PROJECT SUIVIMARY (See instructions): The long-term objectives of this research application is to better understand the cellular and molecular basis of the inflammatory response in order to develop better therapies to augment it in conditions where the host's immune response is compromised, and to inhibit it under conditions where the response is counterproductive, such as in inflammatory diseases like atherosclerosis, rheumatoid arthritis and other autoimmune diseases, septic shock, asthma, and transplant rejection. A critical step in the inflammatory response is the migration of leukocytes out ofthe bloodstream to the site of inflammation. We have been studying the molecules and mechanisms responsible for diapedesis-the step in this process in which leukocytes pass across the endothelial cells lining postcapillary venules at sites of leukocyte egress. In the first funding period of this grant, we discovered a molecule (CD99) and a mechanism (targeted recycling of membrane from an intemal perijunctional compartment called the LBRC) that play significant roles in diapedesis. In the second funding period thus far (i.e., the first 3.5 years ofthe MERIT award) we have already accomplished most of the Specific Aims of the 5 year plane: We have investigated how CD99 regulates diapedesis. We have discovered that it is present in the LBRC and its function requires the presence of PECAM in the compartment as well. We have cloned the mouse version of CD99 and the related molecule CD99L2 and demonstrated that both play a role in transmigration. We have demonstrated that transcellular migration involves the same mechanism as paracellular migration: Targeted membrane trafficking from the LBRC to the site of migration in a microtubule-dependent manner. The goals for the MERIT extension period are to develop the work proposed for these specific aims to answer the next important 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 CD99L2 complement each other's function in vivo? If so, how? Is blocking them therapeutic in models of chronic inflammatory 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 infectious microorganisms and healing wounds.^ However, most diseases are due to or exacerbated by inflammation that is out of control, continuing for too long, or in the wrong place at the wrong time. By understanding the molecular 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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Lishnevsky, Marta; Young, Lena C; Woods, Steven J et al. (2014) Microhemorrhage is an early event in the pulmonary fibrotic disease of PECAM-1 deficient FVB/n mice. Exp Mol Pathol 97:128-36
Winger, Ryan C; Koblinski, Jennifer E; Kanda, Takashi et al. (2014) Rapid remodeling of tight junctions during paracellular diapedesis in a human model of the blood-brain barrier. J Immunol 193:2427-37
Muller, William A (2014) How endothelial cells regulate transmigration of leukocytes in the inflammatory response. Am J Pathol 184:886-96
Sullivan, David P; Muller, William A (2014) Neutrophil and monocyte recruitment by PECAM, CD99, and other molecules via the LBRC. Semin Immunopathol 36:193-209
Sullivan, David P; Rüffer, Claas; Muller, William A (2014) Isolation of the lateral border recycling compartment using a diaminobenzidine-induced density shift. Traffic 15:1016-29
Muller, W A (2013) Getting leukocytes to the site of inflammation. Vet Pathol 50:7-22
Sullivan, David P; Seidman, Michael A; Muller, William A (2013) Poliovirus receptor (CD155) regulates a step in transendothelial migration between PECAM and CD99. Am J Pathol 182:1031-42
Muller, William A (2011) Sorting the signals from the signals in the noisy environment of inflammation. Sci Signal 4:pe23
Muller, William A (2011) Mechanisms of leukocyte transendothelial migration. Annu Rev Pathol 6:323-44
Dasgupta, Bidisha; Chew, Tina; deRoche, Alana et al. (2010) Blocking platelet/endothelial cell adhesion molecule 1 (PECAM) inhibits disease progression and prevents joint erosion in established collagen antibody-induced arthritis. Exp Mol Pathol 88:210-5

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