Plasma Membrane Repair in the Lung
Abstract
The research described in this proposal will fill a fundamental gap in understanding how an understudied gene family – the extended synaptotagmins (ESYTs) – helps repair the surface (termed the plasma membrane) of lung cells. This gap in knowledge must be addressed to develop therapeutic approaches for respiratory health based on this gene family. The long-term goal is to develop new therapies to accelerate plasma membrane repair and bolster membrane integrity. The plasma membrane, also called the cell membrane, is essential for life because it covers and protects all cells. It mediates the transport of compounds and is the cell’s platform for communication with the extracellular environment. ESYTs link the plasma membrane to important intracellular portions of the cell, such as the cortical endoplasmic reticulum (cER), a long membrane structure located just behind the plasma membrane. The cER can protect the plasma membrane from damage and contribute to its repair. The plasma membrane can be damaged by toxins, chemicals, smoke, and pollutants. Under battlefield conditions, the lungs of active-duty Service Members can sustain damage from such airborne contaminants. In addition, military deployment is associated with the initiation of cigarette smoking and repeated usage. Prolonged exposure to airborne pollutants can lead to emphysema, chronic obstructive pulmonary disease (COPD), and lung cancer. Although cells can repair moderate damage to the plasma membrane rapidly, our knowledge of the repair pathway and ways to accelerate repair remain rudimentary. The central hypothesis is that the ESYT gene family is essential for membrane repair in the lung. This hypothesis is based on preliminary data generated in the applicant s laboratory, demonstrating for the first time that loss of ESYT-like genes in yeast profoundly impairs plasma membrane repair, and that the amount of certain ESYTs is reduced in human bronchial epithelial cells from COPD patients. The two specific aims of this proposal are to quantify the contribution of the ESYT proteins to plasma membrane repair in (1) a human lung cell line and (2) in the lungs of mice. In Aim 1, stable human lung cell lines that lack one or more of the ESYT genes will be established. These cell lines and a control cell line will be exposed to membrane-damaging compounds, such as smoke and hydrogen peroxide, and then plasma membrane repair efficiency will be measured. In Aim 2, a mouse colony lacking all Esyt genes will be established. These mice and control mice will be exposed acutely and chronically to smoke, lung physiology will be comprehensively evaluated, and plasma membrane repair efficiency of freshly isolated and cultured primary lung cells will be measured. The research described in this proposal is innovative because it focuses on a gene family – the ESYTs – newly implicated in plasma membrane repair. The proposal is novel because it translates the discovery of a membrane repair role of ESYT-like proteins in yeast – a simple model system – to humans. The research is significant because it may lead to developing therapies that will limit lung damage and accelerate lung repair.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310140
Entities
People
- William Chirico
Organizations
- SUNY Downstate Health Sciences University
- United States Army