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Search Results to Edward I Ginns MD, PhD

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Academic Background       

Edward Ginns completed his PhD in Physical Chemistry at Rensselaer Polytechnic Institute in NY, and went on to receive his MD from Johns Hopkins School of Medicine. Following a Medical Internship at Baltimore City Hospital, he trained in Neurology at Albert Einstein College of Medicine, NY. In 1980 he joined the Developmental and Metabolic Neurology Branch, NINDS at the National Institutes of Health in Bethesda, Maryland where he became a tenured Senior Investigator Neurologist in the Molecular and Medical Genetics Section. In 1986 Dr. Ginns transferred to NIMH as Chief, Section on Molecular Neurogenetics, NIMH. In 2000 he was recruited to the University of Massachusetts Medical School as founding Director of the Brudnick Neuropsychiatric Research Institute from the Intramural Research Program of NIMH where he was Chief, Clinical Neuroscience Branch and Supervising Scientist of the NIMH Transgenic and Targeted Gene Modified Mouse Resource. At the University of Massachusetts Medical School Dr. Ginns was founding Director of the Molecular Diagnostics Laboratory, and he is currently Director of the Program in Medical Genetics and the Lysosomal Disorders Treatment and Research Program. He is Professor of Neurology, Pediatrics, Psychiatry, Clinical Pathology and the Program in Neuroscience. Dr. Ginns is board certified in Neurology with a special interest in developmental and neurogenetic disorders. He is an elected member of the American College of Neuropsychopharmacology.

Research Areas

Our research is directed toward identifying and understanding 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.  Project areas include Gaucher disease associated Parkinsons, Ellis-van Creveld syndrome, and selected psychiatric disorders, including bipolar affective disorder, obsessive compulsive disorder and autism spectrum disorders. These disorders globally affect more than four hundred million individuals and comprise major causes of disability.  Patient symptoms are generally only partially responsive to treatment.  These illnesses are associated with other comorbid chronic conditions, shorter life span and situations having devastating effects on the quality of life of the individuals and their families. 


Despite compelling clinical-epidemiological evidence supporting a genetic susceptibility to develop major behavioral and mental disorders, the identification of the genetic variants and the associated underlying molecular mechanisms or pathophysiology for these disorders have remained elusive.  To circumvent this long standing problem, our approach utilizes an innovative strategy, based on leveraging the properties through which protective alleles exert their dominant effects on causative pathways, to uncover the root causes and molecular pathways responsible for the growing health care burden of mental illness.  Using bipolar affective disorder as a prototype, we have obtained convincing clinical, genetic and statistical data supporting the successful application of this protective allele based strategy.  Our studies identified the sonic hedgehog (Shh) signaling pathway as a key genetic pathway underlying bipolar disorder, a breakthrough that could lead to improved diagnosis and better drugs for treating bipolar affective disorder.

Bipolar Affective Disorder:            

Despite compelling evidence from many studies supporting a significant genetic susceptibility, elucidation of an underlying molecular mechanism causing bipolar affective disorder (BPAD) has remained elusive. Twin, family, and adoption studies have provided strong evidence for an important genetic component in the susceptibility to develop BPAD.   However, unlike for other common medical illnesses, genetic linkage studies have had to mainly rely on categorical diagnoses. Genetic heterogeneity, phenocopies, genotyping errors, and the complexities of performing and interpreting statistical analyses probably contribute to some of the inconsistences observed in genetic studies. Technologies to identify genetic factors associated with complex human disease have dramatically improved, but a major limitation to most current approaches has been the limiting theoretical framework derived from Mendelian genetics, and an incomplete understanding of complex disease physiology.  To date, most genetic studies of affective disorders have been limited to identifying genetic variants that increase the risk of disease. By contrast, I developed the novel hypothesis that there are protective genes, in addition to susceptibility alleles, for psychiatric disorders, and in particular for BPAD. 

            Decades of longitudinal research in collaboration with Dr. Janice Egeland and colleagues in Old Order Amish families of Pennsylvania revealed co-segregation of high numbers of a rare genetic dwarfism, Ellis-van Creveld (EvC), and bipolar disorder (BPAD) in a few special Old Order Amish families in the Amish Study descending from the same pioneer.  Despite more than forty years of research documenting the high prevalence of both EvC and BPAD in these families, no EvC individual has ever been reported with BPI. Our analyses confirmed the association between absence of BPI and the presence of EvC (P=.029, Fisher’s exact test, two-sided, confirmed by a permutation test), supported our hypothesis that EvC confers protection (i.e mental health wellness) from BPI, as well as suggesting a more general protection against the spectrum of affective disorders in these families.  This finding suggested that the genetic cause of this rare dwarfism had a molecular change that is protective of bipolar affective disorder.  Understanding how the Amish mutations causing EvC disrupted sonic hedgehog (Shh) signaling was key to uncovering the molecular mechanism underlying bipolar disorder

            We previously reported strong evidence for a BPAD locus with protective minor alleles(s) on chromosome 4p at D4S2949 and suggestive evidence for a locus on chromosome 4q at D4S397. The EVC and hedgehog interacting protein (Hhip) genes, were subsequently cloned and located within 5 million bases of our chromosome 4p16 and 4q putative loci for BPAD, respectively. The proximity of the EvC gene to our previously reported chromosome 4p16 BPAD locus, coupled with detailed clinical observations and statistical confirmation that EvC and BPI do not occur in the same Amish individuals, led us to postulate that the molecular mechanism underlying EvC is protective against BPI. Since homozygous Amish EVC mutations causing EvC dwarfism do so by disrupting sonic hedgehog (Shh) signaling, our data implicate Shh signaling in the underlying pathophysiology of BPAD. 

            Molecules in the sonic hedgehog signaling pathway transmit information required for regulation of where neurons are located during development and how the neurons function in the adult brain.  At a time when many pharmaceutical companies have all but abandoned the search for new treatments, connecting Shh signaling to bipolar disorder provides a mechanism with new targets for drugs that could dramatically change the way we treat this condition. Our discovery suggests that sonic hedgehog signaling can be modulated to help manage bipolar symptoms in adults by repurposing drugs used for other medical conditions. Shh signaling and reactivation occurring in a wide range of cancers, has led to identification of Shh signaling antagonists that are already in human clinical studies. Research collaborations are underway to unravel more details of the puzzle and to identify changes and biomarkers in the sonic hedgehog signaling and related pathways that correlate with disease symptoms.  Linking abnormal Shh signaling to affective disorders provides a concrete molecular and medical basis for patients’ symptoms.

Autism Spectrum Disorders: 

A goal of our research is to determine the extent and mechanisms by which sonic hedgehog (Shh) signaling is involved in the pathogenesis of ASD. 

Autism spectrum disorder (ASD) is a common developmental disorder affecting more than three million individuals in the US, with a 4:1 male to female occurrence.   Major clinical manifestations include impairments in verbal and nonverbal communication and social interaction that are often accompanied by repetitive, stereotyped behaviors and attention disturbances. Some individuals with ASD excel in visual skills, music, math and art. Most cases of autism appear to be caused by a combination of autism risk genes and environmental stress factors during early brain development. Several rare gene changes have been associated with autism, but the etiology of most cases remains unknown.

            Sonic hedgehog signaling has key roles in nervous system developmental regulation of neuron generation and localization, regeneration and neuronal electrophysiological activity.  Elevated serum levels of Shh protein have been reported in children with ASD.  Our studies should lead to a better understanding of ASD pathophysiology, identification of biomarkers and potentially translate into improved diagnosis and treatments. 

Obsessive Compulsive Disorder: 

We are using highly-accessible, inbred animal models for identifying causal factors that could provide a better understanding of the neurophysiologic pathways in canine compulsive disorder (CCD) and human compulsive disorder (OCD). Similarities in presentations in these devastating canine and human diseases and pharmacological responsiveness suggested common neurobiological etiologies.

Compulsive disorders are severe behaviors with onset in childhood that affect approximately 2% of the world population and cause great personal and societal burden.  They often disrupt academic, social and occupational functioning.  Current treatments are usually only partially effective in reducing symptoms, and often involve adverse side effects. There remains a major unmet public health need for better interventions and diagnostics. 

In addition to our finding that cadherin-2 (CDH2) confers risk for canine compulsive disorder (CCD) in Doberman pinschers, we have identified another locus that implicates serotonergic function.  We are now pursuing molecular and genomic signature studies to identify dogs at risk for CCD and identify and validate endophenotypes of genetic risk while continuing to identify additional risk variants.   Endophenotype studies are being integrated with genetics to identify modifying loci that exacerbate or attenuate compulsive disorder risk or severity. Using canine compulsive disorder as a prototype, we are bridging our canine findings to human compulsive disorders.  Our goal is to provide insights into mechanisms responsible for OCD, overcoming a critical barrier to developing more effective treatments and perhaps even prevention that would dramatically improve the quality of life of individuals both at-risk and currently suffering from this disorder.

Gaucher Disease Associated 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.

Rotation Projects

Potential Rotation Projects

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.

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 A triplet repeat on 17q accounts for most expansions detected by the repeat-expansion-detection technique.
Academic Article Update on the search for DNA markers linked to manic-depressive illness in the Old Order Amish.
Academic Article Identification of three additional genes contiguous to the glucocerebrosidase locus on chromosome 1q21: implications for Gaucher disease.
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 Association of an X-chromosome dodecamer insertional variant allele with mental retardation.
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 Two novel polymorphic sequences in the glucocerebrosidase gene region enhance mutational screening and founder effect studies of patients 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 Re-evaluation of the linkage relationship between chromosome 11p loci and the gene for bipolar affective disorder in the Old Order Amish.
Academic Article Human tyrosine hydroxylase (TH) genomic fragment (pHGTH4) identifies a PstI polymorphism.
Academic Article Linkage between the loci for autosomal dominant Charcot-Marie-Tooth neuropathy type 1 and human glucocerebrosidase.
Academic Article Gene mapping and leader polypeptide sequence of human glucocerebrosidase: implications for Gaucher disease.
Academic Article Joint multi-population analysis for genetic linkage of bipolar disorder or "wellness" to chromosome 4p.
Academic Article A canine chromosome 7 locus confers compulsive disorder susceptibility.
Academic Article Signal sequence and DNA-mediated expression of human lysosomal alpha-galactosidase A.
Academic Article Metaxin, a gene contiguous to both thrombospondin 3 and glucocerebrosidase, is required for embryonic development in the mouse: implications for Gaucher disease.
Concept Chromosomes, Human, Pair 17
Concept Chromosomes, Bacterial
Concept Chromosome Banding
Concept Chromosome Breakage
Concept Chromosomes, Human, Pair 4
Concept Chromosomes, Human, Pair 7
Concept Chromosomes, Human, Pair 6
Concept Chromosomes, Mammalian
Concept Chromosome Disorders
Concept Chromosomes, Human, Pair 22
Concept Chromosomes, Human, Pair 15
Concept Chromosomes, Human, Pair 11
Concept Chromosomes, Human, Pair 1
Concept Chromosome Mapping
Concept Chromosomes, Human, 1-3
Concept Chromosome Aberrations
Concept X Chromosome
Concept Chromosomes, Human, Pair 13

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