1985 — 1987 |
Brown, David R [⬀] |
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. |
Role of Cns Peptides in Gut Fluid and Ion Transport @ University of Minnesota Twin Cities
The major goal of this proposal is to define the action of neuropeptides, administered into the central nervous system (CNS), on net transepithelial fluid and electrolyte transport in the intestine. Although it is recognized that the CNS regulates the activity of the digestive system, the precise mechanisms by which this occurs are not completely understood. A number of peptides, endogenous to the mammalian brain and gut, have been found to alter gastrointestinal functions, such as gastric secretion and intestinal motor activity, after their administration into the brain. However, the CNS actions on ion and fluid transport processes in the gut are unknown. In the present proposal, five families of these substances, eg., opioid peptides, bombesin, somatostatin, thyrotropin-releasing hormone and calcitonin, will be examined by conventional methods for their abilities to modify intestinal fluid and ion transport in the rat intestine after CNS administration. This investigation encompasses four specific objectives: (1) The identification of peptides which, after their administration into the lateral cerebral ventricles, modify net water transport and transmural electrical potential difference (PD) across discrete regions of the small and large intestine in situ. (2) An assessment of the specificity of these CNS effects for intestinal fluid transport through a simultaneous analysis of peptide actions on other physiological parameters (i.e. blood pressure, respiration and intestinal motility). (3) The elucidation of changes in the net transmural fluxes of ions that underlie the effects of peptides on basal and stimulated water transport and PD. (4) An examination of the peripheral neurohumoral mechanisms underlying the CNS actions of peptides on gut fluid transport processes. The results obtained from the proposed experiments will greatly enhance the understanding of the control of digestive system function by the CNS and provide a physiological and neurochemical basis for psychosomatic diseases of the gastrointestinal tract.
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0.912 |
1987 — 1989 |
Brown, David R [⬀] |
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. |
Peptide Receptors in the Intestinal Mucosa @ University of Minnesota Twin Cities
peptides; intestinal mucosa;
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0.912 |
1991 |
Brown, David R [⬀] |
F33Activity Code Description: To provide opportunities for experienced scientists to make major changes in the direction of research careers, to broaden scientific background, to acquire new research capabilities, to enlarge command of an allied research field, or to take time from regular professional responsibilities for the purpose of increasing capabilities to engage in health-related research. |
Regulation of Histamine Receptor Gene Expression @ University of Michigan At Ann Arbor |
0.912 |
1996 — 2010 |
Brown, David R [⬀] |
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. |
Mucosal Defense Mechanisms in Substance Abuse @ University of Minnesota
DESCRIPTION (provided by applicant): In the intestinal tract, the first line of defense against pathogenic microorganisms is the layer of epithelial cells that line its extensive mucosal surface. These cells provide a physical barrier to infection and play critical roles at mucosal immune sites by detecting and eliminating enteric pathogens, including the human immunodeficiency virus (HIV) and Salmonella enterica. The intestinal mucosa contains, in addition to epithelial cells, an extensive nervous system capable of pre-programmed behavior, and it houses the largest lymphocyte population in the body;these three cell types communicate with each other through molecular signals which modulate inflammation and coordinate mucosal defense responses to infection. Opioid abuse is an important co-factor in host susceptibility to HIV and other mucosal pathogens, but its impact on mucosal host defense is relatively unknown. Opioid drugs may impair neuro-immuno-epithelial interactions at immune inductive and effector sites in the intestine. The proposed experiments will test the general hypotheses that opioids impair the immune responses of epithelial cells and lymphoid cells in the intestinal mucosa through actions mediated by neuronal and extraneuronal opioid receptors, and that opioid neuroimmune signaling is enhanced by mucosal inflammation. In Specific Aim 1, we will determine and compare the effects of opioids on proinflammatory cytokine release and changes in opioid receptor expression before and after inflammation in porcine intestinal epithelial cells in culture and from explants of Peyer's patch and absorptive mucosae through measurements of secreted cytokines and their mRNA expression. We will also assess opioid actions on intestinal epithelial cell wound healing by electric cell-substrate impedance sensing. In Specific Aim 2, we will compare the morphological interrelationships between opioid receptors and opioid peptides in epithelial cells, neurons and leukocytes of Peyer's patch and absorptive mucosae by immunocytochemical and in situ hybridization methods. We will also examine opioid effects on an epithelial-neuronal co-culture from porcine intestine through measurements of cytokine release and changes in neuronal excitability evoked by Salmonella infection. Finally, we will characterize changes in the ligand affinity and G protein coupling coupling of specific opioid binding sites in neural membranes from inflamed and uninflamed Peyer's patches by radioligand binding techniques. In Specific Aim 3, we will characterize delta-opioid receptors mediating chemokine-induced chemotaxis of intestinal T lymphocytes, and determine the effects of opioids on neurally-mediated secretory immunoglobulin-A release from intestinal mucosa explants. The results from this multi-faceted transdisciplinary project will provide a fundamental understanding of how opioid drugs act to alter mucosal defense function. Moreover, they will unveil new drug targets for the modulation of mucosal immune responses to HIV and other gut pathogens as well as oral vaccines offering protection from these microbes. PUBLIC HEALTH RELEVANCE The goal of the proposed transdisciplinary investigation is to elucidate the mechanisms by which opioid drugs of abuse disrupt the interplay between enteric neurons, epithelial cells and immunocytes at sites of mucosal immunity, which are key targets for infection by enteropathogens like S. typhimurium and the human immunodeficiency virus (HIV). Our experiments will provide new and significant information on the ability of opioids to influence mucosal responses evoked by Salmonella typhimurium, an enteroinvasive zoonotic pathogen and potential HIV vaccine vector. The results that we obtain in this multi-faceted project will advance our understanding of how opioid drugs act to alter mucosal defense function. In addition, they will reveal new drug targets for the modulation of mucosal immune responses to enteric pathogens including HIV, and provide new information contributing to the development of oral vaccines based on bacterial vectors that are designed to confer protection against HIV infection in gut-associated lymphoid tissue, the major body reservoir for this virus.
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0.912 |
2004 |
Brown, David R [⬀] |
M01Activity Code Description: An award made to an institution solely for the support of a General Clinical Research Center where scientists conduct studies on a wide range of human diseases using the full spectrum of the biomedical sciences. Costs underwritten by these grants include those for renovation, for operational expenses such as staff salaries, equipment, and supplies, and for hospitalization. A General Clinical Research Center is a discrete unit of research beds separated from the general care wards. |
Type 1 Diabetes Trialnet (Formerly Diabetes Prevention Trial - Type I Diabetes ( @ University of Minnesota Twin Cities
chemoprevention; human therapy evaluation; insulin; insulin dependent diabetes mellitus; hormone therapy; diabetes risk; disease /disorder onset; clinical trials; placebos; oral administration; patient oriented research; human subject; clinical research;
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0.912 |
2004 |
Brown, David R [⬀] |
M01Activity Code Description: An award made to an institution solely for the support of a General Clinical Research Center where scientists conduct studies on a wide range of human diseases using the full spectrum of the biomedical sciences. Costs underwritten by these grants include those for renovation, for operational expenses such as staff salaries, equipment, and supplies, and for hospitalization. A General Clinical Research Center is a discrete unit of research beds separated from the general care wards. |
Metabolic &Immunogenetic Evaluation of Dpt-1 Screened Relatives Expressing Bioc @ University of Minnesota Twin Cities
diabetes risk; genetic screening; pancreatic islets; immunogenetics; diabetes mellitus genetics; insulin dependent diabetes mellitus; family genetics; adrenocorticotropic hormone; antibody; adrenal glands; biomarker; peptide hormone; gene expression; oxygenases; pancreatic islet function; insulin; clinical research; glucose tolerance test; human subject;
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0.912 |
2020 — 2021 |
Brown, David R (co-PI) [⬀] Carlson, Cathy S. (co-PI) [⬀] Mccue, Molly E [⬀] |
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. |
Comparative Medicine and Pathology Training @ University of Minnesota
Project Summary/Abstract The Comparative Medicine and Pathology training program was initiated in the fall of 2003 and provides state- of-the-art research training to veterinarians. Five years of continuing support are requested in the present application, including support for six trainees in each year of the program. It is anticipated that the majority of these individuals will have completed a residency in medicine, surgery, or pathology prior to entering the training program. Selection criteria will include: 1) strong interest in research and a desire for a career in academic veterinary medicine; 2) academic credentials and performance during clinical training/residency; and 3) desirable personal characteristics, including integrity, perseverance, and oral and written communications skills. The training program is located in the College of Veterinary Medicine at the University of Minnesota and is directed by Drs. Cathy Carlson, David Brown, and Molly McCue. Thirty-three faculty mentors, all members of the Comparative and Molecular Biosciences (CMB) and/or Veterinary Medicine (Vet Med) graduate programs, will participate in the training program. These individuals represent a diverse group of disciplines, including pharmacology, cell biology, infectious disease, neurobiology, physiology, genetics, molecular biology, and orthopedics. Trainees without a PhD degree will pursue a PhD in the CMB or Vet Med graduate program, well- organized, multidisciplinary graduate programs created to focus graduate education efforts by faculty interested in comparative biomedical sciences and the molecular mechanisms responsible for human and animal health and disease. The goals of our programs are to provide students with the broad-based knowledge, quality communication skills, and advanced research training essential for a career as independent investigators.
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0.912 |