Cardiovascular Medicine IN THE DEPARTMENT OF MEDICINE

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A Message from Dr Cooke..... Thanks for visiting our website!  I am the Professor of Medicine and Associate Director (Education and Training) of the Stanford Cardiovascular Institute. My 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 build new blood vessels, reverse vascular senescence, and to improve vascular health.

GENERATING THERAPEUTIC ENDOTHELIAL CELLS

A major area of focus in the Cooke lab is the generation of therapeutic endothelial cells, which we hope to use to understand and to treat vascular diseases.  We aim to develop methods to minimize non-functional scar tissue and promote the generation of vascularized tissue as well as optimize the derivation of endothelial cells for cell therapies, including cell therapy for PAD. 

We are developing methodologies to reprogram patient skin cells (fibroblasts) into human induced pluripotent stem cells (iPSCs), which are then differentiated into endothelial cells. Additionally, we are developing protocols to transdifferentiate fibroblasts directly to endothelial cells. These approaches include non-integrative methods (permeant proteins or modified-mRNA) and novel small molecules for nuclear reprogramming. We anticipate that these protocols will avoid concerns raised by DNA-based approaches (e.g. integration of foreign DNA into the host chromosome), and will provide more control over the reprogramming process.

Recently we discovered that the exposure of a human cell to a pathogen increases the plasticity of the cell, causing a fluidity of cell phenotype (Lee et al., Cell 2012).  Our findings provided the first evidence that innate immune signaling is necessary for efficient generation of iPSC colonies using the approach first described by Shinya Yamanaka, who was awarded the 2012 Nobel Prize in Medicine or Physiology. We have utilized the activation of this critical signaling pathway to promote the generation of human iPSCs.

Description: PIIS0092867412011816.fx1.lrg.jpg
(from Lee et al., Cell 2012)

We are also developing mRNA-based methods for nuclear reprogramming and transdifferentation. Our RNAcore (funded by the Progenitor Cell Biology Consortium) can generate mRNA and modified mRNA (mmRNA) of any gene of interest and is an innovator of RNA synthesis technology including in vivo application. 

THERAPEUTIC ANGIOGENESIS

Another area of focus in the Cooke laboratory is identifying small molecules that are useful for therapeutic angiogenesis. We have a long-standing interest in two different pathways regulating angiogenesis. Endothelium derived nitric oxide synthase (NOS) plays a critical role in EC survival, proliferation, and angiogenesis. ADMA (asymmetric dimethylarginine) is an endogenous competitive inhibitor of the NO synthase pathway. 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.

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In the late 1990’s, we 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. 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.  Based on our work, clinical trials of a nAChR antagonist to treat the pathological neovascularization in age-related macular degeneration (AMD) are underway.

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