Whereas the vascular complications accompanying diabetic retinopathy have long been recognized, the molecular and cellular events regulating the initiation and progression of pathologic angiogenesis remain poorly understood. And, while recent work has revealed the important role that microvascular endothelial cell and pericyte interactions play in controlling capillary stability and permeability, the mechanisms controlling these cell-cell interactions are poorly understood. Importantly, the regulatory roles that pericytes play in controlling microvascular dynamics during the initiation of pathologic angiogenesis remain largely unknown. Indeed, recent work carried out in the principal investigator's laboratory strongly suggests that pericytes play pivotal roles in regulating the onset and progression of pathologic angiogenesis during diabetes. Central to this paradigm-shifting hypothesis are the preliminary findings that pericyte Rho GTP- and sphingosine-1 phosphate-dependent signaling control the mechano- chemical coupling required to sustain endothelial growth arrest in vivo. Experiments outlined as specific aims for this exploratory research program seek to validate this hypothesis while successful outcomes will unveil those unknown, upstream signals and downstream effectors, which control the pericyte- dependent initiating events responsible for regulating the onset of pathologic angiogenesis and proliferative diabetic retinopathy.

Public Health Relevance

Successful outcomes of this exploratory research program will provide the critical missing information deemed essential for our understanding the molecular and cellular components that regulate the onset and progression of pathologic angiogenesis during diabetes or aging. Anticipated findings will not only enable a newfound awareness for the mechanisms controlling the pathologic progression of microvascular lesion formation in humans, but anticipated results should provide opportunities for the development of innovative anti-angiogenesis therapeutic approaches that are not currently available.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21EY019553-02
Application #
7789451
Study Section
Special Emphasis Panel (ZRG1-CB-G (90))
Program Officer
Shen, Grace L
Project Start
2009-04-01
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2012-03-31
Support Year
2
Fiscal Year
2010
Total Cost
$204,188
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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