John P. Capitanio - US grants

The goal of the proposed study is to determine if psychosocial manipulations influence the progression to disease and death in rhesus macaques who have been inoculated with SIV, the simian immunodeficiency virus. SIV infection in rhesus monkeys produce a disease considered by many (e.g. IOM) to be the best animal model of HIV infection in humans. One important parallel between SIV infection and HIV infection in their respective hosts is the variable time course to progression to clinical disease and death. Considerable research conducted with humans has implicated psychosocial factors in overall health as well as in progress of diseases such as certain cancers and coronary disease. More recently, alterations in immune system functioning have been reported for macaques who have undergone psychosocial manipulations. To determine whether such psychosocial factors affect disease progression in SIV-infected monkeys, an archival methodology will be employed, using colony records at the three NIH-sponsored Regional Primate Research Centers where simian AIDS research with rhesus macaques is being conducted. After careful screening of potential subjects' records for inclusion in this analysis, records pertaining to rearing history, caging history, medical history, SIV inoculation, and clinical outcome will be extracted for all animals (estimated n=300) and the data analyzed using multivariate techniques. The general hypothesis is that changes in housing occurring both before and after viral inoculation will be related to the latency to onset of various physical and immunological signs of disease. Of particular interest are individual differences in the frequencies of housing changes which involve a) separations from familiar companions, b) introduction to unfamiliar companions, and c) social isolation. Support for the hypotheses would provide the basis for further developing this animal model for use in prospective investigations of the mechanisms by which psychosocial processes affect SIV disease progression. Moreover, results of the proposed study will be valuable not only in directing which social processes are related to slower disease progression, but may have potentially important implications for the delivery of psychosocial services to HIV-infected humans to delay disease onset and enhance physical well-being.

DESCRIPTION (Adapted from the Applicant's Abstract): The goal of the proposed project is to understand the relationship between social stress and progression of immunodeficiency disease, and the effects that personality factors may have on this relationship. In humans, AIDS is typically accompanied by socially-induced stresses arising from of sources (e.g. stigma, bereavement). Since early in the AIDS epidemic, the experience of, and ability to cope with such stressors have been proposed as potentially significant contributors to the substantial variability in disease progression seen among HIV-infected people. Successful coping, however, is likely to reflect a close fit between external resources (such as informational, emotional, and social support) and internal resources, such a personality and motivational factors. The proposed research will focus on the role played by sociability, a fundamental component of personality, in the immunodeficiency disease process. The SIV-macaque model of HIV infection will be used, and two experiments are planned. In the first experiment, detailed behavioral and physiological data (including neuroendocrine, immunological, and virological) will be obtained from SIV-inoculated rhesus monkeys. The focus will be on individual differences in the activation of the two major stress-response systems: the sympathoadrenal medullary and hypothalamic-pituitary-adrenal, during social interaction, and the consequences of these differences for progression of SIV disease. In the second experiment, animals high and low in sociability will be studied in standardized situations designed to elucidate the psychological correlates of sociability. Inoculated and control animals will be exposed to stable and unstable social conditions, in order to determine how personality factors and a stressful social milieu might interact to affect psychobiological functioning and disease outcome. Particular interest will be focused in both studies on the role played by stress-induced reactivation of cytomegalovirus, considered a potentially important cofactor in immunodeficiency disease progression. This research aims to provide important new information on the relationships between personality, social stress, and their behavioral, neuroendocrine, virological, and immunological sequelae in the course of immunodeficiency diseases. Data from this research program are likely to focus attention on the importance of personality factors in infectious disease processes and in psychosocial treatments aimed at providing HIV-infected persons with palliative care.

The goal of the proposed project is to understand the relationship between social stress and progression of immunodeficiency disease. In humans, the quality and stability of social life have been implicated as important factors in the progression of diseases such as cancer and cardiovascular disease. HIV disease is often associated with social disruption, (e.g., stigma, bereavement), and social stress has been suggested as contributing to the progression of HIV infection. The proposed research involves study of the role of social conditions (defined as stable and unstable social groups) in immunodeficiency disease progression, using the SIV-macaque model of HIV infection. The research plan specifically aims to continue an ongoing study of social stability and instability, and the consequences of these social conditions for behavioral, neuroendocrine, immunological, and disease processes in SIV-inoculated and control monkeys. The research is expected to provide important new information on the relationships between social stress and support, and their behavioral, neuroendocrine, and immunological sequelae in the course of immunodeficiency disease.

Significance The goal of this project is to document individual differences in behavioral, neuroendocrine, and immunological characteristics of rhesus macaques. We expect that, as in humans, such differences may have health consequences. Objectives In the past budget year, we examined the stability of personality assessments made on our 18 subject animals (adult male rhesus monkeys) in 1993. Animals were observed while interacting with each other in stable social dyads. In addition, we examined individual differences in cortisol and immunological responses to pharmacological manipulations. Blood samples were drawn at 5 time points over a two-hour period during three conditions saline, ketamine, or telazol pretreatment. Results We demonstrated considerable behavioral stability in our personality dimensions, and found personality correlates to early physiological events following SIV inoculation. During our pharmacological challenge, we found significant effects of personality on our measures. In this study, animals judged high in 'Excitability' (i.e. above the median on this trait) had significantly lower plasma cortisol concentrations and significantly higher CD4+ cell numbers at all time points. Moreover, whereas animals low in 'Excitability' showed an increase in their CD4/CD8 ratio over the two hour period, animals high in 'Excitability' exhibited a higher ratio that did not change over time. Future Directions These data demonstrate that there are important differences between individuals on dimensions reflecting personality that persist over time and are reflected in behavioral and physiological measures. The existence of such individual differences has implications for research design. Knowledge of such characteristics may permit investigators to select subjects for research projects that are more homogeneous. By reducing the potential variation in outcome measures, adequate statistical power can be maintained while the number of subjects is reduced. Our future research is aimed at further exploring trait-like physiological characteristics using this, as well as a larger sample. KEY WORDS personality, temperament, immune system, social behavior, cortisol FUNDING NIH Grant RR00169

DESCRIPTION (Adapted from the Applicant's Abstract): The goal of the proposed project is to understand the relationship between social stress and progression of immunodeficiency disease, and the effects that personality factors may have on this relationship. In humans, AIDS is typically accompanied by socially-induced stresses arising from of sources (e.g. stigma, bereavement). Since early in the AIDS epidemic, the experience of, and ability to cope with such stressors have been proposed as potentially significant contributors to the substantial variability in disease progression seen among HIV-infected people. Successful coping, however, is likely to reflect a close fit between external resources (such as informational, emotional, and social support) and internal resources, such a personality and motivational factors. The proposed research will focus on the role played by sociability, a fundamental component of personality, in the immunodeficiency disease process. The SIV-macaque model of HIV infection will be used, and two experiments are planned. In the first experiment, detailed behavioral and physiological data (including neuroendocrine, immunological, and virological) will be obtained from SIV-inoculated rhesus monkeys. The focus will be on individual differences in the activation of the two major stress-response systems: the sympathoadrenal medullary and hypothalamic-pituitary-adrenal, during social interaction, and the consequences of these differences for progression of SIV disease. In the second experiment, animals high and low in sociability will be studied in standardized situations designed to elucidate the psychological correlates of sociability. Inoculated and control animals will be exposed to stable and unstable social conditions, in order to determine how personality factors and a stressful social milieu might interact to affect psychobiological functioning and disease outcome. Particular interest will be focused in both studies on the role played by stress-induced reactivation of cytomegalovirus, considered a potentially important cofactor in immunodeficiency disease progression. This research aims to provide important new information on the relationships between personality, social stress, and their behavioral, neuroendocrine, virological, and immunological sequelae in the course of immunodeficiency diseases. Data from this research program are likely to focus attention on the importance of personality factors in infectious disease processes and in psychosocial treatments aimed at providing HIV-infected persons with palliative care.

behavioral /social science research tag

behavior; Primates; animal colony; behavioral /social science research tag; clinical research;

DESCRIPTION (provided by applicant): As the demand for laboratory-bred rhesus monkeys increases, it becomes crucial to manage our populations more effectively in an effort to optimize physical and psychological health, and ultimately production of sufficient numbers of high-quality animals for research purposes. At all primate facilities, there Ire animals that display poor health outcomes (eg, chronic diarrhea), and impaired behavioral, social, and reproductive outcomes (e.g., stereotypes, self-biting, poor social adaptation, poor maternal behavior), while other animals display none of these problems. What accounts for such individual variation? Two decades of psychobiological research with rhesus macaques have documented the existence of stable individual differences in the organization of behavior and physiology. These differences in biobehavioral organization arise from a number of sources, are detectable at an early age, and can persist throughout life. We propose that individual differences in biobehavioral organization (temperament, stress reactivity, personality) are an important contributor to variability in adaptation that is seen in primate colonies. At the CNPRC, we have successfully implemented a colony-wide assessment program based on this body of research. In the current proposal, we aim to continue this program, and to follow-up on the animals that have been enrolled in the program since 2001 by correlating our infancy measures with measures relating to psychological and physical health that are associated with colony management procedures such as relocations, group formations and indoor pairing. The goal of this analysis is to identify risk factors for negative outcomes and to use this information prospectively in colony management. Information on biobehavioral organization will also be made available to investigators who may wish to select animals with specific, defined characteristics for their research projects. Finally, an important aim is to identify more easily obtainable measures that personnel at other primate facilities might adopt that retain the predictive power of the to-be-identified risk factors identified by our more elaborate assessment program. Quantitative application of the solid research base in nonhuman primate psychobiology to colony management is a novel and innovative aspect of this proposal, and reflects a unique blending of goals between colony management and psychobiological science that is, we believe, unique in the NPRC system.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The objectives of this project are 1) to examine the role played by methamphetamine and stress in alterations in innervation patterns, Type I interferon gene expression, and SIV replication in lymph nodes, and AIDS-related indicators in blood. 2) to examine the role played by methamphetamine and stress in altering permeability of the blood-brain barrier (BBB) in SIV infected monkeys, and 3) to examine whether beta adrenergic blockade or administration of recombinant interferon-beta (rIFN-b) will abrogate the effects of methamphetamine in lymph nodes and at the BBB.

1H-Imidazole-4-ethanamine; AIDS; ATGN; Acquired Immune Deficiency; Acquired Immune Deficiency Syndrome; Acquired Immuno-Deficiency Syndrome; Acquired Immunodeficiency Syndrome; Aerosols; Aliquot; Allergens; Allergy; Animal Model; Animal Models and Related Studies; Animals; Antibodies; Antigens; Antigens, Viral; Antiviral Agents; Antiviral Drugs; Antivirals; Apoptosis; Apoptosis Pathway; Archives; Area; Assay; Bioassay; Biologic Assays; Biological Assay; Blood; Blood Plasma; Body Tissues; Bronchioalveolar Lavage; Bronchoalveolar Lavage; Budgets; CD4 Positive T Lymphocytes; CD4 T cells; CD4 lymphocyte; CD4+ T cell; CD4+ T-Lymphocyte; CD4-Positive Lymphocytes; CRISP; CTL; Cell Death, Programmed; Cell Function; Cell Growth in Number; Cell Mediated Immunology; Cell Multiplication; Cell Process; Cell Proliferation; Cell physiology; Cell-Mediated Immunity; Cell-Mediated Lympholytic Cells; Cell/Tissue, Immunohistochemistry; Cells; Cells, CD4; Cellular Assay; Cellular Function; Cellular Immunity; Cellular Physiology; Cellular Process; Cellular Proliferation; Cholera Enterotoxin CT; Cholera Exotoxin; Cholera Toxin; Choleragen; Computer Retrieval of Information on Scientific Projects Database; Containment; Cytokines, Chemotactic; Cytolytic T-Cell; Cytotoxic T Cell; Cytotoxic T-Lymphocytes; Cytotoxic cell; DNA; Deoxyribonucleic Acid; Detection; Development; ELISA; ELISPOT; Electromagnetic, Laser; Enzyme-Linked Immunosorbent Assay; Experimental Designs; Freezing; Funding; Future; Gamma Globulin, 7S; Gene Amplification; Gene Expression; Gene Products, RNA; Gene Targeting; Genes; Genetic; Grant; Histamine; Homologous Chemotactic Cytokines; Housedust Mites; Human Resources; Humoral Immunities; Hypersensitivity; IHC; IgE; IgG; Immune; Immune response; Immunities, Humoral; Immunity, Cellular; Immunoassay; Immunoglobulin E; Immunoglobulin G; Immunohistochemistry; Immunohistochemistry Staining Method; Immunologic Deficiency Syndrome, Acquired; Immunology; Immunology (Including BRMP); Immunology (NCI Program); Institution; Intercrines; Investigators; K lymphocyte; KLH; KLH antigen; Keyhole Limpet Hemocyanin; Lasers; Lavage, Bronchopulmonary; Leukocyte Culture Test, Mixed; Lung; Lung Lavage; Lymphocyte; Lymphocyte Culture Test, Mixed; Lymphocytic; MLC test; MLR test; Macaca; Macaque; Mammals, Primates; Manpower; Measures; Messenger RNA; Methods and Techniques; Methods, Other; Microscopy; Mites, House Dust; Mixed Leukocyte Reaction; Mixed Lymphocyte Culture; Mixed Lymphocyte Culture Test; Mixed Lymphocyte Reaction; Mixed T Cells, B Cells; Molecular; Monkeys; NIH; NK Cells; National Institutes of Health; National Institutes of Health (U.S.); Natural Killer Cells; Numbers; Operation; Operative Procedures; Operative Surgical Procedures; PBMC; PCR; Peripheral Blood Mononuclear Cell; Phenotype; Plasma; Polymerase Chain Reaction; Preparation; Primates; Procedures; Process; Production; Pyroglyphidae; RNA; RNA, Messenger; RNA, Non-Polyadenylated; Radiation, Laser; Rate; Reagent; Research; Research Personnel; Research Resources; Researchers; Resources; Respiratory System, Lung; Reticuloendothelial System, Blood; Reticuloendothelial System, Serum, Plasma; Ribonucleic Acid; SIS cytokines; SIV; Sampling; Serum, Plasma; Services; Simian Immunodeficiency Viruses; Source; Subcellular Process; Surgical; Surgical Interventions; Surgical Procedure; T-Lymphocytes, Cytotoxic; T4 Cells; T4 Lymphocytes; Targetings, Gene; Techniques; Testing; Tetanus Toxoid; Time; Tissues; Training; Transcript; Transplantation; Tryptase; United States National Institutes of Health; Viral; Viral Antigens; Work; antibody-based immunity; base; bronchopulmonary lavage therapy; chemoattractant cytokine; chemokine; cost; cytokine; design; designing; enzyme linked immunospot assay; helper T cell; host response; immunogen; immunoresponse; keyhole-limpet hemacyanin; lung tryptase; lymph cell; lymphocyte proliferation; mRNA; mast cell protease II; mast cell tryptase; mixed lymphocyte reaction test; model organism; natural gene amplification; new technology; personnel; pulmonary; skin tryptase; surgery; transcription factor; transplant; virus antigen

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The Analytical and Resource Core at the California National Primate Research Center provides services and resources to the scientific research community, both nationally and internationally, as well as to the CNPRC animal colony. The users of this core include investigators studying SIV. Scientists and staff associated with each of the seven Core Laboratories provide consultation in experimental design, sample collection, and data analysis, and offer assays that utilize species-specific reagents wherever possible. Core Laboratory scientists can also work with users to develop new assays to meet research needs. Training is available for all assays, and Core Laboratories equipment can be made available. Nonhuman primate resources developed at CNPRC are available to qualified individuals via the Resource Services component of the Core.

DESCRIPTION (provided by applicant): Asthma has long been recognized as having a significant psychosocial component. Considerable evidence exists that psychosocial factors, such as anxiety, depression, and inhibited temperament, are associated with asthma. While many studies have contrasted asthmatic and non-asthmatic people using these constructs, such an approach cannot determine whether these factors are predisposing to development of asthma. A handful of prospective studies, however, do suggest that individuals possessing some of these characteristics at an early age are more at-risk for developing asthma in the future. The ability to identify at-risk individuals early in development and prior to development of asthmatic symptoms would be of enormous benefit, in that predisposing genetic, immunologic, and neurologic mechanisms could be identified, and interventions developed that might pre-empt the development of asthma. Such an approach has recently been suggested as having great value, although conducting such research with humans is very difficult and expensive, and would take years to accomplish. A preliminary, retrospective study of rhesus monkeys enrolled in an asthma project demonstrated that indicators of inhibited temperament and blunted cortisol responsiveness, assessed in infancy, predicted which animals would develop airways hyper-responsiveness as juveniles, and which would not. In the proposed study, we will contrast prospectively two sets of juvenile animals on a variety of asthma-relevant measures. Animals that showed inhibited temperament and blunted cortisol responsiveness to brief maternal separation in infancy will comprise our "at-risk" sample. The second set will be control animals that did not show those characteristics. Our specific aims are to: 1) confirm prospectively our retrospective finding that infant monkeys with a blunted cortisol response and an inhibited behavioral style show airways hyper-responsiveness as juveniles;2) determine whether differences in temperament are associated with asthma-relevant immune measures;3) determine whether differences in temperament are associated with altered hypothalamic-pituitary-adrenal activity;4) examine how infant temperament relates to current measures of behavioral functioning in juvenile animals, and determine whether measures of current functioning increase the ability to predict which animals display asthma-related outcomes. PUBLIC HEALTH RELEVANCE: The prevalence of asthma is increasing greatly throughout the world, especially in developed countries. Using an experimental animal model that has close parallels to asthma in humans, the proposed project is aimed at identifying individuals that might be at-risk for developing asthma. The eventual goal of this line of research is to identify effective interventions that could be implemented early in life that might pre-empt development of this disease.

DESCRIPTION (provided by applicant): This is a collaboration between experts at UCSD, UCLA, UCSF, UC Irvine, and UC Davis to examine plasticity and regeneration in the non-human primate spinal cord. Our goal is to enhance knowledge and translational relevance of research on spinal cord injury (SCI). Given findings of the last 5 years in this model, we focus this renewal on efforts to better understand and amplify the endogenous plasticity revealed in the primate system, and to test the translation of leading potential treatments discovered in non-primate models. Aim 1: Examine Electrophysiological and Anatomical Mechanisms Underlying Spontaneous Forelimb Functional Improvement After Primate SCI. Like humans, monkeys exhibit spontaneous improvement (but not full recovery) after C7 hemisection, and we have identified a remarkable degree of spontaneous sprouting of the primate corticospinal projection in association with this functional improvement. Aim 1 will examine the time course of molecular, electrophysiological and systems-level (both corticospinal and non-corticospinal) mechanisms associated with behavioral improvement. Aims 2 and 3: Test Candidate Therapies for Promoting Recovery The primate model of SCI is important not only for testing the efficacy of therapies discovered in rodents, but also for developing methods to deliver potential treatments to the larger primate system. We have tested several therapies in the last period of this grant, and plan to focus on new, promising approaches in the current grant period that target enhancement of plasticity and recovery. We will use the same techniques as in Aim 1 to examine the functional, electrophysiological, and anatomical consequences of the following: Aim 2: Chronic, Intermittent Stimulation with Cortically-Implanted Electrodes to Drive Plasticity of Spared Corticospinal Projections and Intraspinal Circuits. Aim 3: Chase Treatment after SCI. PUBLIC HEALTH RELEVANCE: This research program will develop and test promising therapies for spinal cord injury in an animal model that could most closely predict human benefit. This is a collaborative endeavor between five research groups working closely together to accelerate discovery of therapies for human nervous system injury.

PRIMATE SERVICES: BIOBEHAVIORAL ASSESSMENT ABSTRACT Our unique developmental and biobehavioral makeup affects our risk for disease and the effectiveness of medical intervention, a key concept in precision medicine. It is becoming increasingly clear that biomedical models of disease must account for individual variation to achieve peak translatability with human health research. The BioBehavioral Assessment (BBA) Program at the California National Primate Research Center (CNPRC), launched in 2001, has quantified measures of biobehavioral organization (i.e., temperament, physiological reactivity, genetics) in more than 5000 infant rhesus monkeys to date. BBA has provided the basis for more than 70 publications and has contributed important discoveries on the developmental roots of health and disease (e.g., asthma, autism, depression, and diarrhea). BBA has been identified as a keystone CNPRC research resource by our National Scientific Advisory Board and in base grant reviews. The goals of this program have been threefold: 1) to comprehensively inventory individual macaque biobehavioral organization and relate this information to health outcomes; 2) to make data available as a resource for scientific inquiry (e.g., for subject selection); and 3) to contribute to the knowledge and improvement of the nonhuman primate resource at our own center, and through our published studies, provide important information to management staff at other primate facilities in the United States as well. In this revised P51 application to embed BBA as a CNPRC animal resource, we propose to optimize this exceptional program with a new vision to propel the BBA resource into the next decade of NHP research. This four-tiered vision includes: 1.) Developing new constructs from historical BBA data to predict health and disease, 2.) stimulating a longitudinal health span approach in CNPRC research, by formally linking BBA with our NIA geriatric research program 3.) increasing user ship of the resource by offering consulting and custom testing options for PIs, and 4.) making BBA data universally accessible by developing and beta testing an interactive educational and data sharing website to be completed in three phases, made public in 2020 and completed by 2022. It is anticipated that new BBA research directions and accessibility will yield a large leap forward in scientific discovery and public understanding of biobehavioral organization in NHP development.