M Susan Smith - US grants

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. These studies focus on states of negative energy balance that are associated with a suppression of reproductive function. The identity of the specific metabolic signals or afferent neural pathways that convey information about energy balance to gonadotropin-releasing hormone (GnRH) neurons, the central hypothalamic system regulating reproduction, remains elusive. A key hypothesis of this project is that suppression of kisspeptin signaling is the primary factor in the inhibition of GnRH. Although it is a widely held view that hypoleptinemia is the critical factor linking energy balance and suppressed GnRH, our recent studies demonstrate that restoring leptin to normal physiological levels does not reverse the inhibition of kisspeptin or GnRH in either lactation or caloric restriction. Thus, hypoleptinemia does not appear to be the primary metabolic factor responsible for the suppression of reproductive function. Our hypothesis is that brainstem systems, such as glucose sensing neurons, may be the site where information about metabolic signals is relayed to kisspeptin neurons. This project focuses on two hypotheses: 1) Suppression of kisspeptin signaling at the site of GnRH cell bodies and at nerve fibers and terminals are primary components in its inhibition during states of negative energy balance, and 2) Brainstem systems serve as a site of integration of metabolic signals and provide the afferent signals that are responsible for the suppression of kisspeptin during negative energy balance. These studies will identify new pathways that regulate control GnRH neurons and could lead to new treatments for restoring fertility in states of negative energy balance.

Postpartum lactation in humans and monkeys is associated with ovarian quiescence attributed to suckling-induced deficits in GnRH secretion and hyperprolactinemia. The work proposed in this application would investigate the validity and nature of these mechanisms in the rhesus monkey, a primate in which the control of gonadotropin secretion and ovarian function appear similar to the human. 1. Because a reduced frequency of pulsatile GnRH release has the potential of disrupting normal gonadotropin secretion and ovarian cycles, the intermittent discharge of this hypothalamic hormone will be assessed indirectly by measuring pulsatile LH release in chronically catheterized monkeys nursing their infants. Moreover, changes in pulsatile LH release that might occur following abrupt removal of the infant will be recorded at several postpartum intervals. To relate the intensity of the suckling stimulus to the duration of gonadotropin suppression during lactation, some rhesus infants will be retricted to mother's milk during the usual period of weaning in an attempt to delay resumption of maternal pituitary function as assessed by pulsatile LH secretion and the positive feedback action of estradiol. 2. The possibility that the sensitivity of the hypothalamic-pituitary axis to the negative feedback action of estrogen is enhanced during lactation will be tested in ovariectomized monkeys bearing estradiol capsules that produce low circulating levels of the steroid. 3. Exogenous pulses of GnRH will be administered to nursing monkeys in an attempt to re-initiate pituitary and ovarian function. Moreover, the possible role of progesterone in mediating the inhibitory action of lactational hyperprolactinemia on ovarian follicular development will be investigated in monkeys with hypothalamic lesions receiving pulsatile GnRH replacement and progesterone capsules. 4. The central neural mechanisms underlying the inhibition of GnRH secretion in lactating monkeys will be studied by measuring pulsatile LH release during suckling following administration of antagonists to the endogenous opioid peptides, dopamine, and serotonin. These studies, which are difficult to perform under suitable controlled conditions in humans, will serve to delineate the mechanisms involved in lactational amenorrhea in a primate model.

[unreadable] DESCRIPTION (provided by applicant): [unreadable] The ONPRC proposes to purchase caging suitable for housing SPF male Indian-origin rhesus macaques (Macaca mulatta) used in AIDS related research. Increasing demands for SPF rhesus macaques for AIDS related research at the ONPRC and nationally has exceeded the supply efforts to expand production colonies to supply more animals has necessitated retention of female offspring for breeding, leaving male SPF rhesus macaques as the primary model for AIDS-related research projects. The Animal Biosafety Level 2 and 3 (ABLS2 and ABSL3) containment facility which houses animals for AIDS-related research at the ONPRC is not equipped with cages suitable for Group 4 male rhesus macaques. The existing cages do not have the 6.0 sq. ft. of floor space required by USDA and do not provide the option of social housing. It is very important that animals used in AIDS-related research have the opportunity to experience an enriched social environment. Requested in this application are 6.2 sq. ft. cages and associated equipment that will comply with USDA requirements for Group 4 male rhesus macaques and provide a wide range of options for environmental enrichment and social housing of NHPs used in AIDS-related research. [unreadable] [unreadable]

[unreadable] DESCRIPTION (provided by applicant): [unreadable] The renovation project is part of a long-range plan to expand rhesus macaque (Macaca mulatta) production at the ONPRC. The specific aim of this application is to alter and renovate the 30-year-old facilities associated with six one-acre corrals that hold SPF Indian rhesus macaque breeding colonies. The continued use of the corrals for rhesus macaque production is driven by the following: 1) the growth in research projects and the numbers of NHPs assigned to projects requires a substantial increase in the number of available NHPs; 2) the ONPRC is a national resource and must provide accessibility to investigators outside of the Center; 3) the long-range plan calls for the doubling of SPF breeding program to create a self-sustaining supply of NHPs; 4) the reserve capacity for animal housing must be expanded for proper animal management; and 5) the corrals are a cost effective method for breeding and raising animals into adulthood in a complex and environmentally rich social structure. Animals in the corrals are used as juveniles (research programs in AIDS, infectious diseases, developmental neurobiology), adults (research programs in immunology, neuroscience and reproduction) and retired breeders (research programs in aging). The renovation of the corral facilities will make them suitable for long-term use and includes the following: 1) convert the storage area between corrals four and five into a sheltered feeding area for corral five; 2) convert the existing corral five feeding area into an area for safe handling of animals; 3) upgrade the infrastructure (electric service, domestic water, sanitary sewer) for all rhesus corral facilities; 4) replace the deteriorated roofs on all feeding and holding areas; 5) replace damaged and worn metal panels on all structures; 6) repair and reseal concrete in all feeding and holding areas; 7) install additional radiant heaters and lights in all feeding and holding areas; 8) install a water pressure booster pump for wash down systems; 9) add perching to all feeding areas; and 10) replace deteriorating animal enrichment equipment in all corrals. This application will provide funds for the renovation of facilities associated with six one-acre corrals. The renovation is necessary for continued use of the corrals to expand rhesus macaque production and to comply with United States Department of Agriculture (USDA) policies and provisions of the Animal Welfare Act (AWA). [unreadable] [unreadable]

DESCRIPTION (provided by applicant): The Oregon National Primate Research Center (ONPRC) seeks funds to complete the second phase of a two-phase process of converting the Kroc quarantine building (Kroc) to an ABSL 3 facility. This facility will be used for Acquired Immune Deficiency Syndrome (AIDS)-related research using pathogens with aerosol transmission potential and for international quarantine of imported nonhuman primates (NHPs). Our longterm objectives are to: 1) provide ABSL 3 NHP housing facilities suitable for AIDS-related research; 2) protect immunodeficient NHPs used in other AIDS-related research; and 3) improve facilities for international quarantine of imported NHPs. The Kroc quarantine facility has been designated for international quarantine and ABSL 3 projects. The first phase of converting the Kroc to an ABSL 3 facility was completed August 2003. The second phase, requested in this application, will be accomplished with two specific aims. Specific Aim 1 proposes to purchase fixed and movable equipment for inclusion in the Kroc ABSL 3 facility (i.e., a pass-thru autoclave, redundant HVAC supply and exhaust equipment, an effluent kill tank, a downdraft necropsy table, a biosafety cabinet, a portable radiograph machine, an automatic x-ray film processor, and other miscellaneous equipment). Specific Aim 2 proposes alterations and renovations of the Kroc with installation of the purchased equipment to complete the conversion to an ABSL 3 facility.

[unreadable] DESCRIPTION (provided by applicant): [unreadable] The ONPRC requests funds to purchase primary housing units (cages and racks), psychological enrichment devices (play pens, porches and tunnels) and other related equipment used in housing non-human primates (NHPs). Our objectives are to provide housing for NHPs involved in NIH-sponsored AIDS-related research. The primary housing units will be installed in a newly constructed animal housing and support facility called Animal Services Building 3 (ASB3, approximately 35,000 sq. ft). With the expansion of research programs and the number of NHPs assigned to research projects, the need for NHP housing at the ONPRC has continued to grow. The ONPRC has been successful in obtaining NIH construction grants and institutional funds to greatly expand its animal housing facilities. ASB3 is the third addition to the original ASB and will add an additional 900 housing spaces for NHPs in cages and small group housing units. Many of the animals to be housed in ASB3 will be used in support of our AIDS-related research program. Our SPF Indian-orgin rhesus breeding colony has reached 2,060 NHPs and the expanded SPF program continues to grow. These animals are used in the infectious disease and immunology studies, and many will be housed in ASB3. In order to continue to expand our AIDS-related research programs, it is essential that sufficient cage space be available. The primary housing units requested in this proposal will allow the ONPRC to fully occupy the new ASB3 facility and house SPF NHPs under state-of-the-art conditions in an enhanced social environment. The ONPRC has been at the forefront in increasing the social environment of NHPs housed at the Center. The awarding of this G20 application will allow the ONPRC to have approximately 90% of the entire NHP colony in an enhanced social environment. The following aims are proposed in this grant: [unreadable] [unreadable] Specific Aim 1: Purchase 50 mobile stainless steel racks designed to hold four 4.5 sq. ft. cages each (200 total cages). [unreadable] [unreadable] Specific Aim 2: Purchase equipment to enrich the social environment, including mobile play pens for group housing, and tunnels and porches that attach to the cages. [unreadable] [unreadable] Specific Aim 3: Purchase additional equipment, including transfer boxes and capture tunnels for moving monkeys between cages or playpens, and blood collection stations. [unreadable] [unreadable] [unreadable]

[unreadable] DESCRIPTION (provided by applicant): [unreadable] This proposal requests funds to renovate the old cage washing facility in the original part of the Animal Services Building (ASB) complex that houses nonhuman primates (NHPs). Our objectives are to provide outstanding animal care for NHPs by maintaining the highest levels of sanitation and complying with USDA regulations and AAALAC guidelines. The need to renovate the old cage wash facility is driven by growing research programs at ONPRC. Much of this growth has been in AIDS-related and other infectious disease projects. To support these projects, the ONPRC has greatly expanded its SPF and expanded SPF-lndian-origin rhesus macaque populations. An increase in cage wash sanitation capabilities will insure successful growth of this valuable colony while preventing contamination of viruses that confound AIDS-related research. In addition, most of the NHPs involved in AIDS-related research are housed in the original part of the ASB and are dependent on the old cage washing facility for NHP cage sterilization and sanitation. [unreadable] [unreadable] This facility has been in service for over 15 years, and it has had increasing use as the number of animals assigned to projects has increased and as the ASB complex has expanded. Fifteen years of very heavy use have resulted in significant deterioration of all mechanical systems of the cage washer. There have been numerous mechanical malfunctions in the last 4 years, resulting in very poor reliability. Thus, a new cage washer is a critical piece of equipment that would provide reliable service for at least another 15-20 years. In addition, the old cage washer is only a single-sided machine, which limits the through-put of cages and restricts the number of animals that can be housed in the ASB without running additional shifts. The proposed purchase of a new, more reliable cage washer that has double the capacity of the current 15-year-old machine would allow ONPRC to continue to expand the use of NHPs, provide back-up capabilities for other cage washers, facilitate compliance with USDA regulations that require cage sanitation at least every 2weeks, and conserve natural and financial resources through improved operating efficiency. [unreadable] [unreadable] We also propose to refurbish drains and wall and floor surfaces throughout the cage washing facility; these upgrades will improve room sanitation levels, create durable finishes that will insure USDA compliance for the long-term, improve efficiency, and provide for a much safer work environment for employees. The following aims are proposed in this grant: [unreadable] [unreadable] Specific Aim 1: Purchase a Lynx Model 450LX Rack and Cage Washer, double wide. [unreadable] Specific Aim 2: Remodel the site for installation of the double-wide cage washer and refurbish the drains, floors and walls throughout the cage washing facility. [unreadable] [unreadable] [unreadable]

Brain Ischemia; CRISP; Cancer of the Ovary; Computer Retrieval of Information on Scientific Projects Database; Funding; Grant; Institution; Investigators; Ischemic Encephalopathy; Malignant Ovarian Neoplasm; Malignant Ovarian Tumor; Malignant Tumor of the Ovary; Malignant neoplasm of ovary; Mammals, Primates; Modeling; NIH; National Institutes of Health; National Institutes of Health (U.S.); Pilot Projects; Primates; Research; Research Personnel; Research Resources; Researchers; Resources; Source; United States National Institutes of Health; ovarian cancer; pilot study; prevent; preventing