Roles of Synaptotagmin-2 in Airway Obstruction

University Of Tx Md Anderson Can Ctr, Houston TX

Investigators

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Abstract

ABSTRACT Asthma has become the most common chronic respiratory disease in this country. A characteristic of this disease is airway mucus hyperproduction and hypersecretion. The inflammatory milieu in asthma induces airway epithelium secretory cells (AESCs) to increase production of mucins (the glycoprotein core of mucus) at a rate that overwhelms the beneficial basal secretion of mucins, so mucins accumulate in AESC secretory granules. Secretagogues such as ATP, acetylcholine and histamine can stimulate the sudden release of large amounts of accumulated mucins into airways that contain a limited amount of liquid. The accumulation of poorly hydrated and excessively viscoelastic mucus occludes the airways, and airway mucus plugging has been linked to lethal exacerbations of asthma. Another hallmark of asthma is airway hyperresponsiveness (AHR), which was thought to reflect increased contractility of airway smooth muscle around a thickened airway wall, producing airway obstruction. The importance of mucus plugging as another fundamental mechanical factor in AHR was proven in recent experiments in which airway mucus occlusion was required for AHR in a mouse model of asthma. Inflammation is a key feature of asthma. Among inflammatory cells, mast cells (MCs) infiltrate the airway wall, including the mucosa. They accumulate in their secretory granules many substances that are known AESC secretagogues, and they release them upon exposure to an allergen and other stimuli. What is not known is if MC degranulation triggers pathologic AESC secretion and airway mucus occlusion in vivo. Altering mucus viscoelasticity and decreasing mucin production are targets being explored in asthma. We postulate that interfering with mucin secretion is also a viable alternative. We have shown that Synaptotagmin-2 (Syt2) is required for MC degranulation and AESC stimulated secretion. We will explore as part of Aim 1 if lacking Syt2 can also increase the beneficial baseline mucin secretion from AESC since Syt2 deletion increases baseline synaptic vesicle release from neurons. In Aim 2, we propose to study a tissue- specific conditional Syt2 KO mouse in an inhalation-only model of allergic asthma, using in addition to cholinergic stimuli a direct allergen challenge to better simulate clinical situations. We plan to test if blocking MC degranulation as a trigger, or decreasing AESC stimulated mucin secretion as an effector, or increasing AESC baseline mucin secretion to deplete intracellular mucin stores, or all of the above, can prevent airway mucus occlusion and AHR. Our experiments will pave a way to explore the roles of MC and AESC exocytosis in other manifestations of asthma, will validate mucin secretion as a potential step to be manipulated in the management of this disease, and will pinpoint Syt2 as a viable therapeutic target.