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Genetics Department, BRB 624
Case Western Reserve University School of Medicine
10900 Euclid Avenue
Cleveland, OH 44106-4955 |
Principal
Investigator and Contact
Joseph H. Nadeau, Ph.D.
216-368-0581 or 0626; Fax: 216-368-3432
E-mail:
jhn4@pop.cwru.edu
Additional Contact
Eric Lander, Ph.D.
Whitehead Institute
Center for Genome Research
617-252-1906; Fax: 617-252-1933
E-mail:
lander@genome.wi.mit.edu
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To develop and characterize mouse models for genetically
complex human traits and diseases, with emphasis on linkage
analysis, modifiers, expression assays, risk factors, and
enzyme and protein assays.
Development and characterization of new mouse strains for
complex trait analysis. Development and application of new
assays for metabolite levels, enzyme activities, and gene
expression patterns in laboratory mice.
This resource is in an early stage of development. Novel
inbred strains for complex trait analysis are being
produced. Panels of consomic strains (also known as
chromosome substitution strains) with C57BL/6J and A/J as
progenitor strains. Contact principal investigator for
listing of strains available.
Index Terms
Chromosome substitution strains, complex traits, consomic
strains, genetic analysis, mouse models, mouse strains,
risk factors.
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University of California, Davis
Department of Anthropology
209 Young Hall
Davis, CA 95616
URL: www.anthro.ucdavis.edu/~dgsmith |
Principal
Investigator and Contact
David Glenn Smith, Ph.D.
530-752-6343, 8570, or 6665; Fax: 530-752-8885
Message: 530-752-0745
E-mail:
dgsmith@ucdavis.edu
Additional Contacts
Sreetharan Kanthaswamy
530-752-8570
E-mail:
skkanthaswamy@ucdavis.edu
Joy Viray
530-752-8570
E-mail:
jlviray@ucdavis.edu |
Identify and characterize previously unknown (including
PCR-amplified mitochondrial DNA and Y-chromosome, class II
MHC and microsatellite DNA or STR loci) polymorphisms;
study the effectiveness of alternative genetic management
strategies and the effect of demographic factors on the
population/genetic structure of captive groups of primates;
identify marker loci for genes that influence
susceptibility to retroviral, B-virus, and other
infections; and employ both ancient and contemporary
mitochondrial DNA and microsatellite DNA loci for studies
of ancestor-descendant relationships.
To Collaborating Scientists and Graduate Students
All principal investigators of NIH-supported
specific-pathogen-free (SPF) breeding programs or their
designees are eligible to request genetic marker analysis
on rhesus macaques (Macaca mulatta), crab-eating
macaques (M. fascicularis), pigtailed macaques
(M. nemestrina), and other species of Macaca
and Papio in SPF colonies; identify paternity;
calculate kinship and inbreeding coefficients; determine
country of origin; estimate parameters of genetic
diversity, genetic subdivision, and founder representation
within the colony; and collaborate with principal
investigators on colony management strategies and on
research involving those data; amplify and sequence
noncoding control region of mitochondrial DNA extracted
from modern and prehistoric (e.g., skeletal) material.
Index Terms
Colony management, country of origin, genetic diversity,
genetic marker, inbreeding, kinship, macaques,
mitochondrial DNA, paternity, STR loci. |
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Genetic Disease
School of Veterinary Medicine
University of Pennsylvania
3800 Spruce Street
Philadelphia, PA 19104-6051 |
Principal
Investigator and Contact
Mark E. Haskins, V.M.D., Ph.D.
215-898-4852; Fax: 215-898-0719
E-mail:
mhaskins@vet.upenn.edu
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A major objective is the identification of animal homologs
of human disease not previously recognized. After initial
ascertainment, potential models are characterized at the
clinical, pathologic, and biochemical levels and their
homology with the human disorder is assessed. Another
objective of the center is to establish a small breeding
colony for each promising model. Models in which there is
strong evidence of homology and that offer opportunities
for investigation of pathogenesis and therapy not currently
feasible in humans and not available in other species are
further pursued.
Current projects involved in the characterization of animal
models with inherited metabolic diseases that are potential
targets for research on gene therapy include: Alpha
mannosidase deficiency (alpha-mannosidosis); erythrocyte
pyruvate kinase deficient hemolytic anemia; branching
enzyme deficiency (glycogen storage disease IV);
mannose-6-phosphorylase deficiency (I-cell disease) in the
cat; beta-glucuronidase deficiency (mucopolysaccharidosis
VII) in the dog and cat; cystinuria in the dog (renal basic
amino acid transport, RBAT gene); X-linked severe combined
immunodeficiency (common gamma chain mutation), myotonic
myopathy (chloride channel mutation); and
phosphofructokinase deficiency in the dog. The
species-specific genes for these disorders have been cloned
or are in the process of cloning and characterization by
the center, in collaboration with other investigators.
Small nuclear animal colonies of these models are
maintained for study. The center is collaborating with Dr.
David Wenger of Thomas Jefferson University Medical School
to manage a colony of dogs with galactocerebrosidase
deficiency (globoid leukodystrophy, Krabbe's disease) for
studies of gene therapy of this disorder. The canine gene
was previously cloned and characterized in Dr. Wenger's
laboratory. The center is also characterizing a number of
other promising models for the study of genetic disease
pathogenesis and gene therapy that have not yet reached the
level of molecular genetic characterization. These include
X-linked anhydrotic ectodermal dysplasia; autosomal
recessive osteogenesis imperfecta; juvenile dilated
cardiomyopathy; and tricuspid valve dysplasia.
Cloning and Characterization of Animal Model Disease
Genes
This function is limited by resources to genes for diseases
in which the studies can lead to further understanding of
pathogenesis in ways not possible in human patients, or
which are reasonable candidates for gene therapy studies.
Contact Paula Henthorn, Ph.D., 215-898-9061, Fax:
215-573-2162, E-mail:
henthorn@vet.upenn.edu.
Gene Therapy
Potential models for research on gene therapy are evaluated in the context of the present status of the field and the availability of other animal models through contacts with other investigators. Contact Dr. Mark Haskins, 215-898-4852, E-mail: mhaskins@vet.upenn.edu.
Consultation and Diagnostic Services
The center provides consultation, certain diagnostic
services, and preliminary genetic studies to facilitate the
discovery and preservation of new and potentially useful
animal models. Emphasis is primarily on, but not limited
to, models that occur in domesticated species. Services
depend on preliminary consultation and evaluation of the
potential model by scientists at the referral center. These
general classes of genetic diseases are emphasized:
Hereditary Metabolic Diseases
Includes inborn errors of amino acid, organic acid,
carbohydrate, and glycosaminoglycan metabolism, enzyme,
receptor, and transporter defects. Contact Dr. Urs Giger,
215-898-8830, E-mail:
giger@vet.upenn.edu.
Hereditary Defects in Sexual Development
Includes male and female pseudohermaphroditism, sex
reversal, and true hermaphroditism. Contact Dr. Mark
Haskins, 215-898-4852, E-mail:
mhaskins@vet.upenn.edu.
Hereditary Congenital Malformations
Includes congenital heart disease and anomalies of other
organ systems. Particular emphasis given to isolated
malformations or malformation syndromes that may be due to
chromosomal anomalies or defects in single major genes.
Contact Dr. Mark Haskins, 215-898-4852, E-mail:
mhaskins@vet.upenn.edu.
Hereditary Hematologic Diseases
Includes defects in erythrocytes, leukocytes, and
hemostasis (bleeding disorders). Contact Dr. Urs Giger,
215-898-8830, E-mail:
giger@vet.upenn.edu.
Hereditary Diseases of Immune Function
Includes immunodeficiencies and autoimmune disorders.
Contact Dr. Urs Giger, 215-898-8830, E-mail:
giger@vet.upenn.edu
or Dr. Peter Felsburg, 215-898-6678, E-mail:
felsburg@vet.upenn.edu.
If an affected animal is believed to represent a
potentially new and useful model after the initial
consultation, the following services are available:
Clinical Examination
Arrangements for transporting the affected animal to the
center are usually the responsibility of the veterinarian
or other investigator who makes the referral. If an animal
shows sufficient promise as a disease model, the center
pays shipping charges. Physical examinations and routine
diagnostic tests are performed. If the animal is owned by
the client and the examination is primarily in the owner's
interest, a reduced fee for clinical services is charged to
the owner.
Postmortem/Biopsy Examinations
If biopsy specimens are to be sent after initial
consultation, the center provides instructions for tissue
fixation and may provide fixatives where needed. Complete
postmortem examinations include gross and microscopic
studies of organs and tissues, electron microscopy, and
special histochemical stains. Some tissues may be stored or
cells cultured and stored for metabolic studies, and DNA
may be prepared for other tests.
Metabolic Disease Screening
This consists of a series of chromatographic and spot tests
designed to detect abnormalities in the types or
concentrations of metabolites in body fluids. Urine and
serum are usually submitted for initial studies. If
screening reveals evidence of a metabolic defect, the
abnormal metabolites are further evaluated, as appropriate,
by gas/liquid chromatography, amino acid analysis, mass
spectrometry, enzyme assay, or other laboratory methods.
Hematologic Evaluation
If the initial evaluation suggests an inherited hematologic
defect, appropriate erythrocyte, platelet, leukocyte, and
macrophage function tests are performed.
Other Biochemical Studies
Results of histologic studies and/or metabolic screening
determine the additional studies required. Such
examinations include studies of the concentrations of
specific substrates in tissues and body fluids by
gas/liquid chromatography and mass spectrometry, as well as
assays of specific enzymes, receptors, and transporters.
Cytogenetic Studies
Currently these studies are confined to the dog and cat and
include standard and Giemsa-banded karyotyping and
fluorescence in situ hybridization (FISH). These studies
are available only on a limited basis and are conducted
when preliminary studies yield sufficient evidence to
suspect a chromosomal anomaly or when the physical location
of the disease gene locus is to be mapped.
Pedigree Analysis
When family data are available or family studies are
possible, the center classifies the phenotype of family
members and examines pedigree patterns for consistency with
various modes of inheritance.
Breeding Studies
The center maintains an animal colony facility that can
house a limited number of affected animals and their close
relatives for breeding experiments designed to verify
whether a defect is inheritable and to determine the mode
of inheritance. These studies depend on whether affected
animals and their relatives can be obtained as donations or
purchased.
Fees for Diagnostic Services
There is no charge for initial consultation with
veterinarians or other investigators in the center.
Subsequent studies also are free of charge if considered
appropriate by investigators at the center. When clinical
and postmortem examinations are primarily in the interest
of an animal's owner, the owner is charged, usually at a
reduced rate.
Availability of Models to Investigators
Another objective of the center is to establish a small
breeding colony for each promising model, but the center
usually does not serve as a source of animals to be used
directly in studies by outside investigators because of
limited financial and physical resources. However, once
initial characterization of the model is completed, with
sufficient lead time breeding stock or semen can be made
available to those who wish to start their own breeding
colonies. Breeding stock or semen currently is available
for the following models:
Hereditary defects of the conotruncal septum (tetralogy of
Fallot, ventricular septal defect, persistent truncus
arteriosus): dog; hereditary patent ductus arteriosus: dog;
mucopolysaccharidosis VI (arylsulfatase B deficiency): cat;
phosphofructokinase deficiency (glycogenosis type VII):
dog; erythrocyte pyruvate kinase deficiency: cat; alpha
mannosidosis (alpha mannosidase deficiency): cat.
Index Terms
Animal homolog, animal models, congenital malformation,
diagnostic services, disorders of sexual development,
genetic diseases, hematologic disease, hereditary disease,
immunologic disease, metabolic diseases. |
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