Angiogenesis is the formation of new capillaries from pre-existing capillaries. This process is most prevalent during development and growth of an organism, including humans. In adults, angiogenesis is mostly associated with wound healing, endometrial remodeling and the menstrual cycle. Pathogenic angiogenesis has been implicated in many different diseases, such as cancer, diabetic retinopathy, psoriasis, macular degeneration, rheumatoid arthritis, etc. Recent studies have reported identification of several endogenous inhibitors of angiogenesis, such as thrombopondin, angiostatin, endostatin and tumstatin. These endogenous inhibitors function in opposition to several pro-angiogenic factors such as VEGF, FGF, etc., and are thought to provide the regulatory balance for angiogenesis. In this grant proposal, we will investigate the mechanism behind the action of tumstatin, an endogenous inhibitor of angiogenesis. The focus of this grant is to better understand the need for the human body to generate endogenous inhibitors of angiogenesis. We hope to answer questions such as, what happens when endogenous inhibitors are genetically removed from the body? How do these inhibitors work? Why are they non-toxic and specific to dividing endothelial cells that are in the process of making new capillaries around tumor ceils? What is the molecular message sent by tumstatin to a dividing endothelial cell? Successful completion of the experiments proposed in this grant application will provide valuable insight into how these endogenous inhibitors function and their potential use as anti-tumor agents in the clinic.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK062987-01
Application #
6560730
Study Section
Pathology A Study Section (PTHA)
Program Officer
Wilder, Elizabeth L
Project Start
2003-09-15
Project End
2007-06-30
Budget Start
2003-09-15
Budget End
2004-06-30
Support Year
1
Fiscal Year
2003
Total Cost
$405,875
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
Ayala de la Peña, Francisco; Kanasaki, Keizo; Kanasaki, Megumi et al. (2014) Specific activation of K-RasG12D allele in the bladder urothelium results in lung alveolar and vascular defects. PLoS One 9:e95888
Ayala de la Peña, Francisco; Kanasaki, Keizo; Kanasaki, Megumi et al. (2011) Loss of p53 and acquisition of angiogenic microRNA profile are insufficient to facilitate progression of bladder urothelial carcinoma in situ to invasive carcinoma. J Biol Chem 286:20778-87
Teng, Yingqi; Kanasaki, Keizo; Bardeesy, Nabeel et al. (2011) Deletion of Smad4 in fibroblasts leads to defective chondrocyte maturation and cartilage production in a TGF? type II receptor independent manner. Biochem Biophys Res Commun 407:633-9
Hertig, A; Flier, S N; Kalluri, R (2010) Contribution of epithelial plasticity to renal transplantation-associated fibrosis. Transplant Proc 42:S7-12
Lee, Soo Bong; Kalluri, Raghu (2010) Mechanistic connection between inflammation and fibrosis. Kidney Int Suppl :S22-6
Hertig, Alexandre; Gangadhar, Taduri; Kalluri, Raghu (2010) Renal studies provide an insight into cardiac extracellular matrix remodeling during health and disease. J Mol Cell Cardiol 48:497-503
Flier, Sarah N; Tanjore, Harikrishna; Kokkotou, Efi G et al. (2010) Identification of epithelial to mesenchymal transition as a novel source of fibroblasts in intestinal fibrosis. J Biol Chem 285:20202-12
Kizu, Akane; Medici, Damian; Kalluri, Raghu (2009) Endothelial-mesenchymal transition as a novel mechanism for generating myofibroblasts during diabetic nephropathy. Am J Pathol 175:1371-3
Schweitzer, Mary H; Zheng, Wenxia; Organ, Chris L et al. (2009) Biomolecular characterization and protein sequences of the Campanian hadrosaur B. canadensis. Science 324:626-31
Ayala, F; Dewar, R; Kieran, M et al. (2009) Contribution of bone microenvironment to leukemogenesis and leukemia progression. Leukemia 23:2233-41

Showing the most recent 10 out of 60 publications