Wednesday, December 4, 2024
12/4/2024
PROJECT SUMMARY Dry eye syndrome (DES) afflicts over 7 million Americans. DES can cause chronic and severe symptoms, leading to visual disturbances. DES is caused by instability of the precorneal tear film (PCTF) at the surface of the eye. While it is known that the stability of the PCTF plays a central role in DES, there is rigorous debate about what causes PCTF instability. The tear film lipid layer (TFLL) is central to the stability of tear films. The TFLL is an extremely thin layer of ordered lipid molecules separating the PCTF from the air. Researchers have proposed several functions for the TFLL, including but not limited to reducing tear, preventing the collapse of the tear layer, and providing a layer of defense against pathogens. However, it is unclear how changes in TFLL composition, thickness, and arrangement induce PCTF instability and thinning. Several competing hypotheses naturally lead to different strategies for treating DES. Stimulation of tear production, modulation of glandular function, and supplementation with externally applied lipid solutions are all possible treatment routes. However, questions about the causes of DES are difficult to answer because of lack of a detailed molecular structure of the TFLL. Because of the TFLL’s dynamic nature, common experimental techniques are incapable of providing high- resolution structural detail about how molecules arrange in the TFLL at the air-lipid and lipid-water interfaces. Instead, researchers use lower resolution methods to probe composition and structure, sometimes indirectly through model chemical compounds. However, these low-resolution techniques provide ambiguous results, because multiple related molecular arrangements can produce the same signal. Thus, there is not a one-to-one correlation between experimental results and molecular structures. In this study, we will generate and validate a physiochemical computational model of the TFLL which considers the energetics of the system, and which will be used to rationalize experimental observations about TFLL structure, function, and properties. Recent developments in computational power allow researchers to simulate the motion of up to millions of atoms over timescales long enough to allow the prediction of physical properties with a method called molecular dynamics. The model begins with a description of the inter- and intramolecular forces acting on the TFLL’s components. A virtual box of atoms is generated with a hypothetical molecular arrangement. Using classical physics, forces between molecules are translated into motion of all atoms, and simulated snapshots of atomic positions are collected. Analysis of these snapshots and associated energies allows the calculation of theoretical properties that can be matched to experimental data. A successful model will match experimentally observed behavior and provide a well-supported hypothetical TFLL structure for researchers to use for further studies. If successful, the model developed in this work can help provide evidence for or against prevailing and competing hypotheses about the function of the TFLL and the underlying causes of DES. Ultimately, the knowledge gained in this study can be applied to improved design of treatments and therapeutics for DES.
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