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An atypical nicotine receptor: target for anti-angiogenics?

Institution: Stanford University
Investigator(s): John Cooke, M.D., Ph.D.
Award Cycle: 2009 (Cycle 18) Grant #: 18XT-0098 Award: $385,707
Subject Area: Cardiovascular Disease
Award Type: Exploratory/Developmental Award

Initial Award Abstract
According to the U.S. National Institute of Health, cigarette smoking is a major cause of heart disease, tumor and visual loss. Tobacco smoke contains about 4000 different chemicals. One of these chemicals is nicotine. We have discovered that tobacco smoke can cause abnormal vessel formation, because of the nicotine within it. Nicotine hijacks the body’s mechanism for growing new blood vessels (the growth of new blood vessels is a normal process required for wound healing). Nicotine does so by activating specific receptors on blood vessels. These receptors (nicotinic acetylcholine receptors, or nAChRs) are normally stimulated by the body’s own molecules, most particularly acetylcholine. Nicotine over-stimulates the nAChRs to cause abnormal vessel growth. Abnormal vessel growth plays a role in the growth of tumors and vessel plaque. Abnormal vessel growth in the back of the eye (age-related maculopathy or AMD) is the major cause of blindness in this country. The major preventable risk factor for tumor, plaque, and AMD is tobacco.

We have shown that certain drugs, which block the nAChR, can reduce abnormal vessel growth in animal models of tumor, plaque, and AMD. Indeed, based upon our work, the FDA has now approved a study in people with AMD to determine if a drug that blocks the nAChR can prevent visual deterioration (by blocking abnormal vessel formation in the retina).

However, we still know very little about how the nAChR regulates the cells in blood vessels. This study is directed towards understanding how stimulation of the nAChR activates blood vessels to grow. Our work has already resulted in a possible new drug for a tobacco-related disease. The work that we now propose is intended to provide new and useful knowledge about how the nAChRs control other channels expressed in cells that make up the blood vessel. The study is driven by our intent to refine a new therapeutic strategy for tobacco-related disease.

Cholinergic modulation of angiogenesis: Role of the a7 nicotinic acetylcholine receptor.
Periodical: Journal of Cellular Biochemistry Index Medicus:
Authors: Chruscinski A, de Jesus Perez V, Singh H, Pitsiouni M, Rabinovitch M, Utz PJ, Cooke JP ART
Yr: 2009 Vol: Nbr: Abs: Pg:

Chronic exposure to nicotine impairs cholinergic angiogenesis.
Periodical: Vascular Medicine Index Medicus:
Authors: Konoshi H, Wu J, Cooke JP ART
Yr: 2010 Vol: PMID Nbr: Abs: Pg:

Topical mecamylamine for diabetic macular edema
Periodical: American Journal Opthalmology Index Medicus:
Authors: Campochiaro, Shah, Hafiz, Heier, Lit, Zimmer-Galler, Channa, Nguyen, Syed, Do, Lu, Monk, ART
Yr: 2010 Vol: 149 Nbr: 5 Abs: Pg: 839-851

Cholinergic activation of hematopoiesis: A new paradigm for tovacco-induced leukocytosis?
Periodical: Vascular Medicine Index Medicus:
Authors: Chang E, Forsberg C, Wang B, Wu J, Prohaska S, Allsopp R, Weissman IL, Cooke, JP ART
Yr: 2010 Vol: 15 Nbr: 5 Abs: Pg: 375-385

The role of nicotine in the pathogenesis of atherosclerosis
Periodical: Atherosclerosis Index Medicus:
Authors: Lee J, Cooke JP ART
Yr: 2011 Vol: 215 Nbr: 2 Abs: Pg: 281-283

Dietary nitrate, nitric oxide, and restenosis.
Periodical: Journal of Clinical Investigation Index Medicus:
Authors: Cooke JP, Ghebremariam YT. ART
Yr: 2011 Vol: 121 Nbr: 4 Abs: Pg: 1258-60

DDAH says NO to ADMA.
Periodical: Arteriosclerosis, Thrombosis, and Vascular Biology Index Medicus:
Authors: Cooke JP, Ghebremariam YT. ART
Yr: 2011 Vol: 31 Nbr: 7 Abs: Pg: 1462-4

Endothelial cells derived from human iPSCS increase capillary density and improve perfusion in a mouse model of peripheral arterial disease.
Periodical: Arteriosclerosis, Thrombosis, and Vascular Biology Index Medicus:
Authors: Rufaihah AJ, Huang NF, Jamé S, Lee JC, Nguyen HN, Byers B, De A, Okogbaa J, Rollins M, Rei ART
Yr: 2011 Vol: 31 Nbr: 11 Abs: Pg: e72-9

Nicotine and pathological angiogenesis.
Periodical: Life Sciences_x000D_ Index Medicus:
Authors: Lee J, Cooke JP. ART
Yr: 2012 Vol: Nbr: Abs: Pg: epub

Activation of innate immunity is required for efficient nuclear reprogramming
Periodical: Cell Index Medicus:
Authors: Lee J, Sayed N, Hunter A, Au KF, Wong WH, Mocarski E, Reijo Pera R, Cooke JP. ART
Yr: 2012 Vol: Nbr: Abs: Pg: