Localization of plasminogen on cell surfaces is a crucial control point for positive regulation of cell surface plasmin proteolytic activity that facilitates both physiological and pathological processes requiring cell migration. The long-term goal of our laboratory is to understand mechanisms by which plasminogen receptors regulate pathological and physiological processes. This proposal is based on our discovery of a new protein, the plasminogen receptor, Plg-RKT that has a unique structure: Plg-RKT is an integral membrane protein that exposes a C-terminal lysine on the cell surface, in an orientation to bind plasminogen. Plg-RKT functions as a developmentally regulated plasminogen receptor that promotes plasminogen activation on monocytes and regulates invasion of monocytes through extracellular matrices. Plg-RKT is necessary for optimal plasminogen- dependent macrophage recruitment in the inflammatory response in vivo. In other novel results, Plg-RKT is highly co-localized with the receptor for the major plasminogen activator synthesized by macrophages, the urokinase plasminogen activator receptor (uPAR) and physically associates with uPAR. The objective of this application is to elucidate the molecular mechanisms by which Plg-RKT regulates plasminogen-dependent macrophage recruitment in the inflammatory response. The central hypothesis to be addressed is that Plg-RKT regulates plasminogen-dependent macrophage recruitment by promoting plasminogen activation, extracellular matrix invasion and chemotaxis. To address our hypothesis, our specific aims are: 1) to test the hypothesis that Plg-RKT regulates specific uPAR-dependent functions and that uPAR regulates specific Plg-RKT-dependent functions in plasminogen activation and cell migration;2) to identify molecular determinants of the physical association of Plg-RKT with uPAR;3) To identify mechanisms by which Plg-RKT regulates functions of plasminogen in vivo. Studies will be performed in cell based assays and in vivo using novel function blocking anti- Plg-RKT antibodies, peptide mimetics and a new Plg-RKT knockout mouse model. We expect that accomplishment of our specific aims will provide fundamental insights that should apply to understanding mechanisms of regulation of inflammation as well as regulation of other physiological and pathological processes dependent on cell migration.

Public Health Relevance

The proposed research is relevant to public health because new knowledge of mechanisms by which cell migration is regulated will be acquired. This knowledge is directly applicable to understanding the multitude of diseases with key inflammatory components (notably cardiovascular disease), as well as additional pathological processes dependent on cell migration (notably, cancer metastasis). In addition the results of these studies are expected to identify new potential targets for development of new therapies for these diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL081046-07
Application #
8438378
Study Section
Hemostasis and Thrombosis Study Section (HT)
Program Officer
Sarkar, Rita
Project Start
2005-07-01
Project End
2017-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
7
Fiscal Year
2013
Total Cost
$451,010
Indirect Cost
$213,010
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Miles, L A; Baik, N; Bai, H et al. (2018) The plasminogen receptor, Plg-RKT, is essential for mammary lobuloalveolar development and lactation. J Thromb Haemost 16:919-932
Miles, Lindsey A; Parmer, Robert J (2017) tPA and anger management for macrophages. Blood 130:1280-1281
Sugimoto, Michelle A; Ribeiro, Ana Luíza C; Costa, Bruno R C et al. (2017) Plasmin and plasminogen induce macrophage reprogramming and regulate key steps of inflammation resolution via annexin A1. Blood 129:2896-2907
Miles, L A; Baik, N; Lighvani, S et al. (2017) Deficiency of plasminogen receptor, Plg-RKT , causes defects in plasminogen binding and inflammatory macrophage recruitment in vivo. J Thromb Haemost 15:155-162
Briens, Aurélien; Bardou, Isabelle; Lebas, Héloïse et al. (2017) Astrocytes regulate the balance between plasminogen activation and plasmin clearance via cell-surface actin. Cell Discov 3:17001
Miles, Lindsey A; Parmer, Robert J (2016) Angry macrophages patrol for fibrin. Blood 127:1079-80
Miles, Lindsey A; Lighvani, Shahrzad; Baik, Nagyung et al. (2014) New insights into the role of Plg-RKT in macrophage recruitment. Int Rev Cell Mol Biol 309:259-302
Miles, Lindsey A; Parmer, Robert J (2014) Setting the table for macrophages. Blood 124:665-6
Gingles, N A; Bai, H; Miles, L A et al. (2013) Peptidergic regulation of plasminogen activator inhibitor-1 gene expression in vivo. J Thromb Haemost 11:1707-15
Miles, Lindsey A; Parmer, Robert J (2013) Plasminogen receptors: the first quarter century. Semin Thromb Hemost 39:329-37

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