Regulation of Viscerosensory Sympathetic Reflexes: The Role of Diet-Derived Lipid Mediators.

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Principal Investigator: Donal S O'Leary
Organization: WAYNE STATE UNIVERSITY
Fiscal Year: 2024
Award: $416,326
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases

Gastrointestinal and cardiovascular health are intimately linked, yet the mechanism by which diet-derived lipid metabolites and the gut microbial flora impact efferent sympathetic nerve activity is largely unknown. Work from our laboratory and others’ provides increasing evidence that the enteric nervous system directly influences the sympathetic control of systemic blood pressure. The viscerosensory-sympathetic network is a functional neural circuit connecting afferent sensory fibers of the gut and efferent vasoconstrictor neurons at the level of the spinal cord. While this neural circuitry likely influences systemic blood pressure in able-bodied individuals, its role in the development of severe hypertensive crises in patients living with spinal cord injury (SCI) is irrefutable. Autonomic dysreflexia (AD) is often a clinical emergency in SCI individuals and is characterized by paroxysmal hypertension in response to otherwise innocuous visceral stimuli (e.g. fecal impaction). Despite its obvious significance, mechanisms involved in the regulation of viscerosensory-sympathetic reflexes (VSSRs) are poorly understood. Our preliminary studies indicate that C-fiber sensory neurons expressing transient receptor potential cation channel V1 (TRPV1) are involved in the afferent limb of the viscerosensory-sympathetic circuitry. Our proposal seeks to (Aim 1) provide a mechanistic understanding of the role of diet-derived lipid mediators in exaggerating the AD phenotype, (Aim 2) interrogate novel therapeutic strategies for attenuating sympathetic hyperreflexia following SCI, and (Aim 3) define the role of SCI-associated gut dysbiosis in contributing to the production of pathogenic diet-derived lipid mediators. Our central hypotheses identify new pathogenic factors (dietary fatty-acid content and SCI-associated dysbiosis) and a biochemical mechanism (diet-derived TRPV1 lipid ligands) that may be independent targets for therapeutic intervention. Uniquely, our rationally designed therapeutic strategies target the major underlying cause of AD (i.e. visceral C-fiber hypersensitivity) rather than the symptomatic outcome (i.e. acute hypertensive crisis) and thus constitute a major paradigm shift.

Terms: <Acute><Afferent Neurons><Agonist><Allergy><Animal Model><Animal Models and Related Studies><Animals><Autonomic Dysreflexia><Autonomic Hyperreflexia><Autoregulation><Biochemical><Blood Pressure><C Fiber><Cardiac><Cardiovascular><Cardiovascular Body System><Cardiovascular Organ System><Cardiovascular system><Chronic><Clinical><Clinical Research><Clinical Study><Common Rat Strains><Coupling><Custom><Development><Diet><Dietary Fatty Acid><Disease><Disorder><Electrophysiology><Electrophysiology (science)><Emergencies><Emergency Situation><Enteric Nervous System><Exposure to><Extremities><Fatty Acids><Fecal Impaction><Fiber><Frequencies><Future><GI microbiota><Gastrointestinal microbiota><Gnotobiotic><Gnotobiotics><Heart Vascular><Histopathology><Homeostasis><Human><Hyperreflexia><Hypersensitivity><Hypertension><Hypertensive Crisis><Hypertensive Episode><Incidence><Individual><Intestinal><Intestines><Knock-out><Knockout><Laboratories><Ligands><Limb structure><Limbs><Link><Linoleic Acids><Lipids><Medulla Spinalis><Mice><Mice Mammals><Modeling><Modern Man><Morbidity><Morbidity - disease rate><Murine><Mus><N-6 Fatty Acids><Nerve><Nerve Cells><Nerve Unit><Neural Cell><Neurocyte><Neurons><Neurophysiology / Electrophysiology><Non-Trunk><Omega-6><Omega-6 Fatty Acids><Omega-6 PUFAs><Outcome><Paroxysmal Hypertension><Pathogenicity><Pathogenicity Factors><Patients><Phenotype><Physiologic><Physiological><Physiological Homeostasis><Polyunsaturated Fatty Acids><Population><Preparation><Process><Production><Randomized><Rat><Rats Mammals><Rattus><Reflex><Reflex action><Regulation><Research><Rodent><Rodentia><Rodents Mammals><Role><Sensory><Sensory Neurons><Spinal Autonomic Dysreflexia><Spinal Cord><Spinal Cord Trauma><Spinal Trauma><Spinal cord injured><Spinal cord injury><Stimulus><Systemic blood pressure><TRPV1><TRPV1 gene><Testing><Therapeutic><Therapeutic Intervention><Traumatic Myelopathy><Vascular Hypertensive Disease><Vascular Hypertensive Disorder><Vasoactive Agonists><Vasoconstrictor Agents><Vasoconstrictor Drugs><Vasoconstrictors><Vasopressor Agents><Virulence Factors><Visceral><Work><antagonism><antagonist><bowel><cardiovascular health><chronic pain><circulatory system><colon distension><colorectal distension><customs><defined contribution><determine efficacy><developmental><dietary><diets><dysbacteriosis><dysbiosis><dysbiotic><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><electrophysiological><enteric microbial community><enteric microbiota><evaluate efficacy><examine efficacy><fecal microbial transplantation><fecal microbiome transplantation><fecal microbiota transplant><fecal microbiota transplantation><fecal transplant><fecal transplantation><gastrointestinal><gastrointestinal microbial flora><gut commensal><gut community><gut dysbiosis><gut flora><gut microbe community><gut microbes><gut microbial community><gut microbial composition><gut microbial consortia><gut microbial species><gut microbiota><gut microbiotic><gut microflora><hemodynamics><high blood pressure><hyperpiesia><hyperpiesis><hypertensive disease><hypertensive disorder><improved><in vivo><insight><instrument><intervention therapy><intestinal flora><intestinal microbes><intestinal microbiota><intestinal microflora><intestinal tract microflora><lipid mediator><microbial consortia><microbial flora><microbial imbalance><microbiota><microflora><model of animal><mortality><multispecies consortia><neural circuit><neural circuitry><neurocircuitry><neuronal><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><novel><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><preparations><prevent><preventing><randomisation><randomization><randomly assigned><rational design><response><small molecular inhibitor><small molecule inhibitor><social role><synaptic circuit><synaptic circuitry><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><transient receptor potential cation channel V1><treatment strategy><vasopressor><ω-6>