This proposal describes a 5 year training program designed to facilitate the ability of the candidate to pursue an independent career in the field of pleural fibrosis. The candidate came to The University of Texas Health Science Center at Tyler as a post-doctoral fellow, has joined the faculty as an Assistant Professor of Biochemistry and will continue his transition to independence through comprehensive mentorship and by conducting a completely novel, high impact scientific project. This program will shed new light on the pathogenesis of pleural fibrosis, which affects thousands of patients annually and for which treatment options are invasive or of uncertain benefit. In work reported by this laboratory, the mesothelium has previously been shown to promote fibrotic repair by promoting local procoagulant activity and suppressing fibrinolysis in the pleural compartment. The mesothelium can also support pleural organization and unrestricted repair via phenotypic changes of mesothelial cells;mesomesenchymal transition (MT). Our preliminary data support the concept that procoagulants induce MT. The role of factor Xa and thrombin in MT is now unknown and will be elucidated in this project. Dr. Steven Idell will serve as the primary mentor for the principal investigator's scientific development. Dr. Idell is a leader in the field of coagulation nd fibrinolysis in lung and pleural injury who has a long-standing interest in the treatment of pleura fibrosis. He is the Vice President for Research at The University of Texas Health Science Center at Tyler (UTHSCT) and has mentored numerous successful trainees. An advisory committee including Dr. Hua Tang and Dr. Sreerama Shetty resident experts in the field of lung fibrosis and Dr. L. Vijaya Rao a world renowned expert in the field of coagulation will mentor the applicant. They will ensure that the applicant achieves his objective of becoming a successful independent investigator. Our hypothesis is that factor Xa and thrombin are important determinants of MT and pleural fibrosis. Our objective is to elucidate the contribution of coagulation proteases to MT and the development of pleural loculation and fibrosis that follow acute pleural injury.
The Specific Aims of the proposal are: 1) to determine the mechanism of FXa and thrombin mediated MT in pleural mesothelial cells, 2) to elucidate the role of Akt and Wnt/?-catenin-signaling in FXa and thrombin mediated-MT in PMCs, and 3) to determine the role of FXa and thrombin in evolving fibrosing pleural injury in mice. To accomplish this work, a number of techniques, including cell biology, immunologic, protein chemistry and molecular biology techniques will be used. The Biomedical Research Department of UTHSCT is an ideal setting to conduct this research project. The combination of strong institutional support and an enthusiastic, productive advisory committee provides a nurturing environment that will enable the applicant to accelerate his successful transition to an independent investigative career.

Public Health Relevance

This project addresses new potential mechanisms and therapies for the treatment of pleural fibrosis. In this project we will determine the role of coagulation cascade proteases in mesenchymal transition and their contribution to the progression of pleural fibrosis. We also propose new potential therapies for the treatment of this disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
1K01HL115466-01
Application #
8367874
Study Section
Special Emphasis Panel (ZHL1-CSR-F (M1))
Program Officer
Colombini-Hatch, Sandra
Project Start
2012-08-01
Project End
2017-06-30
Budget Start
2012-08-01
Budget End
2013-06-30
Support Year
1
Fiscal Year
2012
Total Cost
$110,160
Indirect Cost
$8,160
Name
University of Texas Health Center at Tyler
Department
Type
Organized Research Units
DUNS #
800772337
City
Tyler
State
TX
Country
United States
Zip Code
75708
Komissarov, Andrey A; Rahman, Najib; Lee, Y C Gary et al. (2018) Fibrin turnover and pleural organization: bench to bedside. Am J Physiol Lung Cell Mol Physiol 314:L757-L768
Boren, Jake; Shryock, Grant; Fergis, Alexis et al. (2017) Inhibition of Glycogen Synthase Kinase 3? Blocks Mesomesenchymal Transition and Attenuates Streptococcus pneumonia-Mediated Pleural Injury in Mice. Am J Pathol 187:2461-2472
Kamata, Hirotoshi; Tsukasaki, Yoshikazu; Sakai, Tsuyoshi et al. (2017) KIF5A transports collagen vesicles of myofibroblasts during pleural fibrosis. Sci Rep 7:4556
Venkatasubramanian, Sambasivan; Tripathi, Deepak; Tucker, Torry et al. (2016) Tissue factor expression by myeloid cells contributes to protective immune response against Mycobacterium tuberculosis infection. Eur J Immunol 46:464-79
Tucker, Torry A; Jeffers, Ann; Boren, Jake et al. (2016) Organizing empyema induced in mice by Streptococcus pneumoniae: effects of plasminogen activator inhibitor-1 deficiency. Clin Transl Med 5:17
Owens, Shuzi; Jeffers, Ann; Boren, Jake et al. (2015) Mesomesenchymal transition of pleural mesothelial cells is PI3K and NF-?B dependent. Am J Physiol Lung Cell Mol Physiol 308:L1265-73
Jeffers, Ann; Owens, Shuzi; Koenig, Kathleen et al. (2015) Thrombin down-regulates tissue factor pathway inhibitor expression in a PI3K/nuclear factor-?B-dependent manner in human pleural mesothelial cells. Am J Respir Cell Mol Biol 52:674-82
Tucker, Torry A; Jeffers, Ann; Alvarez, Alexia et al. (2014) Plasminogen activator inhibitor-1 deficiency augments visceral mesothelial organization, intrapleural coagulation, and lung restriction in mice with carbon black/bleomycin-induced pleural injury. Am J Respir Cell Mol Biol 50:316-27
Keshava, Shiva; Sahoo, Sanghamitra; Tucker, Torry A et al. (2013) Endothelial cell protein C receptor opposes mesothelioma growth driven by tissue factor. Cancer Res 73:3963-73