1991 — 1993 |
Flood, Patrick Michael |
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. |
Immunogenicity of Fimbrillin From B. Gingivalis @ University of North Carolina Chapel Hill
The specific immune response to bacterial infections have been shown to involve the generation of both cellular and humoral immunity directed against bacterial antigens. The activation of these immunologic effector mechanisms is accomplished by the interaction of inducer T cells with immunologic effector cells, either B cells, T cells, or macrophages. Severe adult Periodontal disease is a disorder characterized by the inability to resolve the infection by a pathogen or pathogens within the gingival margins and the periodontium which results in a chronic destructive immunologic response. Bacteroides Gingivalis, a black pigmented gram negative bacteria, has been implicated as one of the major causative agents in severe adult periodontal disease. This proposal describes studies that investigate the nature and specificity of T lymphocyte response to fimbrillin, the constitutive protein of fimbriae of B. Gingivalis strain 381. T cells recognize antigen on antigen-presenting cells as peptides associated with self-molecules encoded by the Major Histocompatibility Complex. Therefore, the immunogenicity of whole Bg, bacterial fimbrae, or purified fimbrillin molecules will be analyzed, and factors influencing the immunogenicity of these molecules compared. Small -synthetic peptides of the fimbrillin molecule from B. Gingivalis strain 381 will be generated based on the predicted amino acid sequence from the cloned fimbrillin gene, and these peptides will be analyzed in order to identify specific amino acid sequences, i.e. epitopes, on the fimbrillin molecule which induce immunologic responses in T lymphocytes. The nature of the T cell response to immunologic epitopes will be analyzed for its specificity for MHC-linked molecules, its production of inflammatory and humoral lymphokines, and its ability to respond to Bg, fimbrae, or fimbrillin antigen on a variety of different antigen presenting cells. Understanding the factors which influence the immune response to immunogenic epitopes on fimbrillin will significantly enhance our understanding of how T cells respond to bacterial antigens in .vivo, and will aid in designing better immunologic -approaches to the treatment of periodontal disease.
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1994 — 1995 |
Flood, Patrick Michael |
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. |
Immunogenicity of Fimbrillin From B Gingivalis @ University of North Carolina Chapel Hill
The specific immune response to bacterial infections have been shown to involve the generation of both cellular and humoral immunity directed against bacterial antigens. The activation of these immunologic effector mechanisms is accomplished by the interaction of inducer T cells with immunologic effector cells, either B cells, T cells, or macrophages. Severe adult Periodontal disease is a disorder characterized by the inability to resolve the infection by a pathogen or pathogens within the gingival margins and the periodontium which results in a chronic destructive immunologic response. Bacteroides Gingivalis, a black pigmented gram negative bacteria, has been implicated as one of the major causative agents in severe adult periodontal disease. This proposal describes studies that investigate the nature and specificity of T lymphocyte response to fimbrillin, the constitutive protein of fimbriae of B. Gingivalis strain 381. T cells recognize antigen on antigen-presenting cells as peptides associated with self-molecules encoded by the Major Histocompatibility Complex. Therefore, the immunogenicity of whole Bg, bacterial fimbrae, or purified fimbrillin molecules will be analyzed, and factors influencing the immunogenicity of these molecules compared. Small -synthetic peptides of the fimbrillin molecule from B. Gingivalis strain 381 will be generated based on the predicted amino acid sequence from the cloned fimbrillin gene, and these peptides will be analyzed in order to identify specific amino acid sequences, i.e. epitopes, on the fimbrillin molecule which induce immunologic responses in T lymphocytes. The nature of the T cell response to immunologic epitopes will be analyzed for its specificity for MHC-linked molecules, its production of inflammatory and humoral lymphokines, and its ability to respond to Bg, fimbrae, or fimbrillin antigen on a variety of different antigen presenting cells. Understanding the factors which influence the immune response to immunogenic epitopes on fimbrillin will significantly enhance our understanding of how T cells respond to bacterial antigens in .vivo, and will aid in designing better immunologic -approaches to the treatment of periodontal disease.
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1996 — 1999 |
Flood, Patrick Michael |
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. |
Tc1 and Tc2 Activity in Malignancy @ University of North Carolina Chapel Hill |
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1997 |
Flood, Patrick Michael |
P20Activity Code Description: To support planning for new programs, expansion or modification of existing resources, and feasibility studies to explore various approaches to the development of interdisciplinary programs that offer potential solutions to problems of special significance to the mission of the NIH. These exploratory studies may lead to specialized or comprehensive centers. |
Development of a Center For Oral Inflammatory Disorders @ University of North Carolina Chapel Hill
Chronic inflammatory disorders are one of the most pervasive health problems in America today, affecting the overall health and quality of life of millions of individuals. To deal with this problem, we propose to develop a Comprehensive Oral Research Center for Inflammatory Disorders, which will be to support a full range of research in the prevention and treatment of oral and systemic inflammatory diseases and disorders. The mission of this Center will be to improve the health of people suffering from chronic disabling inflammatory diseases, with an emphasis on the relationship between oral inflammation and general health. The Center will develop research programs that combine basic research on the molecular and cellular mechanisms of oral and systemic inflammatory responses with translational and applied research on the clinical and behavioral consequences of inflammatory diseases and disorders on oral and systemic health. These programs will also support demonstration research and outreach activities for professionals and patients suffering from inflammatory disorders, and will enhance the training and education of health professionals and the public concerning health promotion and prevention, diagnosis, and treatment of oral and systemic inflammatory diseases. During the developmental phase, we propose to: 1) implement and refine an administrative structure for the Center, which consists of six interactive Workgroups which will function to facilitate the development and implementation of program initiatives; 2) to provide workshops designed to improve communication within and among the interactive Workgroups of the Center; 3) to identify and prioritize individual research projects that provide the most efficient and meaningful translation into public health benefit, and develop these individual research projects into center-wide research programs; and 4) to demonstrate the feasibility of the integration of thematic areas of research into program development within the Center on Inflammatory Disorders. The attainment of these objectives will result in the formation of a functional Center for Oral Inflammatory Disorders that supports a full range of program activities from discovery to public health application in the treatment of oral and systemic inflammatory diseases.
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1999 — 2003 |
Flood, Patrick Michael |
P60Activity Code Description: To support a multipurpose unit designed to bring together into a common focus divergent but related facilities within a given community. It may be based in a university or may involve other locally available resources, such as hospitals, computer facilities, regional centers, and primate colonies. It may include specialized centers, program projects and projects as integral components. Regardless of the facilities available to a program, it usually includes the following objectives: to foster biomedical research and development at both the fundamental and clinical levels; to initiate and expand community education, screening, and counseling programs; and to educate medical and allied health professionals concerning the problems of diagnosis and treatment of a specific disease. |
Comprehensive Center For Inflammatory Disorders @ University of North Carolina Chapel Hill
Chronic inflammatory disorders are one of the biggest health problems in America today. This application describes the Comprehensive Center for Inflammatory Disorders whose mission is to support the identification and implementation of the full range of discovery from research on the basic mechanisms of inflammation to improved methods in the prevention and treatment of oral and systemic inflammatory diseases and disorders. The goals of the Center are to: 1) integrate studies on the fundamental mechanisms of cellular responses to inflammatory stimuli to better understand the basis of cellular activation, motility, and function that occur during inflammatory responses; 2) integrate basic research studies on inflammation with animal, patient-based and population research to better understand the cellular and molecular basis of oral inflammatory disorders; 3) identify several new and innovative approaches to the prevention, diagnosis, and treatment of chronic inflammation and facilitate their development into effective interventions for the treatment of oral and systemic inflammatory diseases and disorders within 5 years; 4) utilize and expand ongoing research on community education, screening, counseling, and related service programs to find better ways to expand public implementation of new advances in the prevention, diagnosis, and treatment of chronic oral and systemic inflammatory diseases and disorders; 5) integrate discovery from laboratory, clinical, population, education or community-based research into ongoing Center activities or new Center initiatives; and 6) promote programs for the education of health professionals and the public on the etiology, prevention, diagnosis, and treatment of chronic inflammatory diseases and disorders. The Center consists of 4 workgroups in the areas of fundamental, clinical, epidemiologic, and community outreach and outcomes research which are supported by an administrative, educational, technology transfer, and research support core. This Center core is designed to: 1) stimulate sharing, mutual interpretation, and integration of information on inflammation or inflammatory disorders obtained through research discovery; 2) provide mechanisms that allow the rapid development of discovery into new research projects, therapies, interventions, or potentially marketable products; 3) educate health professionals and the public on health issues of oral and systemic inflammatory disorders; and 4) make available to each product essential administrative support, research facilities, research services, coordination, and scientific leadership.
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1999 — 2002 |
Flood, Patrick Michael |
P60Activity Code Description: To support a multipurpose unit designed to bring together into a common focus divergent but related facilities within a given community. It may be based in a university or may involve other locally available resources, such as hospitals, computer facilities, regional centers, and primate colonies. It may include specialized centers, program projects and projects as integral components. Regardless of the facilities available to a program, it usually includes the following objectives: to foster biomedical research and development at both the fundamental and clinical levels; to initiate and expand community education, screening, and counseling programs; and to educate medical and allied health professionals concerning the problems of diagnosis and treatment of a specific disease. |
Role of Nf-Kb in T Cell Inflammation @ University of North Carolina Chapel Hill
The existence of type-1 and type-2 cells in the CD4+ and CD8+ T cell populations has been well documented. Little is known, however, about the nature of the cellular signaling pathways that lead to the generation and maintenance of these phenotypes T cells and T cell clones. NF-kappaB is a family of transcription factors that have been shown to be of major importance in the activation and differentiation of T lymphocytes. While virtually nothing is known about the role of NF- kappaB activity in CD8+ T cells, it appears that NF-kappaB is differentially activated and regulated in type 1 versus. type 2 CD4+ T cell clones. We hypothesize that the activation conditions which differentially regulate the transcription factor NF-kappaB contributes to the commitment of T cells to the Th1/Tc1 or Th2/Tc2 cell lineage, and that this differential regulation plays a pivotal role in determining and maintaining their subset commitment. These different activation conditions include stimulation by the T cell receptor, by CD28, and/or exposure to cytokine IL-4 and IL-12. The purpose of this proposal is to determine the different mechanisms by which NF-kappaB is regulated in Th1/Tc1 and Th2/Tc2 cell subsets, and the consequence of this differential regulation on the phenotype and functional activity of these cells. We plan to 1): assess the differential expression of NF- kappaB in the T cell receptor (TcR) mediated activation of type 1 and type 2 CD4+ and CD8+ T cells by assessing how activation through TcR affects the functional activity of the different subunits. of the NF- kappaB. Determine the synergistic effects of cytokines and co- stimulation on NF-kappaB activation by TcR in primary T cells and T cell clones by determining if primary T cells and T cell. 3) Determine how suppression of NF-kappaB activation alters the phenotype and functional activity of T cell by measuring the effect of transducing a trans- dominant IkappaB repressor of NF-kappaB activity into Th1/Tc1 and Th2/Tc2 cell clones; and 4) Determine the effect of suppressing NF- kappaB activation in dendritic cells on the ability of DC to present antigen to Th1/Tc1 and Th2/Tc2. The effect of suppression of NF-kappaB activation in dendritic cells on the activation, development, and effector function of Th1/Tc1 and Th2/Tc2 cells will be assessed. These results will help us better understand how T cell subsets function during inflammatory responses, and determine if Nf-kappaB can be used as a target for therapeutic intervention designed to control T cell inflammation.
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