Visualizing Blood Flow by NIR-II Imaging
Congratulations to Jerry Lee and Ngan Huang on their Nature Medicine paper with Dr. Dai's group. NIR-II imaging allows for precise blood velocity measurements in addition to high spatial and temporal resolution.
2012 American Heart Association Scientific Sessions
Jack Wong, John Cooke, Nazish Sayed
Dr. Nazish Sayed wins the Arteriosclerosis, Thrombosis and Vascular Biology (ATVB) Early Career Investigator Award. The title of his presentation was Activation of Innate Immunity is Required for Efficient Nuclear Reprogramming and Endothelial Differentiation.
Dr. Jack Wong was a finalist for the New Investigator Award, Council of Nutrition, Physical Activity and Metabolism for his work titled Melamine Impairs Renal and Vascular Function in Rats.
Dr. Yohannes Ghebremariam wins a ATVB Travel Award for Young Investigators, LA, California. His work was titled Proton Pump Inhibitors (PPIs) Increase Risk of MACE: Role of DDAH.
Activation of Innate Immunity is Required for Efficient Nuclear Rreprogramming,” is now online in the journal Cell Vol.151, Issue 3, page 547-558.
Links to press articles about this manuscript:
Drs. Jieun Lee, John P. Cooke and Nazish Sayed discussing their findings.
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. We utilized this cellular behavior to promote the generation of human induced pluripotent stem cells (iPSCs).
Earlier this year, the 2012 Nobel Prize in Medicine or Physiology was awarded to Shinya Yamanaka, who developed an approach to make pluripotent stem cells from skin fibroblasts. Using retroviral vectors, he transfected human skin cells with four genes encoding ‘master regulators’ (the transcriptional factors Oct4, Sox2, Klf4 and c-Myc) that activate a network of stem cell genes. Over a period of weeks, some of the transfected cells develop into iPSCs (due to nuclear reprogramming). The iPSCs are very similar to embryonic stem cells, and have the potential to be differentiated into any therapeutic cell desired. But viral vectors may have unwanted effects on the human genome, so investigators have made cell permeant peptide versions of the Yamanaka factors. However, generation of human iPSCs with peptides has been extremely inefficient for unclear reasons.
“We discovered the retroviral vectors used for inducing pluripotency actually contribute to the reprogramming process, while attempting to develop efficient protein-based approaches for generating human iPSCs” said John P. Cooke, MD PhD, Professor of Medicine and Associate Director for Education and Training of the Cardiovascular Institute at Stanford University, and principal investigator of the study. When the cell permeant peptides failed to generate iPSCs, the investigators thought to add an irrelevant virus to the mix, on the hunch that some intrinsic property of the virus was contributing to nuclear reprogramming
Postdoctoral researchers in Dr. Cooke's laboration, Drs. Jieun Lee and Nazish Sayed, observed that the accelerated and sustained induction of stem cell gene expression that was observed with retroviral methodology could be recapitulated by combining reprogramming proteins with retroviral particles encoding non-relevant genes. Ultimately, the investigators determined that the effect of the retrovirus to enhance nuclear reprogramming was due to activation of innate immunity.
Innate immunity is mediated by Toll-like receptors (TLRs) that can recognize pathogen-associated molecular patterns, including retroviral double-strand RNA. “Our findings provided the first evidence that TLR3 activation is necessary for efficient generation of iPSC colonies using the approach first described by Yamanaka,” said Dr. Cooke.
Additionally, Dr. Cooke and his team demonstrate that Poly(I:C), a synthetic analog of double-strand RNA that is specifically recognized by TLR3, enhanced the efficiency and yield of human iPSCs when using the reprogramming factors in the form of proteins. Knockdown of NF-kB or IRF3 impaired iPSC generation indicating TLR-induced activation of both are required for efficient nuclear reprogramming.
Dr. Cooke noted that the activation of TLR3 signaling caused changes in the epigenetic machinery that promoted an open chromatin configuration, which increases the accessibility of transcriptional machinery to DNA. “Innate immune signaling increases cell plasticity in a process we termed ‘transflammation,’ which is characterized by global changes in epigenetic modifiers,” said Dr. Cooke. Dr. Cooke speculates the reprogramming proteins may direct the epigenetic modifiers to the appropriate promoter sequences.
The knowledge that the activation of innate immune responses affects nuclear reprogramming will augment the efficiency and yield of human iPSCs using reprogramming factors in the form of proteins and is expected to radically accelerate the application of iPSCs for translational approaches.
Additional contributors included Arwen Hunter, PhD and Eduard Yakubov, PhD of the Division of Cardiovascular Medicine at Stanford University; Kin Fai Au, PhD and Wing H. Wong, PhD of the Department of Statistics at Stanford University; Edward S. Mocarski, PhD of the Department of Microbiology and immunology at Emory University, School of Medicine; and Renee Reijo Pera, PhD of the Institute for Stem Cell Biology & Regenerative Medicine at Stanford University.
This work was supported by grants from the National Institute of Health (U01HL100397, RC2HL103400) and a Seed grant from the Cardiovascular Institute at Stanford University. Jieun Lee was supported by a postdoctoral fellowship from the Tobacco Related Disease Research Program of the University of California (18FT-0064). Nazish Sayed was supported by a NIH NRSA postdoctoral fellowship (T32HL098049-01A1).
Jieun Lee wins Young Investigator Poster and Travel Award at ISSCR
Each year, the International Society for Stem Cell Research (ISSCR) honors those trainees who present outstanding posters based on their abstract submission and judging at the annual meeting. Congratulations to Dr. Jieun Lee for taking this international prize at last week’s meeting in Yokohama, Japan, for her poster “Activation of innate immunity is required for efficient nuclear reprogramming”. This is the largest international stem cell meeting of the year, and Dr. Lee competed against the best stem cell researchers in the world. The other co-authors on the abstract included Nazish Sayed, Arwen Hunter, Kin Fai Au, Wing H. Wong, Edward Mocarski, Renee Reijo Pera, and John P. Cooke.
Stanford Vascular Team supports the AHA Heart Walk 2011 Silicon Valley, CA
Stanford Hospital and Clinics participated in the 2011 American Heart Association Silicon Valley Heart Walk. All told, more than 120 walkers from Cardiovascular Medicine participated in an effort to stamp out the leading killer in the United States. Fundraising efforts for the Stanford team are still being counted, but are expected to be in excess of $25,000! Representatives from Stanford included John Cooke and Nick Leeper, who introduced longtime Stanford patient, Carolina Tejada, who shared her story about receiving two consecutive heart transplants which allowed her to be with us to walk at the event. Since 1949, the American Heart Association has raised over $2.9 billion for research and supported many Stanford cardiovascular investigators.
Dr. Leeper introducing heart transplant patient. He organized the Stanford effort.
Raising Interest in Science and Engineering (RISE) high school interns visit the Cooke lab
On June 22, 2011, Dr. John Cooke welcomed the RISE (Raising Interest in Science and Engineering) high school interns. RISE targets under-represented minority (Hispanic, African American and Pacific Islander) and low-income students or those who will be the first in their families to attend college. Dr. Cooke provided an overview of the Stanford Cardiovascular Institute, and the educational and research mission. He spoke about the career paths (MD and/or PhD) that the students might follow, and what they could with those careers. “Once you have your MD, or your PhD, the world opens up before you,” with many opportunities available to physicians and scientists to make the world a better place.
Cooke’s Program Officer, Crystal Botham Ph.D., introduced the students to the endothelium, the cells that line blood vessels. She discussed how they perform a number of important functions such as regulating nitric oxide, which is a major risk factor in a number of cardiovascular diseases. The students then visited the Cooke laboratory, and were introduced to two groundbreaking areas of research:
Yohannes Ghebremariam Ph.D., a postdoctoral fellow, began his demonstration by asking if anyone could identify the compound of the structure he was holding; it was aspirin. Understanding structure helps to understand function. He explained to the students that he was screening a library of thousands of compounds with different structures, so as to identify new drugs that could affect key enzymes in the regulatory pathway of nitric oxide. Dr. Ghebremariam anticipates that his findings will be used in the treatment of endothelial diseases.
Instructor Ngan Huang Ph.D. explained how endothelial diseases, such as peripheral arterial disease (PAD), might be alleviated by the application of stem cells to damaged tissue. With the help of Janet Okogbaa, Dr. Huang demonstrated how blood flow in mice limbs is measured using the lab’s laser Doppler machine. Previously, Dr. Huang used this machine, as well as other techniques, to show that stem cells can facilitate endothelial repair in a mouse model, which has important implications for PAD treatment. (Click this link to watch a video on the Cooke’s lab’s mouse model of peripheral arterial disease).
Overall, the students were engaged as well as inquisitive, and left the lab with a heightened interest in careers in medical research.
Photos courtesy of: Christopher Vaughan
Ngan Huang wins Young Investigator Award at Society for Vascular Medicine meeting
Congratulations to Koy Thanaporn and Ngan Huang of the Cooke Laboratory for their winning presentations at the Young Investigator Award Competition at the international meeting of the Society for Vascular Medicine in June 2011. Six young investigators were finalists in this oral communication. Four awards were given, one first prize award for the best basic research and for the best clinical investigation; and two Honorable Mentions.
For his work entitled: "Activation of aldehyde dehydrogenase type 2 (ALDH2) by Alda-1 increases maximum running distance in a hindlimb ischemia model of peripheral arterial disease (PAD)." Dr. Koy Thanaporn received an Honorable Mention.
For her work entitled: "Therapeutic Treatment of Critical Limb Ischemia Using Human Induced Pluripotent Stem Cell-Derived Endothelial Cells." Dr. Ngan Huang received First Prize for Basic Research.
Congratulations Ngan and Koy!
Watch the Cooke Lab featured in the Stanford's Office of Technology of Licensing: Partners in Translational Research
http://www.youtube.com/user/stanfordotl?blend=4&ob=5#p/a/u/1/SNTFsy_kETE
Researchers give school kids a taste of CVI science
When Dr. John Cooke (Professor and Associate Director of the CVI) received an email from the Lego Cells Science Team from Almaden Country School, he was intrigued. The letter read, “We are the Lego Cells, a robotics team in San Jose. We are seven fourth graders, and we need information for the research part of our Lego robotics competition. We are doing research on heart disease and its connection with smoking. We would like to know more about progenitor cells. We think it is interesting that progenitor cells can repair things, and we were thinking of a solution that has to do with repairing the endothelium...” Of course, Dr. Cooke has been thinking about ways to repair the endothelium for the past 25 years, so he was interested to meet these budding young scientists. He invited the team to the CV Institute on Dec 3, 2010, to visit with him and Dr. Robert Robbins (Professor and Director of CVI). The kids heard a lecture on vascular disease, endothelial regeneration and progenitor cells. They asked some perceptive questions. (“What does it take to grow progenitor cells? How do we get them out of the bone marrow? Are there bad side effects to the endothelium from adding progenitor cells? How many progenitor cells do we need? How can you give them to people? Could nanorobots be used to repair the endothelium?”). Drs. Robbins and Cooke were very impressed by the precocious knowledge and insight of these budding young investigators.
Then the team went on a tour of the CVRB and its laboratories, and got to hear from some of the junior scientists at Stanford, including Dr. Ngan Huang who let them view endothelial progenitor cells through the microscope.
Informed by their trip to Stanford, the following day the Lego Cells took 2nd place in their scientific performance among 36 teams of 4th-8th graders and earned an invitation to the NorCal Championship tournament in January 2011.
Dr. Ole Jorgenson (Head of Almaden Country School) later wrote: “Please accept my thanks for ... the warm and gracious welcome you provided the children, and at the level of personal attention and access you afforded them on very short notice. Clearly you appreciate the life-shaping influence you have in helping us make learning relevant for our future scientists (and poets, and teachers, and . . . ) -- I admire the work you do on behalf of the scientific community and your willingness to take precious time to inspire seven eager, curious, and impressionable young people. Who can predict what you made possible today! We need more of this in our world. With much gratitude, Ole!”
New Cooke Lab Publication
Embryonic Stem Cell_Derived Endothelial Cells Engraft Into the Ischemic Hindlimb and Restore Perfusion. Arterioscler Thromb Vasc Biol 2010;30;984-991
2010 CVI Retreat Poster Competition
September 10th, 2010: Congratulations to the winners of the CVI Retreat Poster Competition! Retreat participants assessed 30 posters, with the following judged to be the top 3:
1st place - Rufaihah Jalil (Cooke lab) Directed Differentiation Of Human Induced Pluripotent Stem Cells Into Arterial, Venous And Lymphatic Endothelial Lineages
2nd place - Calvin Hang (Chang lab) Chromatin Regulation By Brg1 Underlies Heart Muscle Development And Disease
3rd place - Ngan Huang (Cooke lab) Vascular Cell Morphology And Function On Aligned Collagen Matrices
John Cooke, MD, PhD Receives Best PAD Research Award
PAD Coalition Sept 8, 2008 Washington DC
The PAD Coalition is an alliance of 75 leading health organizations working to
improve the heath and health care of people with PAD.
Master of the Society for Vascular Medicine
Dr. John Cooke, Professor of Cardiovascular Medicine, was awarded the honorary designation of Master of the Society for Vascular Medicine in recognition of extraordinary service,
selfless dedication and enlightened leadership to the SVM and the field of vascular medicine on May 14, 2009.
These individuals serve tirelessly and without compensation. Such service should be recognized. Such an individual will have been a fellow of the Society for more than 15 years.
Dr Cooke was President of the Society for Vascular Medicine in 2007.
You can read his Presidential Address presented at the
Annual Scientific Session of the
Society for Vascular Medicine
on June 8, 2007 in Baltimore Maryland.
Stroke Manuscript
Stroke is a devastating disease that affects about 750,000/year people in the United States, ranks as the third leading cause of death, causes long-term disability and imposes an economic burden on the health care system. In a recent study, published online on June, 29 2006 in Stroke, it was shown that short term infusion of ADMA in healthy subjects decreased cerebral blood flow. Furthermore, the arterial stiffness, an important prognostic marker of cardiovascular events, also increased in response to ADMA infusion. These results suggest that ADMA is an important endogenous modulator of cerebral vascular tone and may be involved in the pathogenesis of cerebrovascular disease. Click here to read more
Grant awarded to light the link between cigarettes and stroke
A Stanford research team led by Dr. John Cooke, Professor of Medicine and head of the Vascular Biology and Medicine Program at Stanford, has been awarded a grant from the Tobacco-related Disease Research Program (TRDRP) to study the role of tobacco in stroke. The TRDRP was established after California voters approved Proposition 99 “The Tobacco Tax and Health Protection Act of 1988”. This initiative specified that a percentage of the cigarette surtax be set aside to support research efforts related o the prevention, causes and treatment of tobacco-related diseases. The award to Dr. Cooke will support 3 years of research to define the mechanism by which tobacco contributes to stroke.
A stroke occurs when a blood clot blocks a blood vessel to the brain. The interrupted blood flow injures and kills some brain cells in the affected area. However, a large number of brain cells may recover if blood flow can be restored. The injury to the brain can be reduced by its generation of new blood vessels, in a process known as angiogenesis. Angiogenesis can restore blood flow to tissues with blocked vessels. Dr. Cooke’s group will determine how chronic exposure to tobacco may impair the ability of the brain to respond effectively to insufficient blood flow. Specifically, chronic exposure to tobacco may impair the ability of the brain to generate new blood vessels. Dr. Cooke’s group will be assisted by that of Dr. Gary Steinberg of the division of Neurosurgery. Clearing the smoke on the mechanisms by which nicotine causes stroke might open new therapeutic avenues that are badly needed as stroke affects about 750,000 people in the US every year, putting it among the leading causes of death and greatest cause of long-term disability.
Cooke Lab Postdocs Receive Kudos at NAVBO/SVMB meeting 2005
Drs. Jan Kielstein and Hakuoh Konishi were each recognized as finalists in the Junior Investigator competition at the Chicago vascular meeting June 16-19. The meeting (Vascular Medicine and Biology 2005: From Molecules to man) brought together the SVMB (Society of Vascular Medicine and Biology) and NAVBO (North American Vascular Biology Organization) for a conjoint meeting. The meeting attracted international participation and a very competitive group of abstracts for the Junior Investigator Awards. Dr. Kielstein presented his work on the role of ADMA in regulating cerebral blood flow in humans. Dr. Konishi presented his intriguing findings with the DDAH transgenic mouse, which produces more endogenous NO and exhibits faster endothelial healing and less lesion formation. More pictures here.
Dr. Cooke has been elected to the Presidency of the SVM
The SVM is a society dedicated to the mission of promoting clinical care, education, and research in Vascular Medicine and Biology. The SVM has played a leading role in public health initiatives, professional medical education and health care advocacy in Vascular Medicine. For more information about the SVM and Vascular Medicine, please go to www.svm.org
Team Cardiovascular Medicine takes the trophy home
Cooke Lab Dominates Vascular Society meeting 2004
At the Society for Vascular Medicine and Biology Annual Scientific Session, 3 of our postdocs were selected as Finalists for the Young Investigators Competition. After six outstanding presentations, the judges selected Karsten Sydow for 1st place.
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last updated: April 23, 2013