Document text
Principal Investigator: Bradley Joel Undem
Organization: JOHNS HOPKINS UNIVERSITY
Fiscal Year: 2020
Award: $528,619
Funding agency: National Heart Lung and Blood Institute
Asthma, COPD, and chronic cough, as with other visceral inflammatory diseases, are characterized by an
over-excited sensory nervous system. When airway sensory nerves are dysregulated by inflammation it can
lead to excessive coughing, dyspnea, changes in breathing pattern, and reflex bronchospasm and secretions
that can threaten lung function. Our long-range goal is to determine the ion channels and mechanisms that
underlie the excitability of each of the sensory nerve subtypes in the airways. The present proposal focuses on
voltage-gated sodium channels (NaVs). NaV are perhaps the most important ion channels regulating nerve
activity as they are required for action potential generation and conduction, and are also involved in setting the
threshold for nerve activation. There are nine NaV subtypes termed NaV1.1-1.9. This renewal proposal builds
on our seminal observations and strong progress since the original application. We now know that the three
nociceptor subtypes in the airways express almost exclusively NaV 1.7, NaV 1.8, and NaV 1.9. These
channels are not present in skeletal or cardiac muscle and are very modestly expressed in the central nervous
system. This renders them ideal targets for drugs aimed at normalizing an overactive airway sensory nervous
system. We have completed an extensive functional analysis on the role of NaV1.7 and 1.8 in regulating each
of three distinct nociceptor subtypes at the level of their terminals within the airways. In AIM I we will turn our
attention to the mechanisms by which NaV1.9 regulates the excitability of these nerves. In AIM 2 we will
evaluate genetically and functionally the NaV subtypes expressed in non-nociceptive RAR/SAR stretch
receptive fibers. In AIM 3 we will will begin our evaluation of the role of NaV1.8 and 1.9 in the airways
hyperexcitability that is associated with respiratory viral infections. In AIM 4 we will use our newly developed
extrinsically innervated isolated human bronchus to evaluate, for the first time, the translatability of the major
findings we obtain in laboratory animals to the human condition. We anticipate that this work will provide a
conceptual and rational framework with which to base future clinical studies with selective NaV1 blocking drugs
that can be applied directly to the sensory terminals in the airways with topical inhaled delivery methods.
Terms: <Action Potentials><Address><Airway Disease><Airway Hyper-responsiveness><Alzheimer beta-Protein><Alzheimer's Amyloid beta-Protein><Alzheimer's amyloid><Amyloid Alzheimer's Dementia Amyloid Protein><Amyloid Beta-Peptide><Amyloid Protein A4><Amyloid beta-Protein><Amyloid β><Amyloid β-Peptide><Amyloid β-Protein><Area><Asthma><Attention><Axon><Aβ><Behavior><Biology><Body Tissues><Brain><Brain Nervous System><Breathing><Breathlessness><Bronchi><Bronchial Asthma><Bronchial Spasm><Bronchospasm><C Fiber><C-terminal><CNS Nervous System><COPD><Cavia><Central Nervous System><Chemicals><Chronic><Chronic Obstruction Pulmonary Disease><Chronic Obstructive Airway Disease><Chronic Obstructive Lung Disease><Chronic Obstructive Pulmonary Disease><Clinical Research><Clinical Study><Coughing><Data><Disease><Disorder><Drug Targeting><Drugs><Dyspnea><Encephalon><Esthesia><Evaluation><Fiber><Funding><Future><Generations><Genes><Goals><Guinea Pigs><Guinea Pigs Mammals><Health><Human><Inflammation><Inflammation Mediators><Inflammatory><Inhalation><Inhaling><Ion Channel><Ionic Channels><Laboratory Animals><Lead><Life><Mechanics><Medication><Membrane Channels><Methodology><Methods><Mice><Mice Mammals><Modern Man><Molecular Genetics><Murine><Mus><Myocardium><Nerve><Nervous System><Nervous system structure><Neuraxis><Neurologic Body System><Neurologic Organ System><Nociception><Nociceptors><Pattern><Pb element><Peripheral Nerves><Pharmaceutic Preparations><Pharmaceutical Preparations><Physiologic><Physiological><Play><Publishing><Reflex><Reflex action><Regulation><Respiratory Aspiration><Respiratory Inspiration><Respiratory Signs and Symptoms><Respiratory physiology><Role><Secondary to><Seminal><Sensation><Sensory><Skeletal Muscle><Sodium Channel><Sodium Ion Channels><Spike Potential><Stretching><Therapeutic><Time><Tissues><Up-Regulation><Upregulation><Viral Respiratory Tract Infection><Visceral><Voluntary Muscle><Work><a beta peptide><abeta><afferent nerve><airway hyper-reactivity><airway hyperactivity><airway hyperreactivity><airway hyperresponsiveness><airway hypersensitivity><airway symptom><amyloid beta><amyloid-b protein><base><beta amyloid fibril><biophysical characteristics><biophysical characterization><biophysical measurement><biophysical parameters><biophysical properties><cardiac muscle><debilitating symptom><differential expression><differentially expressed><disabling symptom><drug/agent><expression subtypes><heart muscle><heavy metal Pb><heavy metal lead><inflammatory mediator><inspiration><lung function><mechanical><molecular sub-types><molecular subsets><molecular subtypes><nerve threshold><new drug treatments><new drugs><new therapeutics><new therapy><next generation therapeutics><nociceptive><novel><novel drug treatments><novel drugs><novel therapeutics><novel therapy><pulmonary symptom><respiratory function><respiratory symptom><response><sensory nerve><social role><soluble amyloid precursor protein><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><transcriptional differences><viral respiratory infection><voltage>