SELECTED
INTRAMURAL RESEARCH ACCOMPLISHMENTS
19932001
Organized According to Government Performance and Results Act Goals
Goal
A: Add to the body of knowledge about normal and abnormal biological functions
and behavior
Identification
of disease genes
AP-3, a major component of the protein trafficking system, and HPS-1:
defective in two forms of Hermansky-Pudlak syndrome (NICHD)
p16 and CDK4 mutations: responsible for familial melanoma (NCI, NHGRI)
Transcription factor POU4F3, cadherin 23 (Usher syndrome 1D), and claudin
14: involved in familial deafness syndromes, including Pendred syndrome
(NIDCD, NHGRI)
Defect in the regulatory subunit of cAMP-dependent protein kinase: involved
in Carney complex inherited cancer syndrome (NICHD)
Defect in cholesterol synthesis pathway gene: involved in Smith-Lemli-Opitz
syndrome (NICHD)
Mutations in multifunctional ATM gene: responsible for ataxia telangiectasia
(NHGRI)
Mutations in Fas receptor and other steps in JAK-STAT pathway: responsible
for autoimmune lymphoproliferative syndrome and other forms of immunodeficiency
(NIAID, NHGRI, NIAMS, NCI)
von HippelLindau gene: responsible for a familial cancer syndrome
(NCI, NICHD)
MET: involved in papillary renal carcinoma (NCI)
BRCA1 and BRCA2 mutations: major inherited causes of breast cancer (NIEHS);
estimation of their contribution to risk of breast, ovarian, and prostate
cancer (NCI)
IL-1b and IL-RN polymorphisms: linked to gastric
carcinomas (NCI)
Mutations in the a-synuclein gene: associated
with Parkinsons disease (NHGRI, NIMH)
Identification of transporter responsible for Niemann-Pick disease (NHGRI,
NINDS, NIDDK)
Identification of genes involved in familial Mediterranean fever and familial
hybernium fever (NIAMS, NHGRI)
Gene for multiple endocrine neoplasia (MEN) isolated and initially characterized
(NIDDK, NHGRI, NINDS)
Mutations in the patched gene: hereditary cause of nevoid basal
cell carcinoma syndrome (NCI)
Myosin 15 gene: responsible for nonsyndromic deafness (NIDCD)
Serotonin 1B receptor: candidate gene predisposing to alcoholism (NIAAA)
ABC A1 cholesterol transporter: responsible for Tangier disease (NHLBI)
FOXL2 transcription factor: defective in premature ovarian failure (NIA)
Sarcomeric mutations: cause of familial hypertrophic cardiomyopathy (NHLBI)
Important
new animal models
Estrogen receptor a and b
knockout mice (NIEHS)
Cyclooxygenase 1 and 2 knockout mice (NIEHS)
Transgenic mice developed and validated for use in identifying environmental
carcinogens (NIEHS),
Knockout mice for metabolic disorders including Gaucher (NIMH), Tay Sachs
(NIDDK), and Fabry diseases (NINDS, NIDCR)
Mice that develop breast cancer (NIDDK)
Mice lacking fat (NIDDK, NCI)
Mice with chronic granulomatous disease (NIAID)
Mouse knockout of MEN1 gene (NIDDK, NHGRI, NCI)
Mice with cleft palate (NICHD)
Mice with glucose-6-phosphatase deficiency and classic glycogen storage
disease type I (NICHD)
Mouse models for Beckwith-Wiedemann syndrome and Wilms tumor (NICHD)
ABC A1 transporter knockout for studying cholesterol transport (NHLBI)
Myosin light-chain knockout and trans-genic mice for evaluating the role
of this protein in tissue structure and development (NHLBI)
p27, p21, and P27/p21 double knockout mice for evaluating vascular proliferation
diseases and stem cell engraftment (NHLBI)
Cyclin-dependent kinase inhibitor and apoE knockouts for analysis of atherosclerosis
formation and progression (NHLBI)
Basic
discoveries in cell, molecular, and structural biology with implications
for the treatment of human disease
Identification of taste and pheromone receptors (NIDCD)
Improved understanding of signal transduction, including structure of
adenylate cyclase (NIDDK) and signaling via G-a-2
through Jun kinase and Rho (NIDCR)
Isolation and characterization of neural stem cells (NINDS)
Role of co-receptors in HIV entry into cells (first description of fusin
and demonstration that deletions in CCR5 lead to resistance to HIV infection)
(NIAID, NCI)
Mechanism of action of anthrax lethal factor through MAPKK signaling (NCI)
Structure of HIV integrase (NCI)
Structure and function of enzymes critical for HIV replication (NCI)
Discovery of prions in yeast (NIDDK)
Discovery that metalloproteinases increase after subclinical infection
of the amniotic cavity, thereby weakening fetal membranes and causing
25 percent of premature births (NICHD)
Demonstration that adult hematopoietic stem cells can give rise to cardiac
muscle and blood vessels in damaged mouse myocardium (NHGRI, NINDS)
Evidence that the dopamine transporter is the major molecular target for
cocaine and that the serotonin transporter may also be involved (NIDA)
Demonstration that endogenous marijuana-like substances (endocannabinoids)
in the brain contribute to regulation of appetite (NIAAA)
Purification and analysis of multiprotein complexes involved in faulty
DNA repair in premature aging syndromes (NIA)
Identification of nitroxides as a new class of antioxidants and protectors
against radiation (NCI)
Role of reactive oxygen species in cellular signal transduction in aging
and hormone action (NHLBI)
Demonstration that drug-associated cues that produce craving activate
brain "memory" pathways and structures (NIDA)
Ultrarapid visual reflexes that help people see clearly as they move are
disrupted in patients with strabismus (NEI)
Signal transduction pathways involved in the normal proteolytic processing
of a-crystallins are altered in cataracts (NEI)
Basic
discoveries in biology
Clarification of iron metabolism regulation at the translational level
(NICHD)
Role of small RNAs in regulation of genes responsive to oxidative stress
(NICHD, NCI)
Mechanisms of DNA recombination (NIDDK)
Transcription factors can have acetylating and de-acetylating activity
(NICHD)
Discovery of natural killer cell receptor that interacts with HLA class
I molecules (NIAID)
Identification and characterization of novel human mitochondrial DNA polymerases
(NIEHS)
Goal
B: Develop new or improved instruments and technologies for use in research
and medicine
Advances
in imaging
Improved methods to use NMR for structural determinations of proteins
(NIDDK)
New approaches for functional MRI applications to cardiac and brain imaging
(NHLBI, NINDS, NICHD)
New imaging contrast mechanism in MRI based on the exchange of magnetization
of water with macromolecules, termed magnetization transfer contrast (now
used in most commercial MRI scanners) (NHLBI)
Improved 3-D tomographic reconstruction techniques for virology, small
animal, and clinical imaging (CIT, NIAMS, CC, NCI)
New optical reflectance spectroscope for clinical optimal imaging (NICHD)
Hall effect imaging, a new modality based on the interaction of ultrasound
with biological tissues in high magnetic fields (NHLBI)
Advances
in bioinformatics
Database development, including dbEST (NLM)
Software development, including universal medical language (NLM)
Web sites, including PubMed (NLM), visible human project (NLM), cGAP (NCI,
CIT), human genome site (NHGRI, NLM), and the clinical trials database
(NLM)
Advances
in biotechnology
Development of spectral karyotyping for all human chromosomes (NHGRI)
Development of laser capture microdissection technology (NCI, BEPS, NICHD,
CIT)
Goal
C: Develop new or improved approaches for preventing or delaying the onset
or progression of disease and disability
Vaccine
development
Clinical testing and FDA approval of vaccines against Haemophilus influenza
(NICHD), hepatitis A (NIAID), and rotavirus (NIAID) (rotavirus vaccine
use currently being evaluated)
Polysaccharide conjugate vaccines against Salmonella (typhoid) and Shigella
in successful clinical trials (NICHD)
Successful use of acellular pertussis vaccine in Sweden (NICHD)
New vaccine against Escherichia coli 0157, now being tested (NICHD)
Preclinical work underway for a vaccine against papillomavirus (NCI) and
B19 parvovirus (NHBLI)
Improved
chemoprevention of disease
Caloric restriction delays aging in nonhuman primates (NIA)
Monoclonal antibody against respiratory syncytial virus (NIAID)
Vitamin E supplementation reduces risk of prostate cancer (NCI)
Antioxidant combination of b-carotene, vitamin E, and selenium reduces
risk of stomach cancer (NCI)
Diet high in carotenoids or other dietary antioxidants is associated with
a decreased risk of neovascular age-related macular degeneration (NEI)
Goal
D: Develop new or improved methods for diagnosing disease and disability
Gene
Expression Patterns
For diagnosis (and treatment) of breast and prostate cancer, among others
(NHGRI, NCI, CIT)
For diagnosis (and treatment) of anemias, hyperlipidemias, and vascular
diseases (NHLBI)
For evaluation of mechanisms of environmental toxicants (NIEHS)
To analyze the aging process (NIA)
(Note:
See "Goal A" for new diagnostic tests based on isolation of
the disease gene)
Goal
E: Develop new or improved approaches for treating disease and disability
Improved
disease treatment
Taxol to reduce smooth muscle hyperplasia after angioplasty (NIA)
High-dose immunosuppression to treat autoimmune aplastic anemia (NHLBI)
a-Glucosidase replacement therapy for Fabry
disease (NCI)
Immunotoxins to treat cancer (NCI)
IL-2 with HAART to improve HIV and AIDS treatment (NIAID)
Cysteamine to treat cystinosis (NICHD)
Growth hormone to treat osteogenesis imperfecta (NICHD)
Uteroglobin to treat IgA nephropathy (NICHD)
Successful gene therapy for chronic granulomatous disease (NIAID)
Plasmapheresis to treat pediatric autoimmune neuropsychiatric disorders
associated with streptococcus (NIMH)
Synthesis of novel cocaine analogs to treat cocaine dependence (NIDA)
Stem cell allotransplantation to treat metastatic renal cell cancer and
metastatic melanoma (NHLBI)
Paclitaxel to treat Kaposis sarcoma (NCI)
Hydroxyurea to treat sickle cell anemia and inhaled nitric oxide to treat
pulmonary hypertension in sickle cell anemia (NIDDK, NHLBI, CC)
Treatment guidelines for diabetic retinopathy (NEI)
New therapies for the ocular complications of AIDS (NEI)
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