Author ORCID Identifier
Date of Graduation
Masters of Science (MS)
Burton Dickey, M.D.
Jichao Chen, Ph.D.
Xuelian Huang, Ph.D.
Harry Karmouty-Quintana, Ph.D.
Jonathan Kurie, M.D.
Michael Tuvim, Ph.D.
In the conducting airways of the lungs, the mobile mucus gel layer sits on top of the airway epithelium, and through ciliary beating it is propelled up the trachea into the pharynx where it is swallowed and cleared. This gel layer is composed of secreted mucins that become hydrated once reaching the airway lumen. Mucins are secreted at a baseline rate and at a stimulated rate, dependent on the amount of agonist. Baseline secretion is responsible for steady clearance of inhaled particles and pathogens. Stimulated secretion is thought to play a role in trapping helminths though mucus occlusion in small airways.
Mucin exocytosis is mediated by a four helix bundle called the SNARE complex. Prior to complex formation, three of the four helices are located on the target membrane (t-SNARE) and one helix is vesicle bound (v-SNARE). Formation of the complex drives fusion of the exocytic vesicle with the plasma membrane. These SNARE interactions take place on a scaffold provided by a Munc18 protein. Prior work in the Dickey-Tuvim laboratory has shown that different Munc18 proteins mediate baseline and stimulated mucin secretion, indicating that different plasma membrane exocytic machines underlie baseline and stimulated mucin secretion.
My project is to answer several questions pertaining to mucin granule biogenesis and exocytosis, which have implications in treating diseases related to disordered mucin production and secretion. 1) Are the polymeric mucins MUC5AC and MUC5B packaged in the same or separate granules? 2) What components of the exocytic machinery on mucin granules interact with the plasma membrane machines, and can these be used as markers to define mucin trafficking prior to secretion?
3) What is the nature of a mucin granule? Does it contain only newly synthesized proteins, or does it intersect the endolysosomal system as occurs in lung alveolar epithelial secretory cells? 4) Does the mucin granule exocytic machinery become associated with granules in the trans-Golgi network? Does the structure of Golgi bodies in airway secretory cells change with mucous metaplasia?
mucins, exocytosis, Muc5ac, Muc5b, SNARE, exocytic machinery, pulmonary