Academic Article Author Correction: Applications and efficiencies of the first cat 63?K DNA array.
Academic Article Applications and efficiencies of the first cat 63K DNA array.
Academic Article Author Correction: Applications and efficiencies of the first cat 63K DNA array.
Academic Article High-Throughput Mass Spectrometry Assay for Quantifying ?-Amyloid 40 and 42 in Cerebrospinal Fluid.
Academic Article Gaucher disease and SARS-CoV-2 infection: Emerging management challenges.
Academic Article Gaucher disease in the COVID-19 pandemic environment: The good, the bad and the unknown.
Concept High-Throughput Nucleotide Sequencing
Concept S100 Calcium Binding Protein beta Subunit
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