1986 |
Sheridan, John F |
R03Activity Code Description: To provide research support specifically limited in time and amount for studies in categorical program areas. Small grants provide flexibility for initiating studies which are generally for preliminary short-term projects and are non-renewable. |
Viral Infection &Salivary Gland Graft-Vs. Host Disease
Graft-versus-host disease (GVHD), a significant complication of bone marrow transplantation (BMT) frequently affects the salivary and lacrimal glands producing a Sjogren's-like syndrome. The primary and secondary clinical effects of GVHD in these glands are similar to those seen with Sjogren's syndrome: dry, burning mouth and incrased incidence of dental caries and candidal infections. Hisopathological findings of GVHD in these tissues appear similar to Sjogren's syndrome with a lymphocytic infiltrate beginning periductally and the later development of epimyoepthelial islands. Other similarities which exist between GVHD of the salivary and lacrimal glands and Sjogren's syndrome include various immunologic abnormalities, associated with other autoimmune phenomena, HLA associated genetic predisposition, and association with viral infection. A preceeding viral infection has been associated with the development of both GVHD and Sjogren's syndrome in clinical and experimental studies. Preliminary studies have shown that GVHD in the salivary and lacrimal glands and other tissues of the rat BMT model closely parallel GVHD in the human. In order to further develop GVHD in the salivary and lacrimal glands of the bone marrow transplanted rat as a model for Sjogren's syndrome, the link of viral infection to salivary and lacrimal gland GVHD will be studied. The specific aims of this project are: 1) To infect rat salivary and lacrimal glands with the coronavirus Sialodacryoadenitis virus (SDAV) and to cause the development of GVHD in these tissues; 2) To examine the infected tissues and other head and neck tissues for histological evidence of SDAV infection and/or GVHD; 3) To correlate the pattern and timing of the viral infection with the onset of GVHD in the infected and distant tissues using light microscopy and immunofluorescent techniques.
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1 |
1988 — 1992 |
Sheridan, John F |
R29Activity Code Description: Undocumented code - click on the grant title for more information. |
Cmi Regulation and Reinfection--Role of Contralymphokine
Reinfection of an influenza A virus seropositive host with another strain A or homologous virus occurs in both humans and experimental animal models and provides an opportunity to investigate lymphokine regulation of secondary antiviral cell- mediated immunity. The use of an experimental animal model of reinfection provides opportunity to study the immunobiology of the antiviral responses at the site where the antigen is replicating (lungs) and in the regional (mediastinal) lymph node. The long term objective is two-fold: 1) to determine why, following resolution of an influenza viral infection, the seropositive host may still be susceptible to infection with the same strain of serotype of virus; and 2) to determine the operative immunologic mechanism(s) which prevents the expression of a DTH response in lungs of an influenza (A/Bangkok) seropositive host following reinfection with a second (A/PR8) strain A virus. With regard to the first objective, while it is likely that antigenic differences in the homologous virus are responsible for some susceptibility to reinfection, we hypothesize that components of the seropositive host's immune response actually facilitate reinfection and promote limited virus replication upon re- exposure to homologous virus. Further, we propose that the host mechanism which facilitates reinfection, also functions to prevent expression of a delayed-type hypersensitivity (DTH) in lungs of an influenza A seropositive host following reinfection with another strain A virus. The absence of a DTH response in the lungs of an A/Bangkok primed mouse reinfected with A/PR8 reflects the activation of an immunologic mechanism that suppresses the expression of the DTH. The immunologic mechanism appears to involve a small molecular weight protein termed a "contralymphokine" which prevents the expression, but not the production of, lymphokines associated with DTH. In the mouse influenza reinfection model, we have detected a contralymphokine, produced by mononuclear cells in response to viral antigen stimulation, which interferes with the expression of LIF in a migration assay, IL2 in an NK enhancement assay, and IL2 in a proliferation (CTLL-20) assay. In this proposal, the contralymphokine will be purified, characterized and its mechanism of action determined in the LIF migration assay and the IL2 CTLL-20 proliferation assay. These studies will provide information on the regulation of lymphokine expression during viral reinfection of a primed host.
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1 |
1990 |
Sheridan, John F |
R03Activity Code Description: To provide research support specifically limited in time and amount for studies in categorical program areas. Small grants provide flexibility for initiating studies which are generally for preliminary short-term projects and are non-renewable. |
Regulation of Immunity to Herpes Simplex Virus
The hallmark of herpetic disease is the ability of the virus to become latent in ganglia and cause recurrent disease. While recovery from a primary infection with Herpes simplex virus (HSV) is associated with the development of virus-specific immunologic memory, reactivation of latent virus causes symptomatic disease in many patients. The observation that in immunocompetent hosts, HSV lesions are limited and of relatively short duration, whereas individuals with impaired T cell response suffer severe herpetic recurrences, has led to the hypothesis that recurrent disease is associated with regulatory defects in virus-specific T cell responses. Recently, data have been collected that indicate that the immune system and the nervous system communicate through the release of soluble factors (cytokines). It has been argued that this communication is bi-directional with products of the nervous system affecting the biological behavior cells of the immune system and vice-versa. Experimental studies have also demonstrated that neuropeptides (NP) such as vasoactive intestinal peptide (VIP), somatostatin (SOM), substance P (SP), gastrin-releasing peptide (GRP) can affect lymphocyte proliferation and lymphokine production. Furthermore, it has been established that lymphatic tissues are extensively innervated and contain various neurotransmitters. Taken together with the fact that lymphocytes and monocytes express specific receptors for various neuropeptides, these data provide the evidence for a regulatory network that involves NP and immunocyte interactions. HSV causes a latent infection in which the latent viral genome resides in the sciatic (genital infections) or trigeminal (labial infections) ganglia. Upon reactivation of the latent virus, axonal transport mechanisms within the neuron carry the viral entity towards the permissive cells (epithelial). It is postulated that reactivation is associated with the localized release of neurotransmitters and cotransmitters (such as VIP) by the neurons and that these substances can regulate the biologic behavior of lymphocytes that arrive at the site of virus replication. If this is the case, then HSV specific lymphocytes should express functional receptors for neurotransmitters. And further, the binding of neurotransmitter to an HSV-stimulated lymphocyte should alter the biologic response of the cell. Therefore, the specific aim of this proposal is to determine if neuropeptides modulate the proliferation and lymphokine secretion of human lymphocytes stimulated with HSV antigen. To accomplish this goal mononuclear cells (containing monocytes and lymphocytes) will bc obtained from the peripheral blood of normal individuals and patients during recurrent HSV disease. Cell cultures will be established containing cells, viral antigen and neuropeptides. Initially four neuropeptides will be studied (VIP, SOM, SP and GRP). Antigen-specific proliferation will be measured and culture supernatant will be assayed for lymphokine (IL-2, IL-4, INF-gamma, and LIF). Both dose response and kinetics studies will be performed with each of the neuropeptides. The results from patients with recurrent disease will be compared to results obtained from normal volunteers without recurrent disease.
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1 |
1991 — 1993 |
Sheridan, John F |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Stress-Induced Immunosuppression of Anti-Viral Immunity
Research on the relationship between the immune system and the nervous system provides evidence of anatomical and physiological pathways through which stress may modulate the immune response. Studies conducted in humans have demonstrated that an increase in psychological stress sustained over time can lead to adverse immunological changes. Therefore, the long-term objective of this study is to define the mechanism(s) by which stress affects the immune response to an infectious agent. In this application, the mechanism(s) by which stress causes immunosuppression and affects health will be examined in an experimental influenza viral infection in an animal model. Infection of mice by influenza virus provides a model of an acute respiratory infection. The specific aims of the program are to assess the effect of restraint stress on the immune response during the effect of restraint stress on the induction of the pituitary-adrenal axis and catecholamines will be investigated during infection to determine the mechanism of immunoregulation by which these hormones (ACTH and corticosterone) and biogenic amines (norepinephrine, epinephrine, and dopamine) affect a virus-specific immune response. Resolution of an influenza viral infection requires the activation of antigen-specific T lymphocytes. CD4+ T lymphocytes possess an antigen receptor complex that binds specific viral antigen which has been processed and presented by antigen-presenting cells in association with class II major histocompatibility complex molecules (MHC). Activation of CD4+ lymphocytes results in the expression of genes coding for lymphokines and is associated with the development of delayed-type hypersensitivity (DTH) responses. Furthermore, lymphokine production by CD4+ lymphocytes is central to the effective generation of antigen-specific cytolytic T lymphocytes (CD8+) and provides helper functions for the production of virus-specific antibodies. Activated T cells are not sessile, they traffick in and out secondary lymphoid tissues and tend to accumulate in sites of inflammation. During the course of an influenza infection, virus- specific T cells accumulate at the site of virus replication (the lung), in the draining lymph nodes (mediastinal) and in the spleen. In previous studies it was shown that restraint stress significantly altered the inflammatory response in the lung, reduced the accumulation of lymphocytes in the lung during infection, and suppressed the IL-2 response by mediastinal and splenic CD4+ T cells stimulated with influenza virus. Thus, the influenza virus model provides a system in which to examine the immunological, endocrinological, and pathological changes associated with stress during a viral infection.
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1 |
1991 |
Sheridan, John F |
S15Activity Code Description: Undocumented code - click on the grant title for more information. |
Small Instrumentation Grant
biomedical equipment purchase;
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1 |
1994 — 1997 |
Sheridan, John F |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Aging, Stress and Viral Infection--Neuroimmune Modulation
influenza vaccines; stress; sympathetic nervous system; neuroendocrine system; psychoneuroimmunology; aging; influenzavirus A; influenza; adrenocorticotropic hormone; immunologic memory; glucocorticoids; dehydroepiandrosterone; hormone regulation /control mechanism; cellular immunity; cytokine; humoral immunity; active immunization; pituitary adrenal axis; norepinephrine; hypothalamic pituitary axis; psychological stressor; behavioral /social science research tag; animal old age; northern blottings; flow cytometry; laboratory mouse;
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1 |
1995 — 1998 |
Sheridan, John F |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Stress-Induced Immunosuppression of Antiviral Immunity
Recent observations in both humans and animal models have demonstrated that stress is immunomodulatory, and can alter the pathogenesis of microbial infections to the extent that stress may be aversive to health. Stress has been shown to increase the susceptibility to, and severity of, the viral infectious disease process. It is most important that the mechanisms underlying enhanced disease susceptibility be fully understood so that the appropriate therapeutic strategies can be applied, or new ones developed. The mammalian response to a stressor is primarily mediated by two neuroendocrine systems: the sympathetic nervous system (SNS) and the hypothalamic-pituitary-adrenal (HPA) axis. This revised proposal focuses on neuroendocrine regulation of immunity during viral infection, particularly as it pertains to lymphocyte localization, activation, and effector function. The overall purpose is to examine the neuroendocrine mechanisms (with emphasis on glucocorticoid and catecholamine responses) that modulate specific anti-viral immune responses and thus alter the pathophysiology of the infectious disease process. We have shown that restraint stress significantly suppresses Th1 responses (IL-2), while anti-viral antibody responses, which require Th2 activation, are essentially intact. Other studies have shown that elevated glucocorticoid (GC) levels suppress IL-2 and enhance IL-4 responses. We previously have shown elevated and sustained levels of GC in infected/stressed mice, and would expect that neuroendocrine responses regulate the balance of Th1/Th2 subset activation. We also have found that restraint stress reduces leukocyte infiltration into sites of infection as well as decreasing the cellularity of the regional lymph nodes draining those sites. Although lymphadenopathy was restored by treating stressed animals with a glucocorticoid receptor antagonist, T cell activation in the draining lymph nodes remained suppressed unless a Q-adrenergic receptor antagonist was given. Therefore, our preliminary data has led us to hypothesize that the reduced inflammatory response in restraint-stressed mice is due either to direct inhibition of cellular adhesion molecule expression by GC or indirectly via down-regulating secretion of pro-inflammatory cytokines and chemokines from resident cells such as macrophages and neutrophils. In addition, antagonism of the (3-adrenergic receptor suggested a role for catecholamine in regulation of T cell activation. Thus, we hypothesize that stress acts as a co- factor in the progression of infection by enhancing Th2 while diminishing the proinflammatory Th1 responses to viral antigen.
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1 |
1999 — 2003 |
Sheridan, John F |
P50Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These grants differ from program project grants in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes. |
Behavioral/Neuroendocrine Regulation of Wound Healing
DESCRIPTION (adapted from investigator's abstract): The hypothesis of this proposal is that physiologic changes associated with stress, down-regulate pro-inflammatory cytokine, chemokine and growth factor gene expression resulting in alterations in cellular trafficking and activation, thus impairing wound healing. The long term goal of these studies is to understand the mechanisms underlying stress-related changes between the neuroendocrine and inflammatory responses that are responsible for altered wound healing. The aims of the proposal are 1) to determine the influence of stress on the pattern and kinetics of chemokine, pro-inflammatory cytokine and growth factor gene expression during the early stages of wound healing, 2) to determine the stress-induced, neuro-endocrine mechanisms that regulate pro-inflammatory cytokine, chemokine and growth factor gene expression during wound healing and 3) to determine the mechanism of the anti-glucocorticoid actions of androstenediol (a metabolite of DHEA) and delineate its ability to regulate pro-inflammatory cytokines (IL-1 alpha and beta and TNF alpha), chemokines (KC, IP10, MCP-1 and MIP 1 alpha) and growth factor (KGF, VEGF and TGF beta )gene expression as a therapeutic strategy to improve wound healing in stressed individuals. The proposal makes use of histological, molecular biology and pharmacological approaches to address the specific aims. The in vivo study of wound healing is accompanied by in vitro studies of the direct effect of glucocorticoids and AED (a metabolite of dihydroxyepiandrosterone) on cellular expression of transcription factors and cytokines. Restraint stress repeated over several days is to be used as a stress paradigm, skin wounding will be used to determine the rate of healing and the profile of cytokines and chemokines during the healing period. Subsequent studies will use an in vitro approach in which neutrophils and macrophages isolated from female mice will be incubated with corticosterone to determine the effect of LPS induced stimulation of cytokine and chemokine release and on changes in NF-kappa beta. In addition, the influence of AED on wound healing, cytokine and chemokine production and transcription factor NF-kappa beta will also be addressed in vivo.
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1 |
1999 — 2003 |
Sheridan, John F |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Social Reorganization, Hpa Reactivity and Inflammation
DESCRIPTION (applicant's abstract): Increasing evidence suggests that psychosocial stress poses a significant health risk. Although it has been documented that many of the effects of physical restraint stress on the immune system are attributable to glucocorticoid-mediated immunosuppression, recent evidence reveals that exposure to a psychosocial stress, social reorganization (SRO), causes increased mortality in an experimental viral infection by novel mechanisms. A salient finding is that peripheral immune cells from SRO animals fail to respond to the suppressive effects of glucocorticoids. Subsequent viral challenge results in hyper-cellular responses and severe tissue damage. However, the mechanisms by which SRO stress induces the observed aberration in glucocorticoid function leading to hyper-cellular and hyper-inflammatory responses have not been determined. The hypothesis to be tested is that the stress of social reorganization induces a state of functional glucocorticoid resistance, resulting in the inability of the host to restrain inflammatory responses. The following specific aims are proposed to test this hypothesis: 1) Examine the social hierarchy and interactions during social reorganization that lead to the development of functional glucocorticoid resistance. 2) Determine how social reorganization alters the regulation of the hypothalamo-pituitary-adrenal axis, which regulates the production of glucocorticoids. 3) Determine the effects of social reorganization on the inflammatory immune responses. 4) Determine the effects of social reorganization on the balance between TH1 and TH2 responses during infection. 5) Determine the cellular mechanisms of GC resistance. Aim 1 is designed to correlate the magnitude and the type of stress with the development of glucocorticoid resistance. In Aim 2, specific changes induced in the neuroendocrine system that translate the state of psychosocial stress to the state of glucocorticoid resistance will be identified. In Aims 3 and 4, we will clarify whether the observed hyper-inflammation is due to an enhanced innate inflammatory response, or due to an inability to switch from a TH1 to a TH2 response, thus prolonging pro-inflammatory responses. Finally, in Aim 5 we will determine whether the function of the glucocorticoid receptors has been altered during social reorganization. This study will attempt to elucidate the central and peripheral mechanisms by which a psychosocial stressor impacts a host's resistance to challenge.
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1 |
1999 — 2000 |
Sheridan, John F |
R13Activity Code Description: To support recipient sponsored and directed international, national or regional meetings, conferences and workshops. |
Research Perspectves in Pni, Trainee Travel
The funds requested herein are for support of 25 pre- and post- doctoral trainees to attend the conference of the Psychoneuroimmunology Research Society, (PNIRS) entitled, "Research Perspectives in Psychoneuroimmunology IX to be held in Galveston, Texas (April 28th to May 1st, 1999). This is the ninth in a series of international conferences in this field. At present, there are over 200 members of the PNIRS from the U.S. and abroad, of whom about 25 percent are trainee members. The officers are: John Sheridan, President; Virginia Sanders, Secretary/Treasurer; Keith Kelley, President-elect; George Solomon, Past-president. A Program Committee chaired by John Sheridan includes Suzanne Stevens-Felten, Cobi Heijnen, Rodney Johnson, Keith Kelley, Donald Lysle, Virginia Sanders, Linda Watkins, and Richard Weber. This committee is charged with organizing the scientific program and selecting the abstracts for presentation. That psychological factors alter the susceptibility to illness and affect disease progression has been suggested by a considerable body of research. To determine the mechanisms by which psychological factors have this effect, it is essential that interactions among immunologists, neuroscientists, and behavioral scientists be promoted and enabled. This conference will provide an outstanding opportunity for trainees to interact with researchers in the field of psychoneuroimmunology (nervous-immune system interactions and their clinical implications). They will learn about available resources for collaborative work, additional training opportunities, and concerns regarding technical aspects of analysis in the areas of immunology, neurophysiology, neuroanatomy, endocrinology, psychology, and health evaluations, among others. As we conceptualize this conference, it will provide exciting directions for future research. The conference program will include the seventh Norman Cousins Lecture, three symposia, plenary presentations, short oral presentations, poster sessions, and informal group discussions. The oral and poster sessions will be selected from abstracts submitted to the Program Committee. Special efforts will be made at this meeting to foster research collaborations and provide opportunities for students to meet with senior investigators. Special venues will enable student-senior scientists and student-student interactions. A further request is made to fund this meeting annually for a total of five years. While the meeting venue will be moved each year, the organizational structure, meeting objectives, and training opportunities for fellows will remain unchanged.
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1 |
2000 — 2002 |
Sheridan, John F |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Neuroendocrine Regulation of Wound Healing During Aging
Efficient cutaneous wound healing quickly restores the protective barrier to an injured surface. However, delayed healing can occur as a consequence of any number of processes that affect the early inflammatory stages of wound healing. For example, the physiological changes associated with aging and the immunosuppressive influences of psychological stress have been shown to slow wound healing. Pro- inflammatory cytokine, chemokine and growth factor responses are necessary for the coordinated function of polymorphonuclear leukocytes, monocytes and keratinocytes at the wound site. Therefore, the rapid expression of genes encoding immunomodulatory proteins and peptides is necessary for efficient healing. Combined with age-related immunosenescence, stress puts elderly individuals at high risk for infection after surgical or accidental wounds. With advancing age and during times of stress there is an increase in the cortisol/DHEA ration in the blood which may be responsible for catabolic effects associated with both states. DHEA (and its metabolite, AED) have been reported to have immunorestorative, anti-aging and anti-glucocorticoid properties. Therefore, in these studies we will investigate how AED counter balances age- and stress-mediated decrements in inflammatory/immune responses during cutaneous wound healing. An established murine model will be used to examine the kinetics and patterns of gene expression during the early phases. Further studies will seek to identify stress and age associated variables that modulate the expression of pro-inflammatory cytokine, chemokine and growth factor genes. The specific aims of this application are: (a) Determine the influence of stress and aging on the pattern and kinetics of pro-inflammatory cytokine, chemokine, and growth factor gene expression during the early stages of wound healing; (b) Examine the stress-induced neuroendocrine responses that impact gene expression during wound healing; (3) Determine the therapeutic efficacy of androstenediol (a metabolite of DHEA) treatment in the context stress- and age-associated slowing of wound healing.
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1 |
2003 — 2005 |
Sheridan, John F |
T32Activity Code Description: To enable institutions to make National Research Service Awards to individuals selected by them for predoctoral and postdoctoral research training in specified shortage areas. |
Comprehensive Training in Oral &Craniofacial Sciences
DESCRIPTION OF TRAINING PROGRAM: (provided by applicant) This proposal integrates ongoing training programs within the Ohio State University Health Sciences Center under the umbrella of the College of Dentistry to address the urgent need to train faculty in oral health and craniofacial research. The faculty and administration in the College of Dentistry have recognized the acute and long-term shortage of qualified researchers in multidisciplinary research. Over the last decade, training programs such as DDS/PhD and Clinician Scientist programs have been developed in the College of Dentistry to train academic clinicians in multidisciplinary research. The administration has funded these programs by providing stipends and tuition for these trainees. Trainees have responded by acquiring individual NRSA support from the NIDCR. Thus, this proposal engages many training programs already in place within the College of Dentistry and integrates them into a comprehensive multidisciplinary training program. It takes advantage of a strong interdisciplinary faculty working in the framework of a vital and expanding Health Sciences Center. Training opportunities will include: 1) short-term training programs for pre-doctoral students and faculty; 2) Ph.D. training in the Oral Biology Ph.D. program and three multidisciplinary parallel programs in Integrated Biomedical Sciences, Neuroscience, and Biomedical Engineering; 3) combined DDS/PhD and MD/PhD dual training; 4) post doctoral training including post PhDs and Clinician/Scientists; and 5) long term research training/retraining for faculty. The focus of each of these programs is to develop research experiences that will help to identify, recruit, train, and retain qualified researchers in academic careers in the oral health and craniofacial sciences. A central focus of this proposal is the recruitment of highly qualified candidates into flexible training programs that will provide researchers with long-term success in the future. The second focus is to provide additional training opportunities for current faculty. The key features of this training program are an innovative multidisciplinary basic science curriculum that is based upon the mechanisms of human disease, a flexible curriculum in the oral sciences that links trainees from various biomedical programs, and a long-term plan to mentor trainees for careers in academic research.
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1 |
2004 — 2008 |
Sheridan, John F |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Social Stress, Gc Resistance and Innate Immunity
DESCRIPTION (provided by applicant): The overarching concept in this proposal is that social interactions matter to the level of gene expression. A model of repeated social defeat will be used to elucidate the pathways and mechanisms by which social stress affects peripheral physiology. The target physiological system is the immune system, and host resistance to infectious challenge is the health outcome of interest. By examining interactions among the nervous, endocrine and immune systems, ligands and receptors will be identified that are key components in modulating innate resistance during social stress. Innate immune cell activation is frequently accompanied by gene expression induced by the binding of specific cell surface receptors. Gene expression within these cells can be altered by products of the nervous and endocrine systems. Molecules released upon stress-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis and sympathetic nervous system can bind to receptors on innate immune cells and influence their activation and function. In what might be considered an environment by gene interaction, social stress shapes peripheral physiological responses as the host responds to new environmental demands imposed by social stress. The major hypothesis to be tested is that social interaction that involves repeated defeat, will activate a stress response, induce GC resistance and alter host resistance to infectious disease. The following specific aims are proposed to test this hypothesis. 1. Determine which aspects of behavior are important in social disruption (SDR) for the development of glucocorticoid (GC) resistance. 2. Examine the neuroendocrine and growth factor responses activated by SDR. 3. Examine the cellular and molecular mechanisms of GC resistance in splenic CD11b+ mononuclear cells. 4. Determine the effect of SDR on innate immunity and susceptibility to infectious disease. This study will elucidate the mechanisms of immunoregulation and host resistance to disease that are altered by social stress.
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1 |
2006 — 2021 |
Sheridan, John F |
T32Activity Code Description: To enable institutions to make National Research Service Awards to individuals selected by them for predoctoral and postdoctoral research training in specified shortage areas. |
Comprehensive Training in Oral and Craniofacial Sciences
[unreadable] DESCRIPTION (provided by applicant): This proposal is a competitive renewal of an institutional NRSA training grant titled: "Comprehensive Training in Oral and Craniofacial Sciences." The goal of this program is to integrate ongoing training programs within the Ohio State University Health Sciences Center, under the umbrella of the College of Dentistry, to address the urgent need to train faculty in oral health and craniofacial research. Faculty in the CTOC program recognizes the shortage of qualified research faculty in multidisciplinary research to fill positions in academic dentistry. Over the last 15 years, programs have been developed in the OSU College of Dentistry to train academic clinicians in multidisciplinary research. The DDS/PhD and Clinician Scientist programs were started with funding provided by the College. In time, trainees successfully wrote individual NRSA grants to support their training. In this training environment, faculty in the College of Dentistry, together with faculty in the OSU Health Sciences Center, prepared an institutional NRSA that was funded four years ago. The CTOC program has enriched the training environment for in the College and provides opportunities for: 1) short-term training programs for pre-doctoral students and faculty; 2) predoctoral training in the Oral Biology PhD program and three parallel programs in Integrated Biomedical Sciences, Neuroscience/Psychobiology, and Biomedical Engineering; 3) combined DDS/PhD training; and 4) post doctoral training including post PhDs and Clinician/Scientists; 5) long term research training for faculty. The focus of each of these programs is to develop research experiences that will help to recruit, train, and retain qualified academicians in oral health and craniofacial sciences. We have successfully recruited trainees in each of the training programs mentioned above. Currently, there are 9 DDS/PhD trainees, 5 predoctoral and 3 postdoctoral trainees (including one faculty member), and 6 short-term dental student trainees. A central focus continues to be the recruitment of highly qualified candidates into flexible training programs that will provide them with long-term success. A second focus is to provide training opportunities for junior faculty. The CTOC program provides an innovative multidisciplinary basic science curriculum based on the mechanisms of human disease, a flexible curriculum in the oral sciences that links trainees from various biomedical programs, and a long-term plan to mentor trainees for careers in academic research. [unreadable] [unreadable] [unreadable]
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1 |
2012 — 2016 |
Sheridan, John F |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Social Threat Primes Myeloid Progenitor Cells and Microglia: Role in Anxiety
DESCRIPTION (provided by applicant): Psychological stressors, including social stressors, profoundly influence immunity and behavior. In humans, chronic stress is associated with an increased prevalence of mental health complications, including anxiety and depression. While it is well known that these stress-associated conditions significantly affect health and influence quality of life, the mechanisms involved are not completely understood. In this proposal, we present novel data that indicate that anxiety-like behavior caused by exposure to social disruption (SDR), a model of social stress, is associated with the egress and trafficking of bone marrow (BM)-derived, glucocorticoid (GC)-insensitive myeloid progenitor cells (MPCs). Moreover, following SDR we show that these bone marrow-derived MPCs (CD11b+/Ly6Chigh/CCR2+) traffic to specific brain regions. Previous reports indicate that MPC populations, including dendritic cells (CD11c+/CD11b+) and macrophages (CD11b+) collected from the spleens of mice exposed to SDR were insensitive to the anti- inflammatory regulation provided by GCs. This is relevant because GC-insensitive MPCs are associated with hyper-inflammatory immune responses. Along with changes in BM-derived myeloid populations, social threat increases the reactivity of resident microglia in the brain. For example, microglia collected from SDR mice showed a primed phenotype with increased surface expression of several inflammatory markers, including CD86, TLR4, and CD14 (J. Neuroscience 2011, in press). Corresponding with their primed phenotype, microglia from mice exposed to SDR produced higher levels of inflammatory cytokines following mitogen stimulation. Therefore, the overarching goal of this project is to test the hypothesis that social threat activates catecholaminergic pathways that increase the activation of resident microglia and increase the infiltration of MPCs to prolong anxiety-like behavior. To address this hypothesis we propose three specific aims using a mouse model of social threat that results in the activation of neurocircuitry associated with threat appraisal and fear/anxiety-like responses. In the first aim we will elucidate the neuroendocrine pathways that contribute to the development and egress of GC-insensitive MPCs from the bone marrow after social threat. In the second aim we will elucidate the mechanism by which social threat facilitates the recruitment of MPCs to specific brain regions. In the third aim, we will determine how social threat-induced activation of microglia and MPC recruitment contributes to prolonged anxiety-like behavior. These aims are relevant to understanding how stress-associated activation of innate immune cells contributes to anxiety-like behavior and may lead to interventions that diminish neuroinflammation and prolonged neurobehavioral complications. PUBLIC HEALTH RELEVANCE: In humans, chronic stress is associated with an increased prevalence of mental health disorders including anxiety and depression. While it is well known that stress-associated conditions significantly influence health and the quality of life, the mechanisms involved are not completely understood. We propose that stress- induced anxiety-like behavior is exacerbated by inflammatory changes in the brain mediated by the infiltration of bone marrow-derived myeloid progenitor cells (MPCs) into the brain parenchyma. The trafficking of MPCs is regionally specific, and occurs in response to neuronal activation. In this proposal, a murine model of social threat will be used to test the hypothesis that social stress promotes the activation of catecholamine circuits that stimulate bone marrow-derived MPCs to traffic to the brain and produce cytokines that cause prolonged anxiety-like behavior.
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1 |
2013 — 2017 |
Sheridan, John F |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Brain Region Dependent Trafficking of Myeloid Precursor Cells in Repeated Defeat.
DESCRIPTION (provided by applicant): Psychosocial stressors are associated with an increased prevalence of mental health complications including anxiety and depression. While it is known that chronic stressors negatively affect health and influence quality of life, the mechanisms that underlie these neurobehavioral deficits are not well understood. In this proposal, we present novel data that repeated social defeat (RSD)-induced anxiety-like behavior is associated with the egress and trafficking of bone marrow (BM)-derived, glucocorticoid (GC)-insensitive myeloid cells to the brain. Moreover, RSD promotes the infiltration of CD11b+/Ly6Chigh/CCR2+ myeloid cells to specific brain regions associated with fear and threat appraisal. Our data also indicate that IL-1 receptor type-1 (IL-1R1) and ¿-adrenergic receptor (¿-ADR)-dependent pathways are critical in the development of behavioral and immunological alterations promoted by RSD. Additionally, that RSD promotes glucocorticoid (GC) insensitivity in peripheral myeloid cells. This is relevant because GC-insensitive cells are hyper-inflammatory following activation, that is, they express high levels of proinflammatory genes. Here evidence is also provided indicating that CD11b+ cells in the brain (resident microglia and infiltrating myeloid cells) are primed and less sensitive to GC. The goal of this 5 year project is to test the hypothesis that repeated social defeat stimulates trafficking of primed GC-insensitive, CD11b+/LyC6high/CCR2+ myeloid cells from the bone marrow to fear and threat appraisal regions in the brain to promote prolonged anxiety-like behavior. To address this hypothesis, three specific aims are proposed: 1). We will determine the degree to which RSD promotes the development of a permissive neurovascular unit to elicit brain region-dependent infiltration of CD11b+/Ly6Chigh/CCR2+ myeloid cells. We will focus on the role of ¿-ADR and central IL-1R1 pathways in RSD-induced myeloid cell recruitment. Moreover, it is critical to compare and contrast the infiltrating myeloid cells with the resident microglial population after RSD. 2). The phenotype, GC sensitivity, and proliferative capacity of these cells following RSD will be determined. These experiments will also determine time- and brain region-dependent differences in these myeloid populations following RSD. While it is established that circulating myeloid cells will traffic to sites of tissue damage under inflammatory conditions in the CNS, the release and trafficking of this specific myeloid population to the brain is unique in a model of psychosocial stress where significant CNS trauma is absent. 3). The degree to which blockade of the chemokine receptor-2 (CCR2) prevents CD11b+/Ly6Chigh/CCR2+ myeloid cell infiltration and reverses prolonged anxiety-like behavior associated with RSD will be determined. Understanding how stress-associated promotion of myeloid cell trafficking contributes to neuroinflammation and the promotion of long-lasting anxiety-like behavior may lead to novel interventions that target myeloid cell trafficking and attenuate prolonged neurobehavioral complications associated with chronic stress.
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2019 — 2020 |
Godbout, Jonathan P (co-PI) [⬀] Sheridan, John F |
R56Activity Code Description: To provide limited interim research support based on the merit of a pending R01 application while applicant gathers additional data to revise a new or competing renewal application. This grant will underwrite highly meritorious applications that if given the opportunity to revise their application could meet IC recommended standards and would be missed opportunities if not funded. Interim funded ends when the applicant succeeds in obtaining an R01 or other competing award built on the R56 grant. These awards are not renewable. |
Social Defeat and Stress-Sensitization: Neuro-Immune Role of Spleen in Recurrence of Anxiety
PROJECT SUMMARY/ABSTRACT: Neuroinflammation propagated by peripherally-derived monocytes/macrophages may have a causative role in chronic anxiety disorders. We report that repeated social defeat (RSD), a preclinical mouse model, induces a sympathetic-mediated release of myeloid cells from the bone marrow that traffic to regions of the brain associated with fear and anxiety. These peripheral myeloid cells promote a robust interleukin (IL)-1 inflammatory signal in the brain that induces prolonged anxiety-like behavior. Recent clinical data support a link between chronic stress, inflammatory monocytes, and anxiety. Critical to this proposal, RSD causes ?stress- sensitization? which is associated with long-term changes in the myeloid cells in the spleen and brain. This is relevant because clinical studies also detect inflammatory monocytes in circulation with stress and observed increased monocyte production in the spleen. Moreover, an important consequence of stress-sensitization with RSD is recurring anxiety after re-exposure to an acute stressor. This grant proposal will focus on stress- sensitization of the myeloid population that establishes in the spleen. The recurrence of anxiety is dependent on the release of inflammatory Ly6Chi monocytes from the spleen, which traffic to the brain and augment neuroinflammation. We report that splenectomy and blockade of norepinephrine (NE) both prevent increased monocyte trafficking to the brain and both block the recurrence of anxiety in stress-sensitized mice. Furthermore, novel data show that RSD causes substantial engraftment of hematopoietic stem progenitor cells (HSPCs) in the spleen. We highlight novel data that HSPCs in the spleen serve as a generator of ?stress- sensitized? myeloid cells that are readily released following acute stress-induced activation of the sympathetic nervous system (SNS). Thus, we hypothesize that RSD promotes the establishment of a unique splenic myeloid population that becomes a critical cellular inflammatory mediator of recurring anxiety-like behavior. To address this hypothesis, three aims are proposed here using RSD in mice. (Pts.3, 4&12) In Aim-1, we will determine the kinetics and transcriptional profiles of splenic monocytes and HSPCs in stress-sensitized mice. (Pts.5, 11&12) In Aim-2, we will determine the sympathetic-dependent stromal cues that facilitate the development of splenic myelopoiesis with stress-sensitization. Several pharmacological and genetic interventions will be used to address the specific contribution of ?-adrenergic receptor activation in the release, establishment, and maintenance of this unique splenic HSPC population. In Aim-3, selective ablation of splenic monocytes will be used to prevent stress-sensitization and block the recurrence of anxiety. Several advanced strategies will be used to do this. Collectively, completion of these aims will provide new insight into long-term sensitization of myeloid cells by RSD and their critical contribution to recurring anxiety.
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2019 — 2020 |
Godbout, Jonathan P (co-PI) [⬀] Sheridan, John F |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Dynamic Cellular Interactions Associated With Inflammatory Monocyte Accumulation in the Neurovasculature With Social Stress
Program Director/Principal Investigator (Sheridan, JF & Godbout JP): PROJECT SUMMARY/ABSTRACT: Dynamic inflammatory signaling in the brain may have a causative role in anxiety. We report that repeated social defeat (RSD) in mice induces sympathetic-mediated release of primed monocytes from the bone marrow that are actively recruited to the brain. Collectively, we show that RSD promotes prolonged anxiety-like behavior that depends on activation of microglia and recruitment of inflammatory monocytes to threat appraisal regions of the brain. This application demonstrates that microglial recruitment of IL-1? producing monocytes to neurovascular endothelium is necessary for the potentiation of anxiety-like behavior in response to social stress. Despite this knowledge, three key mechanistic questions remain to be answered, which will allow for the development of novel interventions for treatment of neuropsychiatric complications associated with stress: 1) How does RSD activate microglia in threat appraisal regions? 2) How are inflammatory monocytes selectivity recruited to neurovascular endothelium in threat appraisal regions? 3) What are the key factors produced by neurovascular endothelia cells that potentiate neuroinflammation and anxiety? We show that microglial activation in response to RSD depends on neuronal activation within threat appraisal regions. Moreover, preliminary evidence suggests that this is mediated by activation of the purinergic receptor, P2RX7, on microglia. Novel data presented here show that monocyte recruitment and the development of anxiety-like behavior after RSD requires microglial activation. Furthermore, cell-specific transcriptional profiling indicates that microglia recruit monocytes to the brain via chemokine ligand (CCL2) secretion. These recruited monocytes produce IL-1??and promote anxiety-like behavior by endothelial IL-1 Receptor-1 activation. Notably, this IL-1R1 activation is associated with increased neurovascular expression of COX2, the enzyme that synthesizes neuroactive prostaglandins. Thus, the goal of this project is to test the hypothesis that recruitment and subsequent interaction of inflammatory monocytes with neurovascular endothelial cells is critical for the augmentation of neuroinflammation and potentiation of anxiety-like behavior following RSD. To address this hypothesis, three specific aims are proposed. In Aim-1, we will ascertain the extent to which RSD-induced microglial activation is dependent on stimulation of the P2RX7 purinergic receptor. In Aim-2, we will determine the degree to which microglial production of CCL2 is required for monocyte recruitment to threat appraisal regions and the induction of anxiety-like behavior after RSD. In Aim-3, we will assess the role of endothelial COX2 following RSD and determine other key factors produced by IL-1R1-stimulated endothelial cells that facilitate anxiety-like behavior after RSD. Understanding how microglial recruitment of IL-1? producing monocytes to threat appraisal regions potentiates neuroinflammation and anxiety-like behavior will lead to new interventions for neuropsychiatric complications associated with stress. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page
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