Inflammation is the root cause of the pathology of diseases such as atherosclerosis, rheumatoid arthritis, inflammatory bowel disease, and psoriasis. Therefore, there is great interest in developing therapies to inhibit unwanted inflammation and in particular to target specific steps in the inflammatory process. A critical ste in the inflammatory response is the emigration of leukocytes out of the blood and into the tissues, since this is the first irreversible step in the process. Leukocytes extravasate across endothelial cell junctions in a process called transendothelial migration, or diapedesis. Our lab has discovered a membrane compartment that is crucial for diapedesis. This compartment, the lateral border recycling compartment (LBRC), contains membrane proteins that are recycled from beneath the surface of endothelial cells to the site at which attached leukocytes will transmigrate. Movement of LBRC membrane to surround the leukocyte is required for leukocyte diapedesis to take place. Our lab has shown that intact microtubules and functioning kinesin molecular motors are needed to move membrane from the lateral border recycling compartment to the site of diapedesis, in a process called targeted recycling. My research will identify the specific kinesin molecular motor(s) needed for transendothelial migration of leukocytes. Identifying the molecules that regulate the process of targeted recycling will provide insights int the regulation of the inflammatory response and offers the opportunity to identify novel targets for anti- inflammatory therapies. I will first determine the kinesin molecular motor(s) required fo targeted recycling for transendothelial migration in Aim 1 and then determine the kinesin light chain(s) that interact with the LBRC membrane cargo in Aim 2. Small interfering RNA will be used to knock down the specific motor(s) and light chains. Established transmigration and targeted recycling assays will be used to determine their roles in recruitment of the LBRC. Identifying the molecules that regulate the process of targeted recycling will provide insights int the regulation of the inflammatory response and offers the opportunity to identify novel targets for anti-inflammatory therapies.
Understanding the processes involved in inflammation is crucial to understanding the pathology of various diseases caused by inflammation. The passage of white blood cells across the blood vessel wall (a.k.a. transendothelial migration) is a critical step in the inflammation process. This project will identify the molecular motor(s) involvd in recruiting vesicular structures that contain specific molecules necessary for transendothelial migration. Once these are identified, they may be potential therapeutic targets for treating inflammation in disease.
|Cyrus, Bita F; Muller, William A (2016) A Unique Role for Endothelial Cell Kinesin Light Chain 1, Variant 1 in Leukocyte Transendothelial Migration. Am J Pathol 186:1375-86|
|Gonzalez, Annette M; Cyrus, Bita F; Muller, William A (2016) Targeted Recycling of the Lateral Border Recycling Compartment Precedes Adherens Junction Dissociation during Transendothelial Migration. Am J Pathol 186:1387-402|