1985 — 2014 |
Wood, Jackie D. |
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. 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. |
Function of the Enteric Nervous System
The program is a continuation of the study on the neurophysiology of the enteric nervous system and of the investigation of the mechanisms by which the intrinsic nervous system of the gut participates in the control and integration of gastrointestinal function. The objectives of the study are: (1) To compare the electrical behavior of enteric neurons with the behavior of the effector systems in the specialized regions along the alimentary canal. (2) To map the interneuronal connectivity that mediates the various reflex responses that occur within the gut. (3) To determine the effects of pharmacological agents, ischemia and intrinsic humoral factors circulating in the blood on electrical behavior of enteric neurons. (4) To determine if the internal environment of enteric ganglia is regulated by a selectively permeable barrier. (5) To determine the metabolic properties of the enteric nervous system and to obtain an explanation for the low susceptibility of enteric neurons to hypoxia. (6) To compare effector function in the large intestine of mice with herditary aganglionic megacolon with effector function in mice with normal innervation of the bowel. (7) To elucidate the etiology and pathophysiology of Hirschsprung's disease and related disorders that are associated with malformation and malfunction of the enteric nervous system.
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1987 — 1989 |
Wood, Jackie D. |
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. |
Ethanol Disturbance of Gastrointestinal Nervous System
This project is designed to investigate the effects of ethyl alcohol on the electrical and synaptic behavior of neurons in the nervous system of the gastrointestinal tract. The results of the studies are expected to provide basic neurophysiological information that will improve insight into: (1) the gastrointestinal disturbances associated with ethanol ingestion; (2) the mechanisms of action of ethanol on individual nerve cells; (3) ways in which alcohol disrupts synaptic function within integrative circuitry of the nervous system. Intracellular electrical recording methods will be used to evaluate the functional behavior of neurons in the myenteric plexus of the guinea-pig small intestine, in vitro. This will be done both by acute exposure of the neurons to ethanol by application in the tissue bath and by recording from neurons in the small intestine of guinea-pigs that have developed tolerance to chronic administration of ethanol over a period of several days. Some of the specialized functions on which ethanol will be investigated are: (1) Hyperpolarizing after-potentials that reflect operation of calcium-dependent potassium channels in the neuronal membranes; (2) Closure of calcium-dependent potassium channels and the dramatic enhancement of neuronal excitability that occurs during slow synaptic excitation; (3) Interaction of cholinergic, peptidergic and aminergic neurotransmitters with postsynaptic receptors; (4) Presynaptic receptors and the presynaptic mechanisms of neurotransmitter release at enteric neuronal synapses; (5) Receptor operation of adenylate cyclase and second messenger function of cAMP in slow synaptic excitation.
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1988 — 1990 |
Wood, Jackie D. |
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. |
Signal Transduction in Gastrointestinal Neurons
This is a proposal to study the role of the adenylate cyclase-cAMP system in signal transduction in enteric neurons. The project is based on the following interpretations of results obtained by electrical recording of electrical and synaptic behavior of the neurons: (1) Slow synaptic excitation (slow EPSP) is a long-lasting increase in excitability that has important function in neural control of the intestine. (2) Biogenic amines, brain-gut peptides and acetylcholine mimic slow EPSPs in subpopulations of neurons. (3) Activation of adenylate cyclase by forskolin mimics slow EPSP. (4) Elevation of cAMP by intraneuronal injection, application of permeable analogs of cAMP or treatment with phosphodiesterase inhibitors also mimic slow EPSPs. (5) Second messenger function of cAMP is involved in the transduction process for slow EPSPs. (6) Application of adenosine simulates slow synaptic inhibition and blocks the action of forskolin (7) The inhibitory action of adenosine reflects purinergic suppression of enzymatic activity of adenylate cyclase. (8) Adenosine blocks the slow EPSP-like actions of histamine, CCK, VIP and bombesin, but not substance P, serotonin or calcitonin gene-related peptide. (9) All of the slow EPSP mimetics, except substance P, CGRP and serotonin, act by stimulation of adenylate cyclase and adenosine blocks these effects by preventing activation of the enzyme. This project is designed to test these electrophysiological interpretations by direct measurement of changes in cAMP levels in response to the same perturbations that were applied in the electrophysiological studies. cAMP determinations will be made in a newly-developed preparation consisting of dissociated ganglia from the myenteric plexus of guinea-pig small intestine.
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1990 — 1993 |
Wood, Jackie D. |
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. |
Colitis and Colon Cancer in Cotton-Top Tamarins
This is a proposal for studies on idiopathic ulcerative colitis and spontaneous large intestinal carcinoma in a promising new animal model. The animal is the cotton-top tamarin (Saguinus oedipus), which is a small South American monkey that has been discovered recently to suffer from colon cancer in association with chronic, non-infectious colitis. It is the only known animal, besides humans, in which ulcerative colitis is associated with a high incidence of cancer. The investigative work would center on The Ohio State University colony of cotton-top tamarin which is one of the three or four colonies of these animals in the Unites States. These tamarins will be experimental controls in parallel comparative studies on wild tamarins. Urgency of the work is related to these animals being on the world lid\st of endangered species and the danger of extinction of the most likely model for providing the clues to understanding of two significant human diseases. This proposal is directed to the major aim of identifying the etiologic factors involved cotton-top tamarin. The project will determine if spontaneous colitis and cancer occur in tamarins living in their jungle habitat or if the diseases are manifestations of captivity. Preliminary field studies in animals and that unidentified conditions in captivity might be precipitating factors. The methods will involve endoscopic examination and biopsy of the colon and will not harm the animals in any way. Wild tamarins will be captured, examined and released, unharmed, back into their native habitat. Specific aims of the project are to: (1) Document the development and progression of colitis and cancer in the Ohio State colony; (2) Determine the incidence and severity of colitis and cancer in feral tamarins; (3) Determine if captivity is the precipitating factor is development of colitis and the cancer sequel; (4) Determine if cold environmental temperatures are stress factors in captivity; (5) Determine if humoral indicators of stress are elevated in captive relative to feral animals.
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1994 — 1995 |
Wood, Jackie D. |
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. |
Colitis and Colon Cancer
This is a proposal for studies on idiopathic ulcerative colitis and spontaneous large intestinal carcinoma in a promising new animal model. The animal is the cotton-top tamarin (Saguinus oedipus), which is a small South American monkey that has been discovered recently to suffer from colon cancer in association with chronic, non-infectious colitis. It is the only known animal, besides humans, in which ulcerative colitis is associated with a high incidence of cancer. The investigative work would center on The Ohio State University colony of cotton-top tamarin which is one of the three or four colonies of these animals in the Unites States. These tamarins will be experimental controls in parallel comparative studies on wild tamarins. Urgency of the work is related to these animals being on the world lid\st of endangered species and the danger of extinction of the most likely model for providing the clues to understanding of two significant human diseases. This proposal is directed to the major aim of identifying the etiologic factors involved cotton-top tamarin. The project will determine if spontaneous colitis and cancer occur in tamarins living in their jungle habitat or if the diseases are manifestations of captivity. Preliminary field studies in animals and that unidentified conditions in captivity might be precipitating factors. The methods will involve endoscopic examination and biopsy of the colon and will not harm the animals in any way. Wild tamarins will be captured, examined and released, unharmed, back into their native habitat. Specific aims of the project are to: (1) Document the development and progression of colitis and cancer in the Ohio State colony; (2) Determine the incidence and severity of colitis and cancer in feral tamarins; (3) Determine if captivity is the precipitating factor is development of colitis and the cancer sequel; (4) Determine if cold environmental temperatures are stress factors in captivity; (5) Determine if humoral indicators of stress are elevated in captive relative to feral animals.
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1995 — 1999 |
Wood, Jackie D. |
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. |
Patch Clamp Study of Gastrointestinal Neurons
This is a proposal for a patch clamp study of ionic currents in neurons of the myenteric plexus from the guinea-pig small intestine. The study has four specific aims directed to improving understanding of the ionic basis of excitability changes during synaptic or paracrine signaling. Protocols of the initial aim are designed to identify and characterize the ionic currents that are activated by changes in transmembrane voltage, elevation of intraneuronal calcium levels and ligand binding to receptors in AH/Type 2 and S/Type 1 myenteric neurons. The second aim will test the hypothesis that elevation of intraneuronal cAMP in AH/Type 2 neurons enhances excitability by suppressing: 1) conductance in calcium channels open at rest; 2) voltage activation of high threshold N-type calcium channels; 3) conduction in calcium-activated potassium channels; 4) voltage activation of A-type and delayed rectifier potassium channels. Experiments of Aim 3 are organized to determine the action of chemical mediators of slow synaptic excitation (substance P, 5-HT and histamine) on sodium, potassium and calcium currents in AH/Type 2 myenteric neurons. This phase of the study will also test the hypothesis that these mimetics of slow synaptic excitation will behave like elevation of cAMP in their actions on the ionic currents underlying slow synaptic excitatory behavior. The final aim is to determine the action of chemical mediators of slow synaptic inhibition (galanin, metenkephalin and adenosine) on sodium, potassium and calcium currents in AH/Type 2 myenteric neurons. This phase of the work will also test the hypothesis that these mimetics of slow synaptic inhibition act through G-proteins coupled to opening of one or more types of potassium channels in their actions on the ionic currents underlying slow synaptic inhibition in AH/Type 2 and S/Type 1 myenteric neurons. The work to accomplish each aim will be done on acutely dissociated myenteric ganglia from adult intestine and on myenteric neuronal cultures derived from adult intestine. The focus of the work is on adult ganglia that develop into a replica of the myenteric plexus when cultured. Observations to be made in acutely dissociated ganglia are controls for any changes in phenotypic expression of channels or receptors in the culture conditions. Other than preliminary data from the proponents' laboratory, no results of patch clamp studies on adult myenteric neurons have been reported. Consequently, application of patch clamp methodology is needed to acquire the information necessary for filling existing voids in understanding of the electrical and synaptic behavior of the neurons that make up the integrated circuits of the enteric nervous system.
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2001 — 2005 |
Wood, Jackie D. |
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. |
Bradykinin in Enteric Neuroimmune Communication
This project will use methods of electrophysiological recording and molecular biological techniques for study of gene expression to test the hypothesis that bradykinin is an important inflammatory mediator in the enteric nervous system (ENS). Pilot/feasibility studies found that bradykinin excites neurons and produces presynaptic inhibition in the ENS. These effects are mediated in part by increased release of endogenous prostaglandins (PGs) following activation of cyclooxygenases including constitutive cyclooxygenase-1 (COX- 1) and inducible cyclooxygenase-2 (COX-2). This proposal focuses on electrophysiological responses to bradykinin and functional expression of the bradykinin BZ receptor, COX- 1 and COX-2 proteins and their genes in the ENS. The studies are designed to test the hypothesis that bradykinin activates Bz type receptors together with activation of COX- 1 and induced expression of COX-2 which in turn catalyze the biosynthesis of the PGs from arachidonic acid. PGs release appears to be partly responsible for presynaptic inhibition of neurotransmitters release and postsynaptic excitation of enteric neurons. Integrated output of these effects is a stereotypical pattern of intestinal behavior consisting of copious secretion of water and electrolytes across the mucosa in coordination with a powerful propulsive motility pattern that propagates over extensive lengths of bowel. This is especially important under pathophysiological circumstances such as inflammatory bowel disease where bradykinin is increased. Aim 1 will identify the actions of bradykinin and mechanisms of signal transduction in electrophysiologically and morphologically identified enteric neurons in the myenteric and submucous plexuses of the small intestine. Aim 2 will test the hypothesis that B2 receptor protein and mRNA are functionally expressed in the myenteric and submucous plexuses. Aim 3 will test the hypothesis that B2 receptors are expressed by specific enteric neurons and/or glia. Aim 4 will identify the PGs postulated to be involved in bradykinin actions. Aim 5 will identify the ENS cell types expressing COX-2 protein and mRNA after bradykinin exposure. The overall goal of the study is to better understand the role of bradykinin in motility disturbances, diarrhea, abdominal pain and inflammation.
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2004 — 2008 |
Wood, Jackie D. |
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. |
Purinergic Neurogenic Mucosal Secretion
[unreadable] DESCRIPTION (provided by applicant): The overall aim of this project is to characterize a novel purinergic slow excitatory postsynaptic potential (EPSP) that is mediated by a metabotropic ATP receptor (P2Y1 receptor) in the enteric nervous system. Evidence for the existence of the purinergic slows EPSP emerged from pilot studies in which the P2Y1 receptor antagonist MRS2179 selectively blocked both the slow EPSP and slow EPSP-like responses evoked by ATP in submucosal neurons. The hypothesis that the purinergic slow EPSP is mediated by synaptic release of ATP and P2Y1 receptors in submucosal secretomotor neurons will be tested pharmacologically in morphologically identified neurons. Molecular cloning and functional expression will be used to better characterize the P2Y1 receptor. The proposal emerged from pilot/feasibility results, which suggest the hypothesis that intestinal secretomotor neurons receive purinergic slow excitatory synaptic input from neurons in the myenteric plexus, from neighboring neurons in the submucosal plexus and from sympathetic neurons in prevertebral ganglia. Added support for the hypothesis came from the discovery that the selective P2Y1 receptor antagonist MRS2179 suppressed neurogenic secretory responses evoked by application of ATP and by transmural electrical stimulation of secretomotor neurons in Ussing chamber experiments. Fulfilling the aims of this proposal will lead to better understanding of the role of a newly discovered purinergic slow EPSP in the enteric nervous system at the cellular, molecular and integrated system levels. The pilot/feasibility data are the first to demonstrate a functional purinergic slow EPSP in the enteric nervous system. The discovery that a P2Y1 receptor mediates the slow EPSP in intestinal secretomotor neurons might help in development of new drugs for treatment of the irritable bowel syndrome, inflammatory bowel disease and other disorders of defecation by targeting the P2Y1 receptor or ATP metabolic pathways in the pool of enteric neurons that control intestinal secretion. [unreadable] [unreadable]
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