Date of Award

2022

Document Type

Thesis

Degree Name

Master of Science (MS)

Department

Pathology

First Advisor

Brian Cunniff

Abstract

Allergic asthma is a serious socioeconomic and health issue that is characterized by chronic inflammation of the lungs and affects as many 300 million people worldwide of all ages. Inhaled environmental factors, such as allergens, can disrupt the airway epithelium, which is the physical barrier and the first line of defense against external irritants. Consequently, exposure to allergens can cause episodes of airway inflammation, increased mucus production and tissue remodeling, that leads to the obstruction and narrowing of the airways, which may present as difficulty breathing, wheezing, and persistent coughing. Unfortunately, there is no cure for allergic asthma, but allergen avoidance and prescription of medication can help manage symptoms. However, current treatment options fail in almost 10% of patients, making it necessary to study uncharacterized molecular causes to better understand this condition.

Evidence suggests that mitochondria play a vital role in lung health and disease. Mitochondria are dynamic organelles that can change in size, shape, and distribution depending on cellular demands and are transported through the cell on microtubules. Miro1, a calcium-binding membrane-anchored GTPase that is strongly associated with mitochondrial transport, is the primary adaptor protein required for the subcellular positioning of this organelle. While mitochondria play an important role in lung physiology, the role of localized mitochondrial function in response to allergen-induced inflammation remained unknown.

The main goal of this study was to investigate the effects Miro1-mediated mitochondrial trafficking in allergen-induced inflammation and provide a comprehensive phenotypic readout. To achieve this, our laboratory developed a novel tissue-inducible mouse model that allowed for the deletion of Miro1 from club cells, an abundant epithelial cell subtype in mice, and utilized this system with an established model of chronic allergen-induced inflammation. Our results show that epithelial deletion of Miro1 leads to a heightened inflammatory response, enhanced mucus metaplasia, pronounced tissue remodeling and smooth muscle levels that leads to increased airway hyperresponsiveness following chronic exposure to a complex allergen. Results from this study indicate a possible role for Miro1 in the development and progression of allergic asthma, providing insights into the role of Miro1-mediated mitochondrial positioning in allergic asthma severity. Future studies should be conducted to gain a better understanding of the mechanisms of Miro1 and mitochondrial positioning in asthma.

Language

en

Number of Pages

83 p.

Included in

Pathology Commons

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