Program Director/Principal Investigator (Last, First, Middle): duller, William A.PROJECT SUIVIMARY (See instructions):The long-term objectives of this research application is to better understand the cellular and molecular basisof the inflammatory response in order to develop better therapies to augment it in conditions where thehost's immune response is compromised, and to inhibit it under conditions where the response iscounterproductive, such as in inflammatory diseases like atherosclerosis, rheumatoid arthritis and otherautoimmune diseases, septic shock, asthma, and transplant rejection. A critical step in the inflammatoryresponse is the migration of leukocytes out ofthe bloodstream to the site of inflammation. We have beenstudying the molecules and mechanisms responsible for diapedesis-the step in this process in whichleukocytes pass across the endothelial cells lining postcapillary venules at sites of leukocyte egress. In thefirst funding period of this grant, we discovered a molecule (CD99) and a mechanism (targeted recycling ofmembrane from an intemal perijunctional compartment called the LBRC) that play significant roles indiapedesis. In the second funding period thus far (i.e., the first 3.5 years ofthe MERIT award) we havealready accomplished most of the Specific Aims of the 5 year plane: We have investigated how CD99regulates diapedesis. We have discovered that it is present in the LBRC and its function requires thepresence of PECAM in the compartment as well. We have cloned the mouse version of CD99 and therelated molecule CD99L2 and demonstrated that both play a role in transmigration. We have demonstratedthat transcellular migration involves the same mechanism as paracellular migration: Targeted membranetrafficking from the LBRC to the site of migration in a microtubule-dependent manner. The goals for theMERIT extension period are to develop the work proposed for these specific aims to answer the nextimportant questions. These include: What signals from CD99 are required to complete transmigration?Why does CD99 function depend on PECAM? (How do these molecules interact?) Do CD99 and CD99L2complement each other's function in vivo? If so, how? Is blocking them therapeutic in models of chronicinflammatory disease? How is LBRC membrane recruited for transcellular migration in vitro and in vivo?

Public Health Relevance

Inflammation is the body's response to tissue damage of any kind. It is critical for fighting off infectiousmicroorganisms and healing wounds.^ However, most diseases are due to or exacerbated by inflammationthat is out of control, continuing for too long, or in the wrong place at the wrong time. By understanding themolecular basis of inflammation, we will better be able to control it. This will lead to better therapies.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Method to Extend Research in Time (MERIT) Award (R37)
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Special Emphasis Panel (NSS)
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Srinivas, Pothur R
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Northwestern University at Chicago
Schools of Medicine
United States
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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
Muller, William A (2016) Transendothelial migration: unifying principles from the endothelial perspective. Immunol Rev 273:61-75
Muller, William A (2016) Localized signals that regulate transendothelial migration. Curr Opin Immunol 38:24-9
Muller, William A (2016) How monocytes guard the glomerulus. Proc Natl Acad Sci U S A 113:10453-5
Winger, Ryan C; Harp, Christopher T; Chiang, Ming-Yi et al. (2016) Cutting Edge: CD99 Is a Novel Therapeutic Target for Control of T Cell-Mediated Central Nervous System Autoimmune Disease. J Immunol 196:1443-8
Sullivan, David P; Watson, Richard L; Muller, William A (2016) 4D intravital microscopy uncovers critical strain differences for the roles of PECAM and CD99 in leukocyte diapedesis. Am J Physiol Heart Circ Physiol 311:H621-32
Weber, Evan W; Han, Fei; Tauseef, Mohammad et al. (2015) TRPC6 is the endothelial calcium channel that regulates leukocyte transendothelial migration during the inflammatory response. J Exp Med 212:1883-99
Muller, William A (2015) The regulation of transendothelial migration: new knowledge and new questions. Cardiovasc Res 107:310-20
Maisa, Anna; Hearps, Anna C; Angelovich, Thomas A et al. (2015) Monocytes from HIV-infected individuals show impaired cholesterol efflux and increased foam cell formation after transendothelial migration. AIDS 29:1445-57

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