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Mechanisms of Tobacco-Induced Retinal Neovascularization

Institution: Stanford University
Investigator(s): John Cooke, M.D., Ph.D.
Award Cycle: 2006 (Cycle 15) Grant #: 15IT-0257 Award: $155,211
Subject Area: Cardiovascular Disease
Award Type: Inno Dev & Exp Awards (IDEAS)

Initial Award Abstract
This grant is a first step toward a novel therapy for the tobacco-related disease of age-related macular degeneration (AMD), the major cause of blindness in the United States. AMD is a disease of the retina, which involves the growth of abnormal blood vessels. These abnormal vessels can leak fluid or blood, which can disturb visual acuity or even cause scarring and blindness. Notably, the major preventable risk factor for AMD is smoking. Those who smoke are at a greater risk for developing this eye disease. We believe that the nicotine in tobacco is primarily responsible for the abnormal vessel growth. In this proposal, we intend to determine if nicotine accelerates the formation of abnormal vessels in the eye, and we plan to test a new therapy.

This grant builds on our previous work (funded by the TRDRP) revealing that nicotine triggers abnormal vessel growth. This surprising effect of nicotine provides a new paradigm for tobacco-related diseases such as cancer, atherosclerosis, and AMD. We have shown (in animal models) that nicotine can accelerate tumor growth by stimulating the growth of tumor vessels. We found that the effect of second hand smoke to promote tumor angiogenesis and tumor growth can be blocked by mecamylamine, an antagonist of nicotine-induced vessel growth.

In this study, we will use a mouse model of AMD to determine how nicotine stimulates abnormal vessel growth. We will look for nicotine receptors on the blood vessels of the eye. Subsequently, we will determine if second hand smoke and/or nicotine can stimulate these receptors to accelerate the growth of abnormal vessels and/or if nicotine influences the leakiness of these vessels. We will determine how much nicotine gets into the eye, and will determine the effects of intra-ocular nicotine on proteins involved in vessel growth. Finally, we will determine if the growth and/or leakiness of abnormal vessels in the eye can be inhibited by the drug mecamylamine (which blocks nicotine receptors) and/or other methods to block nicotine receptors in the eye. These studies are intended to provide new insights into a major tobacco-related disease, and to lead directly toward a new approach to treating AMD.

A Central role for nicotinic cholinergic regulation of growth factor- induced endothelial cell migration -Novel insights into angiogenesis.
Periodical: Arteriosclerosis, Thrombosis, and Vascular Biology Index Medicus:
Authors: Cooke JP ART
Yr: 2007 Vol: 1 Nbr: 27 Abs: Pg: 106-12

Non-bone marrowderived circulating cells contribute to postnatal neovascularization followinf tissue ischemia.
Periodical: Circulation Research Index Medicus:
Authors: Cooke JP ART
Yr: 2007 Vol: 4 Nbr: Abs: Pg: 581-589

Dimethylarginine dimethylaminohydrolase promotes endothelial repair after vascular injury.
Periodical: Journal American Coll Cardiol Index Medicus:
Authors: Cooke JP ART
Yr: 2007 Vol: 49 Nbr: 10 Abs: Pg: 1099-105

A novel bioluminescent tumor model of human renal cancer cell lines ; an in vitro and in vivo characterization.
Periodical: Journal of Urology Index Medicus:
Authors: Cooke JP ART
Yr: 2007 Vol: 6 Nbr: 117 Abs: Pg: 2342-6

Alterations in No and ADMA with with acute cerebral ischemia. amelioration with the chaperonin GroEI.
Periodical: Neuroscience Letters Index Medicus:
Authors: Cooke JP ART
Yr: 2007 Vol: 2 Nbr: 17 Abs: Pg: 201-4

Asymmetric dimethyl L-arginine (ADMA) is a critical regulator of myocardial reperfusion injury.
Periodical: Cardiovascular Research Index Medicus:
Authors: Cooke, JP ART
Yr: 2007 Vol: 2 Nbr: Abs: Pg: 417-425

Differentiation survival and function of embryonic stem cell-derived endothelial cells for ischemic heart disease.
Periodical: Circulation Index Medicus:
Authors: Cooke JP ABS
Yr: 2007 Vol: Nbr: Abs: Pg:

Overexpression of Dimethylarginine Dimethylaminohdrolase Inibits ADMA-Induced Endothelial Dysfunction in Cerebral Circulation.
Periodical: Stroke Index Medicus:
Authors: Cooke JP ART
Yr: 2007 Vol: Nbr: Abs: Pg:

Angiogenesis and the role of the endothelial nicotinic acetylcholine receptor.
Periodical: Life Sciences_x000D_ Index Medicus:
Authors: Cooke JP ABS
Yr: 2007 Vol: 80 Nbr: 24-25 Abs: Pg: 2347-51