Daniel M. Dorsa - US grants

The specific aims of this project are to: 1) pharmacologically characterize binding sites for arginine vasopressing (AVP) in the rat brain; 2) to measure the effectiveness of AVP-related peptides to displace 3H-AVP from binding sites in the rat brain; 3) to anatomically locate specific brain regions which possess VP specific binding sites; 4) to study ontogeny and regulation changes of the brain AVP receptor. The rationale for this proposed project stems from evidence that the central nervous system (CNS) may be a target organ for AVP, which has been long known to act peripherall on smooth muscle and kidney epithelia, but whose role as a neuromodulator or neurotransmitter has only recently come to light. Evidence that AVP influences memory, as well as other behaviors, when administered peripherally or intracerebrally, along with anatomic studies showing that extrahypothalamic projections of AVP axons projecting from the magnocellular nuclei to many brain regions strongly suggests that AVP receptors should be distributed in foci throughout the brain. In order to determine whether these regions possess AVP binding sites that might mediate these behavioral and physiological effects of AVP on the CNS, we will use a 3H-AVP which we have successfully used in preliminary studies to localize AVP specific binding sites in rat kidney and several CNS regions. The principal methods will be to incubate frozen, slide-mounted slices of rat brains with 3H-AVP and localize the anatomic sites of binding by autoradiography. Quantitative measures of binding will be done on the brain slices by autoradiographic grain counting and by densitometric image analysis, and by wiping the slices from slides with filter paper and counting radioactivity by scintillation spectroscopy. The location of AVP binding sites will be compared to AVP pathways as determined by immunocytochemistry. Characteristics of binding to anatomically identified regions on the brain slices will be determined with protocols designed to assess specificity of binding, time and temperature dependency, affinity of binding sites for AVP-like peptides, and saturability. To determine the relationship of these specific binding sites to AVP mediated biological and behavioral responses, we will investigate the brain AVP binding system in brains of: 1) Brattleboro rats, which lack AVP; 2) fetal and neonatal. The results of this research will be significant in that they will clarify our understanding of vasopressin's roles in regulation and modification of behavior, and other CNS functions, and could lead to new clinical strategies for the treatment of disorders of these functions.

The long-term objective is to understand the role of the neuropeptide vasopressin (VP) as a neurotransmitter or neuromodulator in the mature and developing central nervous system (CNS). The specific aims are 1) to define the pharmacologic characteristics of brain VP receptors and the post-receptor events involved VP's CNS effects; 2) to determine whether changes in number and affinity of VP receptors in brain and peripheral tissues of Brattleboro rats which lack vasopressin influence cellular responsiveness to the peptide, and whether VP treatment can reverse any changes observed; 3) to determine whether VP binding sites which are expressed in certain brain regions during the early post-natal period in the rat are similar to those which are present in other areas of the adult rat brain, and whether exposure to high levels of vasopressin during the developmental period can alter CNS VP receptor characteristics long-term, and 4) to ascertain whether vasopressin and/or messenger RNA for vasopressin is expressed by neurons which project to brain regions in which developmental VP binding sites are present. To accomplish these goals, a combination of membrane binding techniques and in vitro receptor autoradiography with computer-assisted image analysis will be used. Post-receptor events in vasopressin effects will be measured using tritiated inositol to monitor the hydrolysis of phosphatidylinositol in brain tissue slices and cultured hepatocytes. Vasopressin will be measured in microdissected brain tissue by radioimmunoassay, and will be immunostained in brain neurons using the peroxidase-antiperoxidase technique. Messenger RNA for vasopressin will be localized by in situ hybridization using a radiolabeled oligonucleotide probe and measured by quantitative autoradiography. The ultimate goal is to understand the pharmacologic, developmental, and pathologic characteristics of brain vasopressin receptors. Vasopressinergic function may be impaired in neuropsychiatric disorders such as Alzheimer's disease. Vasopressin treatment has been reported to enhance memory in animals and man. The information obtained in these studies is essential to the development of clinically useful vasopressin analogs with CNS activity.

The long-term objective of this research is to understand at a neurochemical and molecular level the neurotransmitter-neuromodulatory functions of the neuropeptide vasopressin (VP) in the mature and developing brain. Vasopressin containing neurons which originate in the bed nucleus of the stria terminalis (BNST) and medial amygdala (MA) which project to the septum, a structure rich in VP receptors, will be developed as a model system in which to study VP-ergic neurotransmission. The hypotheses to be tested are: 1) that adult septal VP receptors are of the V1-subtype and are coupled to inositol phospholipid (PI) metabolism through interaction with GTP binding proteins, 2) that continuous exposure of VP receptors in adult animals to VP or VP antagonists will induce regulatory changes in these binding sites and in VP-sensitive PI hydrolysis, and that these changes will be different from those observed in similarly treated Brattleboro rats, 3) that exposure of VP receptors to high levels of VP in the early postnatal period will lead to paradoxical "up-regulation" of peripheral and brain receptors, 4) that VP deficiency in developing Brattleboro rats leads to reduced expression of VP receptors in these animals, 5) that transitory VP binding sites which are expressed in the cingulate gyrus, dorsal hippocampus, and caudate nucleus of the rat brain are pharmacologically distinct from those present in adult brain, 6) that gonadal steroids act directly on VP containing neurons of the BNST and MA to regulate expression of the VP gene, 7) that the timing and magnitude of VP gene expression is determined by early postnatal androgen exposure, and 8) that glucocorticoid hormones also regulate VP gene expression in the BNST and MA. To test these hypotheses, a combination of membrane binding, in vitro receptor autoradiography, and in situ hybridization for VP mRNA with computer assisted image analysis will be used. Effects of VP on inositol phospholipid metabolism will be studied in brain tissue slices. Clinical studies have suggested diminished of VP-ergic function is involved in memory impairment in Alzheimer's disease. These studies are essential to understanding the neurotransmitter effects of VP, and in the development of analogs useful in the treatment of cognitive impairment in humans.

Estrogens have been shown to modulate growth, phenotype, and connectivity of neurons of the developing rodent and human basal forebrain and hippocampus. This ability to alter neuronal morphology and connectivity is retained in certain regions of the adult brain. Recent reports have suggested that the incidence of AD in estrogen replaced postmenopausal women is much lower than in women not given this treatment. How might estrogen treatment alter the expression of AD? Since the work of this ADC has implicated genetic causes of the disease, it seems reasonable to suggest that estrogen treatment might protect neurons from pathological changes associated with the AD genotypes, or exert trophic effects which reverse the AD-related changes. This proposal will further investigate the hypothesis that exposure of the aged (or AD) brain to neurotrophic effects of estrogens results in regenerative (or protective) effects on the functional activity of particular brain neuronal systems. If estrogen exposure promotes neurite outgrowth and remodels neuronal connectivity, it might influence the expression of genes encoding proteins important in growth and synaptogenesis. We propose to examine estrogens effects on expression of a subset of these including Synapse Associated Protein (SNAP-25), Microtubule Associated Protein 2 (MAP-2, a dendritic marker), Tau (a component of the microtubule apparatus and neurofibrillary tangles) and neuromodulin (GAP-43, associated with the neuronal growth cone). We have established that GAP-43 mRNA expression is responsive to estrogen in both the developing and adult basal forebrain. We will examine estrogen's effects on neurons in three different regions of the aged female rat brain. (1) Neurotrophic Effects in Classical Estrogen Target Neurons: Can gonadal steroids restore neuronal function in the bed nucleus of the stria terminalis and medial preoptic area of the aged female rat (as previously seen in male rats)? Estrogen's effects on GAP-43, tau~ SNAP-25, and MAP2 in phenotypically identified neurons will also be examined. (2) Trophic Effects of Estrogen on Basal Forebrain Cholinergic Neurons: Does estrogen treatment of aged female rats enhance choline acetytransferase activity and mRNA in medial septal-basal forebrain system? We will also examine the direct effects of estrogen on cholinergic neurons using co- localization techniques. To relate these studies to possible effects of estrogens in AD brain, we will carry out similar studies in human basal forebrain brain tissue from AD and control subjects available through the ADC autopsy core. If estrogen receptors are present in cholinergic neurons, we will also assess differences in the degree of co-localization from individuals with AD associated with differing genetic backgrounds. (3) Restorative effects in non-classical estrogen responsive neuronal populations of the striatum. Although few estrogen receptors are present in the striatum, estrogen treatment enhances dopaminergic transmission in this structure and improves striatally-dependent motor behaviors. We will examine trophic effects of estrogen in aged rat striatum, and relate these effects to postsynaptic responses to antipsychotic drugs commonly administered to AD patients. These studies will provide new information at the molecular and cellular level about neurotrophic effects of estrogens in the aged brain. This may aid our understanding of protective effects of estrogens.

The University of Washington Health Sciences "Biomedical Research Identification of Graduate Education Successful Student Support Services (BRIDGES4) Program is a comprehensive and carefully orchestrated initiative designed to decrease the attrition rates of program participants majoring in the sciences. The BRIDGES4 program is a series of innovative services and support mechanisms which will dramatically increase the ability of our biomedical graduate programs to attract, retain, and promote the success of underrepresented minority students. Both direct and indirect benefits to all health sciences graduate students are anticipated, from participation in scientific and career development seminars to an enhanced atmosphere of commitment to student success among graduate programs that are both academically rigorous and multiculturally sensitive. The BRIDGES4 Program's goals are: 1. To provide early exposure to the health sciences and rigorous academic preparation for entering underrepresented students interested in science and engineering. 2. To increase the retention rates of underrepresented undergraduate students in science and engineering and to prepare them for application to health sciences graduate programs through sustained academic support, career development activities and research opportunities. 3. To assure the retention, success and career development of underrepresented students in basic health science graduate programs. 4. To provide information, counsel, and technical assistance to departmental faculty, administrators, and advisors on effective practices and policies that promote student success/retention and will ultimately increase the number of underrepresented students in health sciences graduate programs. 5. To establish collaborative relationships with local and regional higher educational institutions and scientific industry within the Washington, Wyoming, Alaska, Montana, and Idaho (WWAMI) consortium to assist in fostering the interests, talents, and career goals of underrepresented students interested in pursuing biomedical research careers. 6. To communicate regularly with program participants (students, faculty and staff), local and regional affiliated institutions, and scientific industry representatives regarding BRIDGES4 activities, policies and program growth.

Neuroendocrine neuropeptides such as vasopressin, oxytocin, and neurotensin serve as neurohormones, and neurotransmitters in the mammalian brain. The expression of the genes which encode these peptides, and their receptors, in brain neurons is regulated by steroid hormones such as estrogen, corticosteroids, and testosterone. This laboratory has for several years attempted to understand the importance of this hormonal modulation in the function of these neuropeptide systems, has used them to understand the cellular and molecular events which mediate the effects of steroids on neurotransmitter gene transcription in brain neurons. Data gathered in neuroblastoma cells, in primary neuronal cultures, and in the rat and mouse brain in vivo suggests that estrogen acts not only through the "classical" mechanism of action involving nuclear hormone receptor dimerization and binding to consensus hormone response elements, but also via "cross-talk" with other protein kinase-dependent signal transduction pathways such as protein kinase A, and the mitogen activated protein kinases. The studies proposed in this renewal application will test the hypothesis that estrogenic regulation of neuropeptide gene expression in vitro and in vivo. They will also investigate the relative roles of estrogen receptor-subtypes (ERalpha and the newly identified ERbeta) in these responses involves a mix of "classical" and protein kinase-dependent transcriptional actions. It is, thus, the combination of these effects which confer the dramatic effects of hormones such as estrogen on the brain involved in neuroendocrine regulation, reproductive behavior, as well as neurotropic effects in the developing and aging. The approach will involve identification of signal transduction cascades which respond to estrogen, determination of their ability to enhance transcription of neuropeptide/receptor promoter-reporter gene constructs in vitro, and profiling their sensitivity to estrogen receptor agonists and antagonists. Local implantation of ER agonists and antagonists, and pharmacologic agents which activate or inhibit the relevant signal transduction pathways will be used.

Estrogens have well-documented effects on the survival and growth of target neurons in various regions of the mammalian brain. In the adult and aged brain, estrogen may be trophic to and/or protect from damage neuronal populations important in cognition such as the basal forebrain cholinergic system. Aging in both the male and female is associated with a decline in the secretion of estrogens and androgens and it is possible that this decline could have implications for aging of brain neurons. Whether effects of this type occur in the human brain are unknown, but interesting reports have suggested that estrogen treatment improves condition in young and elderly women and that the incidence of Alzheimer's disease in estrogen-replaced in postmenopausal women is much lower than in women not given this treatment. Neuronal development appears to be in large part dependent upon the actions of neurotrophins such as nerve growth acting through tyrosine kinase receptors, specifically trk A and p75. We have recently reported that estrogen and certain agents termed selective estrogen receptor modulators (SERMs) can discretely activate certain of the downstream signal transduction cascades used by growth factors such as the MAP-Kinase pathway. In the present application, we propose to develop primary cultures and human neuronal cell-line models in which to evaluate further the neuroprotective effects of estrogen and its interaction with neurotrophin and MAP kinase-related signaling mechanisms. Specific Aim 1: To assess the neuroprotective effects of estrogen, SERMs, and ER-beta selective phytoestrogens in primary neuronal cultures. Specific Aim 2. To identify the signal transduction events which mediate the neuroprotective effects of estrogens in primary neuronal cultures. Specific Aim 3. To identify structural features of the estrogen receptors alpha and beta and the proteins which they interact to mediate neuroprotection in transfected cell systems. Specific aim 4. To investigate the ability of estrogen to induce neuroprotective genes such as Bcl-2 in human NT2N neurons.

neurotrophic factors; gene expression; estrogens; aging; Alzheimer's disease; hormone regulation /control mechanism; neuroprotectants; choline acetyltransferase; receptor expression; estrogen receptors; tau proteins; vasopressins; neurotensin; preoptic areas; thalamus; corpus striatum; acetylcholine; synapses; microtubule associated protein; northern blottings; in situ hybridization; human tissue; laboratory rat; male; female;

The specific aim of this project is to enhance human subjects safety by improving efficiency and oversight of electronically tracking and managing human subjects protocols and associated reports and regulatory documents. OHSU includes four schools (Medicine, Nursing, Dentistry, Science & Engineering), two hospitals, numerous primary care and specialty clinics, research institutes and centers and community service programs. Competitive funding awards have more than quadrupled at OHSU during the last decade--from $49 million in 1991 to almost $217 million in 2001. OHSU ranks 29th out of 483 higher education institutions that receive research grants from NIH. The commitment of OHSU to growth in research includes a strong focus on clinical research. The OHSU GCRC is in its 36 thyear of funding, currently at $4.2 million annually. The OHSU Cancer Institute (OCI) was designated a NCI clinical cancer center in 1996 and, during this past year, received over $71 million in funding for 320 projects. OHSU's strategic plan positions the institution on a course that will create a world-class research organization in Oregon. OHSU has also embarked on The Oregon Opporttmity, a $500 million investment initiative. OHSU's current research infrastructure is strained given the current rate of annual increases in extramural fimding and will be challenged to an even larger extent as the institution implements its Oregon Opportunity initiative. This rate of growth has strained the research compliance infrastructure for protocols that are conducted on the main campus and provided even greater challenges for those conducted at off-campus locations. At this point, OHSU has not fully utilized technological advantages for handling protection of human subjects. The IRB, the GCRC, the OCI and some investigators each have their own databases to track the administrative status of human research projects. Information is not shared between the databases and the ultimate source of information is in paper files. A large amount of communication (memos, email and telephone) is necessary to ensure that only the latest approved versions of consent forms, protocols, etc. are being used. OHSU proposes to contract with a vendor to help develop an electronic research compliance system that will allow the creation, submittal, and review of all applicable human subjects research documentation, including but not limited to protocols, consent forms, directly entered adverse event and protocol deviation reports, and institutional information currently transmitted via paper forms. Having this information in electronic form will allow OHSU to more readily share the most up-to-date information about a human subjects research study between the various institutional participants including the investigators and their staffs, the IRB, the Research Subject Advocate/GCRC, the OCI, and other institutional administrative offices. There are many advantages to making the review process of human subjects research electronic. One important example is providing the investigator with the capability of entering and submitting adverse event report information on-line. Capturing the data electronically is critical for tracking adverse events in real time. The system will be able to be set up so that notifications of the adverse event report submittal could be sent almost instantaneously to all other parties that might be impacted by the report. The development of an electronic research compliance system described in this application will greatly increase the likelihood of success in creating the desired seamless, electronic interface between oversight committees and the research centers.

OHSU submits this request for an additional, final, one-year award for short-term, interim support of its program for strengthening human subjects research protections. In addition, we will use this second round of funding to collaborate with other institutions that are not eligible to apply for these funds. We propose to continue the process of enhancements for our program that were initiated with funds awarded under NIH RFA OD-02-003 and have added three specific aims. One specific aim is to share the processes, technologies, and other "portable" components of our enhanced human subjects protections system with four identified collaborators. Because we have made the decision to purchase a commercial (Webridge) system to enhance our e lectronic management of documents, reports, submissions, and tracking, we are working with that vendor to insure that we may share per tions of our new system with these non-OHS U collaborators. A second specific aim is to host a statewide conference on hum an subjects protections. We will convene a group to include representatives from our four collaborating sites and others throughout the state to develop an agenda and select faculty for this one-day conference. T he conference will share business and best practices learned through the process of implementing our new systems, discuss human research topics of current interest, and include a nationally recognized keynote speaker. T he third new specific aim is to begin the process of accreditation of our system of hum an subjects protections. OHSU will be applying for accreditation by the Association for Accreditation of Human Research Protection Programs (AAHRPP) and will benefit from a gap analysis and external audit of our program. We propose to use funds awarded under this RFA for performing that audit.

[unreadable] DESCRIPTION (provided by applicant): [unreadable] Oregon Health & Science University (OHSU) seeks funds to construct Phase I of a new building at the Oregon National Primate Research Center (ONPRC). The proposed facility will be called the Non-SPF Group Housing and Central Support Building. Rapid research growth, expansion of Specific Pathogen Free (SPF) breeding colonies, and enforcement by USDA of the "Draft Policy on Environment Enhancement for Nonhuman Primates," necessitate additional social housing for nonhuman primates (NHPs) and increased animal central support space. Our long-term objectives are to: 1) provide housing for NHPs in social groups or pairs whenever possible; 2) protect growing populations of SPF Indian Origin Rhesus Macaques; 3) free-up cage space for the growing number of research projects; and 4) provide state-of-the-art central support facilities to benefit all NHPs at ONPRC. To accomplish these objectives, we are proposing to construct a Non-SPF Group Housing and Central Support Building in two phases, the first phase to be funded with this C06 grant. Phase 1 of the proposed building will be 12,690 gross square feet (gsf) and will include 16 animal holding rooms to house up to 160 adult non-SPF NHPs in groups of 8-10 animals, a non-SPF clinic/hospital/nursery, a new central diet kitchen with pantry, walk-in cooler, walk-in freezer, centralized commercial feed storage, and a separate room to prepare and distribute produce for NHP enrichment as part of the Psychological Well Being program. Specific Aim 1 proposes to construct indoor group housing and support facilities (clinic, hospital, nursery) for non-SPF NHPs. Specific Aim 2 proposes to construct central nutritional and enrichment support facilities (diet kitchen, pantry, cooler, freezer, produce processing, and feed storage) to service all OHSU NHPs. [unreadable] [unreadable]

[unreadable] DESCRIPTION (provided by applicant): Estrogen has numerous effects in the brain which include modulation of neurotransmitter systems and their receptors, neuroendocrine regulation, modulation of reproductive and cognitive behaviors, and neurotrophic and neuroprotective effects. It is likely that these effects involve the ability of estrogen to induce transcription of genes important in these processes. Increasing evidence is available to suggest that estrogen can promote gene transcription by signaling through pathways other than those traditionally associated with steroid hormone response element-dependent gene transcription. The estrogen receptors alpha and beta are widely and differentially distributed in the brain. Using cell culture models, we have been able to show that both receptors are capable of transducing rapid, membrane-initiated effects with reference to neuroprotection, protein phosphorylation, and gene transcription. We have provided in vivo evidence that activation of the MAP kinase pathway appears to be a prominent, initial effect of the hormone. We propose to use a combination of in vitro and in vivo approaches to further our understanding of this emerging class of steroid hormone effects. Specifically, the studies investigate differences between ERa and ER[unreadable] with respect to: Mode of interaction with the cell membrane, timing of signaling events transduced, and the down-stream transcriptional responses which result from them. We will test the following Hypotheses: 1. Estrogen induces the translocation of ER[unreadable], but not ERa, to the membrane compartment of neurons to interact with other proteins. This difference results in altered kinetic characteristics in rapid signaling, and their subsequent down-stream effects on gene expression. 2. In brain regions which express ERs, E2 acts on ERa which is localized to the plasma membrane resulting in more rapid, transient changes in MARK and CREB phosphorylation than ER[unreadable]. Slower, more prolonged signaling responses result from ER[unreadable], which must translocate to the membrane in order to couple with rapid signaling mechanisms. 3. In glial cells, membrane ERs couple to different cascades than in neurons, and E2 acting at ERa, but not ER[unreadable], results in a suppression of cAMP-dependent CRE-mediated gene transcription. Expression abolishes this signaling phenotype. [unreadable] [unreadable] [unreadable]

This application seeks to renew the Oregon BIRCWH program entitled "Scholars in Women's Health Research across the Lifespan". The goal of the program is to create a stimulating and nurturing environment for junior faculty to develop into leading Physician Scientists in Women's Health. Our program recognizes that research can modify the course of disease at one point in a woman's lifespan which will affect the rest of lifelong development and aging. The program pairs basic and clinical junior faculty scientists with established mentors from different backgrounds who have expertise in Women's Health Issues in order to enhance the scholar's research capabilities. The mix of career paths and backgrounds is integral to increasing collaboration and invigorating research in Women's Health across the lifespan. The extensive intellectual and research resources at the Oregon Health &Science University (OHSU) are available and committed to developing BIRCWH scholars. Integration is interdepartmental and is Center driven to enhance collaborations between scientists and trainees in the Center for Women's Health, the Heart Research Center, the Primate Research Center, the Cancer Institute, and the Center for Gender Biology and Medicine. Sophisticated research core laboratories specializing in Molecular Biology, Cell Culture, DNAanalysis, Imaging, Statistics,Assisted Reproductive Techniques, Endocrine Assays, Laboratory Animal, Transgenic and Molecular Genetics Cores, among others, are established and available to the BIRCWH Scholars. Advanced training in designing clinical studies and statistical evaluation for clinician scientists will be coordinated through the highly successful Human Investigations Program. Writing skills are enhanced through structured workshops. The mentors of this BIRCWH Program are accomplished and funded scientists who will provide diverse and in-depth mentorship for scholars in areas of women's health that extend across the lifespan. Our program, with its institutional commitment, multicenter interdisciplinary resources, accomplished mentors and focus on the importance of a lifespan approach has proved successful for our initial six BIRCWH Scholars. All have submitted a major independent NIH grant and five have now received funding. The BIRCWH Scholars have been successful as Principal Investigators (PI) or Co-Pis on 8 National Awards, Co-investigators on 4 National Awards and PI or Co-Pi on 16 industry or regional grants.

DESCRIPTION (provided by applicant): Oregon Health &Science University (OHSU) is requesting funds to renovate 5,431 gross square feet of core facilities space that will integrate two important research areas: flow cytometry and genomic analysis. The goal of this initiative is to improve facilities for molecular and cellular characterization. Specific Aim 1 consolidates space for the Flow Cytometry Center, which is currently scattered throughout the OHSU campus. Specific Aim 2 consolidates space for OHSU's microarray technologies and creates new space for a new Massively Parallel Sequencing Shared Resource that, with the Microarray Shared Resource, will constitute the a new Genomics Center at OHSU. Importantly, however, locating the Genomics Center adjacent to the Flow Cytometry Center will create scientific synergy by facilitating the generation of gene expression profiles and DNA variation measurements from pure cell populations. The proximity of these facilities will increase both the quality of service provided to investigators and the efficiencies by which these resources can integrate their synergistic activities. Integration of these resources will enable co- development of methods and technologies to minimize the number of cells required for array or sequencing assays, and the ability to rapidly hand off purified cells from the Flow Cytometry Shared Resource to the Genomics Center will minimize the chances of changes in gene expression profiles and enhance the potential to isolate intact/high quality RNA from smaller numbers of cells. Together, the aims of this proposal will greatly expand the resources for PHS-funded researchers at OHSU by creating sustainable efficiencies in the delivery of services and enhancing the capacity for scientific synergies. In addition, this proposal is expected to create 24 jobs during the renovation phase and will create the capacity to hire long-term scientific and technical staff.

DESCRIPTION (provided by applicant): Oregon Health &Science University (OHSU) seeks funds to construct new outdoor group housing and a clinic and hospital support facility at the Oregon National Primate Research Center (ONPRC). The proposed outdoor group housing will be called the Primate Enclosures in a Natural Setting (PENS). Rapid research growth, expansion of Specific Pathogen Free (SPF) breeding colonies, and compliance with the USDA "Draft Policy on Environment Enhancement for Nonhuman Primates" necessitate additional social housing for nonhuman primates (NHPs) and increased animal central support space. Our long-term objectives are to: 1) provide housing for NHPs in social groups in a natural setting;2) protect growing populations of SPF Indianorigin rhesus macaques;3) free-up cage space for the growing number of research projects;and 4) provide state-of-the-art central clinic and hospital support facilities to benefit all NHPs at ONPRC. To accomplish these objectives, we are proposing to construct outdoor group housing, called PENS, to provide a natural setting in which to raise NHPs in social groups and to accommodate the need for expansion of the SPF Indian-origin rhesus macaques, which are an invaluable resource for biomedical research. The design incorporates innovative features that will offer animals multiple environmental choices. Each PENS will consist of a 2,021 NSF grassy Outdoor Area Enclosure to simulate a natural setting and a 478 NSF Enclosed Area Shelter that provides excellent protection against inclement weather and also serves as a feed and catch area. Each of the 6 individual PENS will provide housing for 40 - 60 rhesus monkeys. We are also proposing to construct an important and much needed Clinic and Hospital Support Facility located adjacent to the six PENS. This will add an additional 80 cages to the current 60-cage clinic located on the opposite side of the campus. Specific Aim 1: Construct 6 PENS for SPF rhesus macaque breeding colonies. Providing a heated Enclosed Area Shelter connected to a large grassy Outdoor Area Enclosure is thought to be the best means possible for the ONPRC to raise healthy, naturally enriched SPF rhesus macaques. Specific Aim 2: Construct a 2,344 NSF Clinic and 80-cage Hospital Support Facility adjacent to the proposed PENS (Specific Aim 1) to provide much needed clinical/support space. In addition to providing medical facilities for up to 360 rhesus to be housed in the six PENS, it will also provide much needed hospital support space for the approximately 1,000 rhesus located in corrals adjacent to the proposed PENS site.

DESCRIPTION (provided by applicant): AIDS related research is a major focus of the Division of Pathobiology and Immunology at the Oregon National Primate Research Center (ONPRC). The nonhuman primate (NHP) resource and disease models for AIDS at the ONPRC have contributed importantly to the search for effective vaccines and therapies, however, the ONPRC AIDS research program is currently limited due to a lack of sufficient bio-containment space. Annual usage of bio-containment space has increased from 50 NHPs in 2005 to 330 NHPs in 2010. This tremendous growth in demand for space has resulted in project delays in 2010 of up to six months. Although improved operating procedures are making effective and efficient use of existing bio-containment space, the physical space limitation cannot be overcome by operating procedures alone. This project proposes to construct an addition to the Animal Services Building (ASB) bio-containment space that will add six animal rooms and a kitchen. The addition of the animal rooms will add 96 cage spaces for the conduct of AIDS related research, and the kitchen will ensure that all services for research and animal welfare can be provided within the bio-containment barrier.

DESCRIPTION (provided by applicant): This competing renewal application seeks to continue and enhance the OHSU BIRCWH program entitled Oregon BIRCWH: Scholars in Women's Health Research Across the Lifespan. Our overarching goal is to create a stimulating and nurturing environment for junior faculty to develop into leading interdisciplinary research scientists in women's health; we plan to maintain four scholars/year. Over the last two grant cycles, the Oregon BIRCWH has trained a diverse cadre of researchers who advance basic, biomedical, behavioral, and translational research in women's health across the lifespan. OHSU provides a resource-rich environment whose culture promotes interdisciplinary team science. The Oregon BIRCWH has been successful with scholars receiving approximately $40 million dollars in research funding, publishing over 200 publications, and assuming national leadership positions. The BIRCWH is the only K12 career development program at OHSU specifically dedicated to career development in women's health research. The institution is deeply committed to the BIRCWH, providing each scholar up to 50 hours of statistical support, tuition free education through the Human Investigations Program, and direct financial contributions to support their research. We will continue the existing best practices that have made our program highly successful. In this renewal we expand the centers, institutes, and mentors affiliated with the BIRCWH to address all 6 high priority NIH ORWH research goals and propose the following innovative expansions to: I) Develop and promote best practices in mentoring interdisciplinary scientists by: a) providing formal mentorship training, b) conducting a national BIRCWH survey to identify successful practices in mentoring interdisciplinary scientists, c) developing and testig tools to support the mentor-mentee relationship locally and d) disseminate best practices (lessons and tools) for mentoring nationally; and II) Catalyze the development of women's health research leaders at the institutional, state, and national level by: a) developing core competencies in women's health research that incorporate the NIH ORWH research priorities to better define the research needs of the field and target educational research training programs, b) providing formal leadership training to promote effectiveness of the next generation of women's health research leaders, c) disseminating competencies and expanding interdisciplinary research in women's health through a Statewide Annual Women's Health Research Conference, and d) formalizing a program to promote inter-institutional BIRCWH collaborations to advance women's health research and further programmatic excellence at a national level. The Oregon BIRCWH is dedicated to training the next generation of leaders in women's health research whose discoveries improve the health of girls, women, and populations. We are pleased with our program's and scholars' successes and are excited about the opportunities in this renewal to increasingly contribute at a national and programmatic level.

The National Science Foundation (NSF) Graduate Research Fellowship Program (GRFP) is a highly competitive, federal fellowship program. GRFP helps ensure the vitality and diversity of the scientific and engineering workforce in the United States by recognizing and supporting outstanding graduate students who are pursuing research-based master's and doctoral degrees in fields within NSF's mission. GRFP provides three years of support for the graduate education of individuals who have demonstrated their potential for significant achievements in science and engineering research. The award to this GRFP institution supports NSF Graduate Fellows pursuing graduate education at the institution.