John Cooke, MD, PhD
Academic Appointments
- Professor, Medicine - Cardiovascular Medicine
- Member, Child Health Research Institute
- Member, Bio-X
Key Documents
Contact Information
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Clinical Offices
Cardiovascular Medicine Clinic 300 Pasteur Dr MC 5319 A260 Stanford, CA 94305 Tel Work (650) 723-6459 Fax (650) 723-8392
- Academic Offices
Personal Information Email Tel (650) 723-6141 Tel (650) 725-3778Alternate Contact Scott Reiff EmailNot for medical emergencies or patient use
Professional Overview
Clinical Focus
- Cardiovascular Disease
- Cardiovascular Medicine
Administrative Appointments
- Associate Director (Education and Training), Stanford Cardiovascular Institute (2007 - present)
- Director, Training program in Vascular Medicine and Biology (1991 - 2007)
Honors and Awards
- Master of the Society for Vascular Medicine, Society for Vascular Medicine (2009)
- Established Investigator Award, American Heart Association (1995)
- Teaching Award, Dept of Medicine (2001)
- "Best Doctors in the Bay Area", San Francisco Magazine (2003,2005)
- President, Society for Vascular Medicine (2005-2007)
Professional Education
| Fellowship: | Mayo Graduate School of Medicine MN (1987) |
| Residency: | Mayo Clinic - Rochester MN (1983) |
| Internship: | Mayo Clinic - Rochester MN (1981) |
| Board Certification: | Cardiovascular Disease, American Board of Internal Medicine (1987) |
| Fellowship: | Mayo Graduate School of Medicine MN (1985) |
| Board Certification: | Internal Medicine, American Board of Internal Medicine (1983) |
Postdoctoral Advisees
Sheena Abraham, Jan Brandt, Peter Chang, Yohannes Ghebremariam, Ji Eun Lee, Nazish Sayed, Wing Tak Jack Wong
Graduate & Fellowship Program Affiliations
Internet Links
Scientific Focus
Current Research Interests
Dr. Cooke is Professor of Medicine and Associate Director (Education and Training)of the Stanford Cardiovascular Institute. His research group performs translational work in vascular regeneration from molecule to man. The goal is to transfer basic research insights into clinical trials using a vertically integrated approach with an array of biochemical and molecular tools, cellular and animal models, and clinical research techniques. Our mission is to to build new blood vessels, reverse vascular senescence, and to improve vascular health.
The basic research is focused on induced pluripotential stem cells (iPSCs) for vascular regeneration. We are developing cell-permeant proteins and new chemical entities for nuclear reprogramming, and for differentiation of iPSCs into endothelial cells. Human iPSC-derived endothelial cells are currently being tested in our murine model of PAD. Studies underway include genetic, epigenetic, mitochondrial, and functional characterization of human iPSCs derived from viral versus protein-based strategies. We anticipate that cell permeant peptides will avoid the concerns raised by DNA-based approaches (eg. integration of foreign DNA into the host chromosome), and will provide more control over dosing and duration of action of the reprogramming factors. We are also interested to discover new determinants of endothelial lineage that may enhance the yield of ECs derived from iPSCs. It will be important to determine if iPSC-derived ECs from patients with PAD have normal function, and can incorporate into the host microvasculature and enhance perfusion. Ultimately, we intend to develop clinical grade iPSC-ECs for vascular therapy, and to conduct the first trials of iPSC-EC in patients with PAD.
We have a long-standing interest in two different pathways regulating endothelial function. Endothelium derived nitric oxide synthase(NOS) plays a critical role in EC survival, proliferation, and angiogenesis. There is an endogenous competitive inhibitor of the NO synthase pathway called ADMA (asymmetric dimethylarginine). We find that this molecule is elevated in disorders associated with endothelial dysfunction, and plays a significant role in causing vascular disease. ADMA becomes elevated in people with hypercholesterolemia, diabetes, and other vascular disorders. We find that oxidative stress impairs the activity of the enzyme (DDAH) that degrades ADMA. ADMA accumulates and blocks NO synthesis. Overexpression of DDAH (in our transgenic mouse or in endothelial cell culture) can reduce ADMA levels and increase NO synthesis, with significant consequences on vascular homeostasis and angiogenesis(Jacobi et al Circulation 2005).
More recently we have serendipitously discovered a new pathway modulating angiogenesis (Heeschen et al, Nature Medicine 2001). Nicotinic acetylcholine receptors on endothelial cells are upregulated with hypoxia, and when stimulated (by the endogenous transmitter acetylcholine), these receptors mediate endothelial tube formation in vitro, and angiogenesis in vivo. Of great interest, this pathway is hijacked by nicotine. Thus nicotine can pathologically activate tumor angiogenesis and tumor growth. Nicotine can also stimulate the neovascularization of atherosclerotic plaque, leading to its further growth. These findings suggest a new paradigm for tobacco-related diseases, and provide for a new platform for therapeutic manipulations of the pathway.
Our clinical research is focused on patients with peripheral arterial disease (PAD). We are testing new therapies for angiogenesis and vascular regeneration including novel small molecules and cell therapy. The usual endpoints of our trials are functional capacity (eg. peak walking time), relief of ischemic pain or wound healing. Ongoing trials include gene and cell therapy for enhancing angiogenesis; as well as small molecules for increasing oxygen diffusion, or enhancing skeletal muscle contraction
Publications
- Therapeutic transdifferentiation: a novel approach for vascular disease. Circ Res. 2013; (5): 748-50
- Activation of innate immunity is required for efficient nuclear reprogramming. Cell. 2012; (3): 547-58
- Endothelial cells derived from nuclear reprogramming. Circ Res. 2012; (10): 1363-75
- Multifunctional in vivo vascular imaging using near-infrared II fluorescence. Nat Med. 2012; (12): 1841-6
- DDAH says NO to ADMA. Arterioscler Thromb Vasc Biol. 2011; (7): 1462-4
- Dietary nitrate, nitric oxide, and restenosis. J Clin Invest. 2011; (4): 1258-60
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