Retinal microvascular morphogenesis is a complex and highly coordinated process, which occurs during embryonic development, post-natally and in association with several visually-impairing diseases, including retinopathy of prematurity (ROP), age-related macular degeneration and diabetic retinopathy. Recent work carried out in the principal investigator's laboratory has revealed that isoactin-based cytoskeletal remodeling is integral to the microvascular migration and proliferation observed during developmental and pathologic angiogenesis, including the pericyte-based remodeling seen during retinal microvascular maturation. In a focused, inter-disciplinary research plan that will take advantage of in vitro and in vivo models using a spectrum of well-established molecular, cell biology-based and molecular genetic approaches, we aim to reveal the molecular mechanisms and the isoactin-based signaling cascades regulating (i) retinal endothelial migration driving normal and pathologic angiogenesis, and (ii) pericyte-based control of endothelial proliferation and capillary contractility. Quantitative analyses of retinal microvascular endothelial cell cultures will be performed in conjunction with experiments aimed at over-expressing the novel beta-actin specific binding and filament capping protein, betacap73, discovered in the lab. To reveal the molecular mechanisms driving isoactin-based control of developmental and pathologic angiogenesis, we will take advantage of a 'two-mouse' transgenic approach, where we will specifically induce betacap73 over-expression within the post-natal vascular endothelium. These combined results, revealing alterations in endothelial motility and impaired angiogenesis, will serve to guide cDNA expression array analyses aimed at identifying key signaling effectors controlling these pivotal microvascular events. Further, to reveal the molecular signaling mechanisms regulating pericyte contractility and retinal endothelial growth, we will characterize the role that Rho GTPase family members play in signaling vascular cytoskeletal remodeling and isoactin dynamics during microvascular morphogenesis. Based on the preliminary data recently obtained and the experimental approaches proposed, we anticipate that our research plan will provide important new insights into the molecular mechanisms regulating retinal microvascular morphogenesis during normal development and in association with the pathologic angiogenesis accompanying diabetic retinopathy.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY015125-04
Application #
7269856
Study Section
Biology and Diseases of the Posterior Eye Study Section (BDPE)
Program Officer
Shen, Grace L
Project Start
2004-08-01
Project End
2010-07-31
Budget Start
2007-08-01
Budget End
2010-07-31
Support Year
4
Fiscal Year
2007
Total Cost
$357,220
Indirect Cost
Name
Tufts University
Department
Physiology
Type
Schools of Medicine
DUNS #
039318308
City
Boston
State
MA
Country
United States
Zip Code
02111
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Durham, Jennifer T; Dulmovits, Brian M; Cronk, Stephen M et al. (2015) Pericyte chemomechanics and the angiogenic switch: insights into the pathogenesis of proliferative diabetic retinopathy? Invest Ophthalmol Vis Sci 56:3441-59
Durham, Jennifer T; Surks, Howard K; Dulmovits, Brian M et al. (2014) Pericyte contractility controls endothelial cell cycle progression and sprouting: insights into angiogenic switch mechanics. Am J Physiol Cell Physiol 307:C878-92
Geevarghese, Anita; Herman, Ira M (2014) Pericyte-endothelial crosstalk: implications and opportunities for advanced cellular therapies. Transl Res 163:296-306
Willard, Abbott L; Herman, Ira M (2012) Vascular complications and diabetes: current therapies and future challenges. J Ophthalmol 2012:209538
Dulmovits, Brian M; Herman, Ira M (2012) Microvascular remodeling and wound healing: a role for pericytes. Int J Biochem Cell Biol 44:1800-12
Demidova-Rice, Tatiana N; Wolf, Lindsey; Deckenback, Jeffry et al. (2012) Human platelet-rich plasma- and extracellular matrix-derived peptides promote impaired cutaneous wound healing in vivo. PLoS One 7:e32146
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Schultz, Gregory S; Davidson, Jeffrey M; Kirsner, Robert S et al. (2011) Dynamic reciprocity in the wound microenvironment. Wound Repair Regen 19:134-48
Durham, Jennifer T; Herman, Ira M (2011) Microvascular modifications in diabetic retinopathy. Curr Diab Rep 11:253-64

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