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National Institutes of Health (U.S.) Division of R.

Report of program activities : National Institutes of Health. Division of Research Resources (Volume 1975) online

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with a total funding of $6.6 million. In addition, the 432 collaborative
scientists from a number of universities utilized the facilities to conduct
research on 127 grants and contracts with a total funding of $11.0 million.
.The Centers also provided the research environment for 163 graduate students
to undertake their thesis research. The program provided salary support
for 170 doctoral level staff and 706 technical and administrative personnel.

During this year, the problem of obtaining sufficient primates for research
purposes reached a critical stage; therefore, it became necessary to
significantly increase the domestic production of the primate species
commonly used in the research programs . The Centers have provided the
necessary basic knowledge required in the establishment of large primate
breeding programs and are developing plans to expand their breeding
programs in order to become self-sufficient in the production of primates
for their own needs . They are currently producing approximately 50 percent
of their annual requirements for experimental primates with a total of
1055 infant primates being produced during this year. The missions and
examples of research accomplishments at each of the Centers are as follows :

OREGON PRIMATE RESEARCH CENTER

The missions of this Center are reproductive biology, cardiovascular
diseases, and metabolic and immune diseases. The following is an example
of their research accomplishments :



11



Effects of Development and Early Nutrition on Brain Composition:

In all species, aging is accompanied by a sequence of changes in the
composition of the different parts of the central nervous system. During
the period of most rapid change, a given area is usually susceptible to
various insults, including nutritional deprivation. The rhesus monkey
has been used for a correlative biochemical, histological and behavioral
study of the effects of maternal and infant protein malnutrition on the
development of the young. It was found that protein malnutrition during
early development reduced the size of the brain, particularly the brain
stem.

DELTA PRIMATE RESEARCH CENTER

The primary mission of this Center is infectious disease research and an
example of their research activities is as follows:

Potential Developments of a Vaccine for Chickenpox:

There were 121,985 cases of chickenpox in the United States during 1974
and 90 percent of these occurred in children under 10 years of age.
Currently, there is no effective vaccine available as a suitable animal
host for the development and testing of a vaccine has not been identified.
A recent outbreak of a disease among a colony of monkeys at this Center
has been identified as being caused by a virus almost identical to the
chickenpox virus (varicella) in man. It is believed that the monkey will
serve as a model for the development and testing of vaccines against
this human disease. In addition, it will provide an opportunity to study
the manner in which this virus can remain dormant in human tissue and
then reactivate years later to cause diseases like zoster and shingles.

YERKES PRIMATE RESEARCH CENTER

The missions of this Center are neural and behavioral research and the
study of neoplastic diseases. This Center has the largest colony of
great apes available anywhere in the world for biomedical research.
The following is an example of their research:

Development of a Remotely-Controlled Injection and Blood Withdrawal System:

In a number of research and clinical problem areas, there are needs for
assessing variations in blood constituents in unanesthetized, ambulatory
animals. Scientists at this Center have designed an instrument that can
be worn by humans and primates that is remotely controlled through a
radio link. This device enables them to withdraw blood samples through
an indwelling catheter, flushing the catheter between samples to achieve
separation. Telemetry is incorporated into the design of the instrument
so that the temporal sequence of events is signalled to the investigator
without any cue to the subject. The infusion capabilities of the device
enables the investigators to inject, intravenously, biologically active
substances and to then measure their subsequent blood levels or effects.
This device is now being used in research on alterations in endocrine

12



activity that are induced as consequences of stimulation of the central
nervous system and in response to the stress of social environments.

WASHINGTON PRIMATE RESEARCH CENTER

The mission of this Center is research in neurophysiology relating to the
cardiovascular system and the support of 'an extensive collaborative
research program involving a number of scientists in many disciplines.
The following is an example of the research conducted at this Center:



Sudden Infant Death Syndrome:

This research using infant monkeys is directed toward identifying factors
which may be involved in human crib deaths. These studies are focused on
observations made by pathologists and others who have done extensive autopsy
studies on crib death babies. Baby monkeys can be brought to the point of
death by stimulating the nerves controlling the muscles of the larynx.
In addition, the reflex pathways which serve to protect the larynx and the
balance of the airways can be stimulated in a manner which results in
death of the infant monkey. This result cannot be obtained in adult
monkeys. This would indicate that the upper airways of infants can be thrown
into a spasm which impairs respiration and other vital functions. These
investigations also suggest that infant monkeys are sensitive to reduced
oxygen in the air, and breathing a low-oxygen mixture alters their sensi-
tivity to other stimulation. This indicates that changes in the composition
of the air breathed by human infants can produce adverse effects upon the
respiratory system. These studies are important for the identification
and investigation of factors which could not otherwise be evaluated in human
infants as potential contributors to crib death.

WISCONSIN PRIMATE RESEARCH CENTER

Neural and behavioral sciences and reproductive biology are the basic
missions of this Center. An example of their research accomplishments is
as follows:

Primate Ecology

A new program in primate ecology was established during this year and is
the only activity of this nature in the Primate Research Centers Program.
A senior investigator will undertake extensive field studies in Cameroon
on a number of African primate species. These studies concern the con-
servation of some of Africa's endangered species and the determination of
whether the more common species of African primates can play a greater
role as subjects in future biomedical research. The latter goal is
especially important due to the reduced imports of primates from India
and other countries .

NEW ENGLAND PRIMATE RESEARCH CENTER

The core staff of this Center is conducting research in areas of infectious
diseases and primate pathology. In addition, a number of collaborative






13



scientists from several institutions conduct a major portion of their
research activities at this Center. The following is an example of the
research activities undertaken at this Center.

New Technique for the Identification of Microfilaria:

A technique has been developed which allows precise identification of
circulating parasite larvae in peripheral blood. Identification of these
parasites, heretofore, was exceedingly difficult and, in some cases,
impossible. The method utilizes the location of the enzyme, acid
phosphatase, within the parasite. This method has been used to identify
two filarial parasites of humans which were almost impossible to tell apart
with other techniques. Their differentiation is important as one causes
disease and the other does not.

CALIFORNIA PRIMATE RESEARCH CENTER

The mission of this Center is in the area of infectious diseases and
environmental health sciences, and one of their research accomplishments
is as follows:

Effects of Ozone on Pulmonary Function:

In these studies, monkeys were exposed to 0.2, 0.35, 0.5, and 0.8 ppm
of ozone for 8 hours per day on 7 consecutive days. These concentrations
of ozone range down to the oxidant level not uncommon in regions severely
affected by air pollution. Lesions were produced in lungs of all ex-
perimental monkeys with more severe lesions caused by the higher
concentrations of ozone. Most of the damage occurred in the respiratory
bronchioles; the response being characterized by hyperplasia and hypertrophy
of nonciliated bronchiolar epithelial cells. Large conducting airways
were also affected, but in a more random pattern. The similarities in the
morphology of distal airways in man and the monkey, and the localization
of the ozone-induced lesions in the respiratory bronchioles of the latter,
make the monkey particularly useful for studies concerning the long-term
relationships between air pollution and respiratory diseases In man.

LABORATORY ANIMAL SCIENCES PROGRAM

The Laboratory Animal Sciences Program (LASP) assists institutions in
developing and improving animal resources for biomedical research and
training through the award of research and resource grants. Currently
active program areas include support for animal colonies of unusual and
special value for research; studies directed at finding animal models
which are needed for research on human diseases; projects to assist
institutions to comply with the legal and policy requirements for care of
laboratory animals; laboratories for the diagnosis and control of disease
of laboratory animals; research related to improving health care and
determining environmental requirements of animals used in research;
reference and information centers dealing with selected problems; and
training of specialists in the field of laboratory animal medicine.
The program awarded funds totaling $7,782 million in fiscal year 1975,

14



which supported 88 discrete animal research and resources projects,
5 training programs, 6 fellowship awards, and 10 contracts.

ANIMAL MODELS AND SPECIAL COLONIES

The major objectives of this program area are (1) to define, characterize
and exploit the relevant biological attributes of selected animals which
display potential for use in several areas of biomedical research;

(2) to establish, improve or expand special colonies of well characterized
animals which are of proven value for specialized areas of biomedical
research, but which are not generally available from other sources; and

(3) to preserve unique and valuable stocks and strains of animals which
may otherwise be lost due to particular circumstances.

Support for projects related to the establishment of special animal
colonies and animal model development has remained rather static during
the past several years. Twenty-one projects in these categories were
supported during FY 1975 (approximate total of $1,267 million), as
compared to 22 projects supported during FY 1974 (approximately $1,250
million) and 20 projects supported during FY 1973 ($1,141 million).

The majority of the currently active projects in these categories are
related to vertebrate species (e.g., rats, mice, guinea pigs, hamsters,
dogs, rabbits, nonhuman primates, armadillos, degus , etc.). One of the
projects very recently funded relates to the investigation of systems
for the laboratory culture and maintenance of sea urchins. Support has
also been provided for model development and/or special resources of
several species of invertebrate animals, e.g., rare species of Drosophilia
and Xyleborus (wood-boring beetle) . Two contracts were awarded during
the past year for development of laboratory mariculture techniques to
rear and maintain species of Aplysia (sea-hare) and two related species
of marine gastropods (i.e., Hermissenda and Pleurobranchaea ) . Both
studies have reported good progress to date. If successful, methodology
will become available for the cultivation and rearing of these marine
invertebrate species in any laboratory, thus precluding problems of
uncertain health status and seasonal availability from their native marine
habitats which currently confront researchers.

Projects devoted to the definition, characterization and development of
new types of animal models have generally been limited to those species
or strains which evidence good potential for use in several disciplines or
disease categories. Full exploitation of the potential usefulness of
such animals normally requires the efforts of investigators in several
disciplinary areas over an extended time period.

Examples of model development projects currently supported by the LASP
include:

1. Studies at Washington State University on inherited neurological
types of diseases including leukodystrophy, an autosomal recessive
trait in cats; progressive myoclonic epilepsy (La Fora's Disease)



15






. !-



in dogs; Ehlers-Danlos syndrome, an autosomal dominant disorder in
dogs and mink; a lower motor neuron disease in dogs; and a lysosomal
disorder of cats similar to the mucolipidoses of children.

2. The characterization of eight strains of germfree mice and three
strains of germfree rats for use in several research areas, including
gerontology, cancer therapy and environmental pollutants at the
Lobund Laboratory, Notre Dame University.

3. The biological characterization and development of 10 new inbred
lines of Syrian hamsters which were derived from the first animals to
be brought to the United States from their native source in Syria
since 1930. These new inbred lines have good potential as
appropriate models for many areas of health-related research,
including studies of viruses, aging, hibernation, dental caries,
transplantation, tumor induction, myopathy, etc.

4. A colony of PBB/Ld mice at the University of Alabama Medical
Center which have high concentrations of plasma cholesterol and
triglycerides are being characterized and developed as a potential
model of familial hyperlipoproteinemia, Type IV (Fredrickson) ,
This inbred mouse strain also shows considerable promise as a model
of obesity and dental caries.

5. A colony of squirrel monkeys at the Bowman Gray School of
Medicine which are being studied as potential models of cholelithiasis,
chronic glomerulonephritis and the nephrotic syndrome, and lactose
intolerance.

Examples of ongoing projects which provide support for the maintenance of
special colonies and serve as institutional and/or national resources
include:

1. A colony of genetically obese rats (Harriet G. Bird Foundation,
Stow, Massachusetts) which serves as a resource for many
investigators in nutritional and metabolic research.

2. A resource of gnotobiotic mice, rats, guinea pigs and rabbits
which is being made available from the Lobund Laboratory of Notre
Dame University to the biomedical community for studies including
cancer induction and chemotherapy, immunosuppression, and bone
marrow transplantation.

3. A colony comprised of highly inbred lines of rabbits at the
University of Illinois College of Medicine which are utilized as
models for studies of transplantation, immune response and
cancer immunotherapy.

4. A colony of nine-banded armadillos at the Gulf South Research
Institute, New Iberia, Louisiana, which has contributed sig-
nificantly to recent breakthroughs in the use of this animal as

a model for studies on human lepromatous leprosy and production
of purified leprosy antigen for prognostic skin testing of human



16



lepers .

5. A colony of Inbred strains and mutant-bearing stocks of rabbits
at the Jackson Laboratory, Bar Harbor, Maine, which are made widely
available to investigators of important human disease conditions
including ataxia, epilepsy, buphthalmia, lymphosarcoma, hemolytic
anemia, renal cysts and mandibular prognathism.

6. A resource colony of degus (a South American rodent) at the
University of Vermont which is useful for research in immundlogy
and development of eye cataracts .

7. A resource of rare Drosophila species at the University of
Texas which is made available to investigators in research areas
such as cytogenetics, biochemical genetics, behavior, evolution and
taxonomy .

During FY 1975, 14 of these special colony resources provided support
for 70 NIH-funded research projects with a total funded value of
$5,331,000 and 130 biomedical research projects which received funding
from other sources (total research funding value of $3,400,000).

Only one institutional nonhuman primate resource received support during
FY 1975. Support for this area has gradually diminished over the past
several years due to a general LASP policy that well established primate
resources should become financially self-sufficient through charges to
users for their maintenance operation. However, the initial establish-
ment of primate resources at institutions for interdepartmental usage
is of proven value and remains as an eligible area in the Program.
The LASP has continued to assess its possible role in the support of areas
which are experiencing critical shortages of experimental animals. For
example, -the acknowledged national shortage of frogs from their native
habitats prompted the organization of a conference on this subject under
LASP auspices in March, 1975. The future role of the LASP in supporting
studies to alleviate the shortage of frog resources for biomedical
researchers is currently under active consideration.

INSTITUTIONAL ANIMAL RESOURCE IMPROVEMENTS

Upgrading of existing animal facilities and development of new centralized
animal resource programs has continued to be the most active program area.
Requests in this area usually include animal cages to meet current regula-
tions, general sanitation equipment such as cage washers, renovation of
animal facilities, and addition of trained professional and technical
personnel. The projects are supported for one to three years after
which time the applicant institution is expected to take over complete
financial responsibility for its basic animal resource. The amount of
funded research involving the use of animals and the sources of funding
are important factors in establishing funding priorities. The Program
Analysis Branch has identified 1433 projects ($90 million current
annual funding) involving the use of animals which are supported by NIH
at those institutions with currently active resource improvement projects.



17



Institutional improvement projects have been supported since the inception
of the Laboratory Animal Sciences Program; however, they received in-
creased emphasis beginning in FY 1972 when Congress appropriated an
additional $1.5 million. These funds were added to the regular budget
to help research institutions achieve compliance with the Animal Welfare
Act of 1970 (P.L. 91-579). The NIH policy on "Care and Treatment of
Laboratory Animals" (issued June 14, 1971) and the subsequent DHEW policy
on "Animal Welfare" (issued May 14, 1973) also contributed to the overall
response in this area. The following figures demonstrate progression of
support :



FY 1971



FY 1972 FY 1973 FY 1974 FY 1975




No. of Improvement Projects 14 24 28 46 38
Dollars Awarded (in $l,000's) 673 2,169 2,318 3,217 2,582
Percentage of LASP Budget 11% 35% 37% 55% 42%

The number of new applications for developing institutional animal resource
programs has continued at approximately the same level as last year
(FY 74 - 19, FY 75 - 21). Seventeen projects were recommended for approval
and 15 of these were funded. In addition, 4 of 7 projects from previous
years were supported making a total of 19 new projects ($2,143,950). The
three projects dating back nearly two years will be administratively with-
drawn. Thus, the large backlog of unfunded projects in this area which
developed over a period of several years has been reduced to two projects.

DIAGNOSTIC LABORATORIES

The objectives of these laboratories is to provide for improved animal
health programs through investigation of naturally occurring laboratory
animal disease, to support indepth studies resulting in new information
on disease processes and their etiology, to aid in the elucidation of
new laboratory animal models of human disease, and to develop resources,
including tissues, slides, photographs, etc., for research and training
in laboratory animal medicine and comparative pathology. There are 13
programs which are currently being supported ($1,217 million - 20% of
LASP budget) . A shortage of appropriately trained specialists (veterinary
pathologists and microbiologists) has been a limiting factor, precluding
any rapid establishment of new programs. However, two new laboratories
were funded during FY 1975. Special attention is being given to
laboratories which have the potential of serving more than one institution
in the same metropolitan area. Unfortunately, several proposals of this
type were not approved due to weaknesses in the projected staffing and
basic animal care program of the participating institutions.

By under girding an institution's animal health program, the laboratories
make a direct contribution to approximately 885 NIH supported research
projects using animals with total funding of nearly $56 million. In
addition to the service aspects of diagnosis, the laboratories have been
productive in terms of new information and techniques. In-depth studies
of laboratory animal disease problems resulted in over 70 publications
and presentations during the past year. The value of routine surveillance



18



activities continues to be demonstrated. Various suppliers of rats were
evaluated for the incidence of respiratory pathogens at one institution.
Providing this information to investigators coupled with changes in the
sources of supply resulted in a much lower incidence of disease in rat
colonies. Early recognition of Tyzzer's disease in newly received rabbits
resulted in modifications in quarantine procedures and control of this
potentially serious problem. One laboratory has continued its close
association with a major amphibian facility. Various disease problems
have been investigated and a number of publications have resulted. The
importance of diet as a source of aerobic gram negative bacteria isolated
from cloacal contents was established. These bacteria originated in
arthropods being fed as live food. A serious disease problem was reported
in one group of Rana pipiens due to naturally occurring infection with a
pigmented fungus. The fungus was transmitted experimentally to healthy
Rana pipiens , demonstrating a potentially serious clinical problem in
laboratory housed frogs. Several laboratories have been investigating
regional enteritis, a well known enzootic disease of hamsters. One
laboratory was able, for the first time, to establish conditions for the
experimental induction of this disease. Future studies to elucidate the
etiology and pathogensis will be pursued under a recently funded research
grant. A laboratory in Florida receives specimens from a number of
exotic species including reptiles and marine mammals. It was noted that
the BSP clearance time for healthy indigo snakes was 45-50 hours as
compared to times of 30 minutes in rat snakes. This study shows
promise in providing an important model for liver function studies. Another
potential model for retinitis pigmentosa in humans was discovered following
routine screening of an inbred colony of rats. The condition was found in
100% of the rats and was characterized as a slow, progressive degeneration
of photoreceptor cells.

RESEARCH PROJECTS

The Program has provided support to a relatively small number of discrete
research projects over the past several years. This may be summarized
as follows :



Number of Projects
Awarded (in thousands)
Percentage of Total $



FY 71 FY 72



FY 73



FY 74



FY 75



4


6


8


10


9


403


449


593


591


490


9%


7%


10%


10%


8%



Projects falling into this category generally have one of the following
objectives: (1) to investigate the etiology, pathogenesis, and control
of laboratory animal disease problems, (2) to determine various
environmental requirements of laboratory animals. For example, currently
active projects include studies of sialodacryoadenitis in the laboratory
rat, definition of environmental conditions for laboratory animals,
development of a vaccine to control feline viral rhinotracheitis, and
diagnosis and control of mammalian encephalitozoonosis. Work during the
past year on the latter project has resulted in the development of a new



Online LibraryNational Institutes of Health (U.S.) Division of RReport of program activities : National Institutes of Health. Division of Research Resources (Volume 1975) → online text (page 13 of 34)