Grant: $10,168 - National Institutes of Health - Jun. 5, 2009
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Award Description: 'Neurotrophins affect airway smooth muscle tone. Air flows into the lungs through the conducting airways (trachea and bronchi) and, with every breath we take, the airways rhythmically contract and relax with each breath; this change in airway smooth muscle tone (as well as mucous secretion) is regulated by nerves in the parasympathetic nervous system. In people who have asthma, the airways contract too much and there is too much mucous secretion. Parasympathetic nerves cause contraction of airway smooth muscle by the release of the neurotransmitter, acetylcholine, and these parasympathetic nerves are referred to as ?cholinergic?. In addition to parasympathetic cholinergic nerves, noncholinergic parasympathetic nerves are also found in the airways. When activated, noncholinergic-parasympathetic nerves initiate smooth muscle relaxation (also known as bronchodilatation). These relaxations have been attributed to the actions of the neurotransmitter, vasoactive intestinal peptide (VIP and related peptides), as well as nitric oxide (NO) which is formed from the precursor arginine by the neuronal isoform of NO synthase (NOS). Several lines of experimental evidence indicate that noncholinergic parasympathetic nerves become dysfunctional in airways disease. Dysfunction of airway parasympathetic nerves accounts in large part for the symptoms associated with asthma and chronic obstructive pulmonary disease (COPD), and chronic bronchitis. Over the past decade, we have provided experimental evidence that airway parasympathetic ganglionic neurons regulate signals from the brain and how this is altered by neighboring nerves or by inflammation. Neurotrophins, such as NGF, are increased in the inflamed or infected airways and many symptoms of these diseases (hyperactivity, cough, mucous production) may be related to altered or aberrant functions of the airway nervous. Neurotrophins function during development, particularly as survival factors, but also as factors involved in differentiation and axon growth. However, both the neurotrophins themselves (NGF, BDNF, NT-4/5 and NT-3) and their high affinity receptors (trkA, trkB and trkC) continue to be expressed post-natally indicating that their function goes far beyond their role in development. Central to this supplemental funding is the hypothesis that molecules known as neurotrophins, especially nerve growth factor (NGF), regulate the function of adult airway parasympathetic neurons. We propose to study their role in modulating the airway parasympathetic nervous system in adult animals. The central hypothesis associated with this supplemental funding is that neurotrophins, formed tonically within the airways by structural cells or formed in excess during inflammatory responses, regulate airway parasympathetic ganglia neuronal excitability and neurochemistry. The effects of neurotrophins on airways reactivity have been documented experimentally in animals. More recently, the PI has shown that nerve growth factor (NGF) acutely and profoundly enhances airway parasympathetic ganglia neuron excitability. NGF also initiated neurite outgrowth in the airway parasympathetic ganglia neurons. The consequence of this effect of NGF on airway parasympathetic nerves is predicted to be a marked enhancement of airway smooth muscle contraction upon nerve activation. A similar effect of NGF on parasympathetic nerve evoked mucus secretion would also be expected. One of the primary aims of this grant was to quantify the functional consequences of neurotrophins on airway smooth muscle responsiveness. This supplemental support funded a summer student, Ms. Kayla Marchese, to evaluate the functional consequences of neurotrophins on parasympathetic nerve regulation of smooth muscle tone.
Project Description: ' The effects of molecules released during inflammation in the lower airways (trachea and bronchi) include a class molecules known as neurotrophins. We are only beginning to understand how these molecules affect nerves and, consequently, airways reactivity (bronchoconstriction). More recently, our labs have shown that one neurotrophin, nerve growth factor (NGF), acutely and profoundly enhances airway parasympathetic ganglia neuron excitability. One of the primary purposes of this research was to quantify the functional consequences of neurotrophins on airway smooth muscle responsiveness. American Recovery Act funding for our summer student, Ms. Kayla Marchese, will be use to train her in biomedical techniques associated with this research enabling her to evaluate the functional consequences of neurotrophins on parasympathetic nerve regulation of airway smooth muscle tone. During the summer, Ms. Marchese addressed the hypothesis that neurotrophins alter the neurochemistry of noncholinergic parasympathetic nerves, inducing a cholinergic phenotype. This change will be studied using immunohistochemical and functional assays. For the functional studies, Ms. Marchese evaluated changes in nerve evoked contractions and relaxations of airway smooth muscle maintained in organotypic culture for 12, 24, 48 and 72 hours in the absence and presence of NGF, brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3), selective ligands for the neurotrophin receptors TrKA, TrKB, and TrKC, respectively. Contractions and relaxations of airway smooth muscle preparations were evoked electrically and studied by frequency-response analysis (0.5-48 Hz, 10 sec trains, optimal stimulus intensities (8V, 1 msec pulse duration, ~200 mA)). In parallel studies, Kayla evaluated the neurochemistry and density of nerve fibers innervating the airway smooth muscle before and after exposure to neurotrophins.
Jobs Summary: No jobs were created or retained. (Total jobs reported: 0)
Project Status: Less Than 50% Completed
This award's data was last updated on Jun. 5, 2009. Help expand these official descriptions using the wiki below.