Research Spotlight on Amir A. Zeki, M.D.
Dr. Amir Zeki's research interest is broadly in the area of metabolic and lipid regulation of chronic inflammation and remodeling in the lung. More specifically, he has studied the mevalonate pathway in lung biology. “This is the same pathway that controls cholesterol biosynthesis and regulates the location and function of the small G-proteins (GTPases) which are important cell signaling proteins. The statin drugs (known as the ‘cholesterol-lowering’ drugs) target this pathway and are increasingly being appreciated to have significant anti-inflammatory effects in many tissues beyond the cardiovascular system. In addition to lowering cardiovascular mortality, there is some suggestion that they may also have benefits in lung health, e.g. asthma and COPD.” He is also interested in determining which of the statins and by which route of administration could have the greatest benefit in lung disease.
Dr. Zeki’s translational research interest is in developing novel or innovative therapeutics for airway diseases such as asthma or COPD, two of the most common and costly lung diseases worldwide. “I have focused on investigating whether or not the statin drugs can mitigate chronic inflammation in asthma and COPD. My mentor, collaborators, and I have used animal models, in vitro cell culture systems, and clinical investigations to find answers.” He is currently the Principal Investigator of the first randomized clinical trial to evaluate whether simvastatin can reduce acute asthma exacerbations, improve lung function, and reduce chronic allergic airway inflammation in patients with severe asthma. In the near future, he plans to develop the statins as a novel inhaler for targeted airway application to maximize their airway/lung effects.
Most recently, he has developed an interest in cell fate phenomena such as endoplasmic reticulum (ER) stress/unfolded protein response, autophagy, and apoptosis as they relate to disease pathogenesis in severe asthma, COPD, and lung fibrosis. Dr. Zeki’s favorite collaborative work is with Dr. Saeid Ghavami at the University of Manitoba, in Winnipeg, Canada. Drs. Zeki and Ghavami are exploring the role of autophagy in asthma. ‘Autophagy’ is a fundamental cellular process, an adaptive intracellular and lysosome-dependent degradation mechanism necessary for cell survival, recycling of cellular components, and maintenance of homeostasis. Autophagy also has the potential to promote cell death, and thus is a critical cellular event that controls cell fate in different organs. Its role in airway diseases remains a mystery. Dr. Zeki and his colleague have ongoing collaborative experiments to determine whether or not autophagic responses are mediating pro-inflammatory cytokine release and pro-fibrotic responses in airway epithelial and mesenchymal cells, respectively. They believe these events mediate adverse airway structural remodeling leading to persistent symptoms in patients with severe asthma. Interestingly, there is also cross-talk between the mevalonate pathway and autophagy revealing potentially novel pleiotropic effects of the statins.
When Dr. Zeki was asked why he loves research, he responeded “I see no barriers, no real differences between the curiosity that a clinician or scientist has, and the effort it takes to find answers to challenging questions. Both involve inquiry and a process to find the right answers. Research is a natural human impulse as one contends with mysterious phenomena in life. The scientific method which underpins basic or clinical research is simply a tool to find the best answers possible. This requires a skill set different from the typical training that a physician receives. However, the spirit of that pursuit is the same in my mind. The decision to do research as part of my career path is rooted in a passion to investigate problems that could have a clinical impact. Research is a practical response to the questions that arise from the clinical realm. In truth, despite its many challenges, risks, and failures, research is also fun and personally rewarding.”
Recent Grants and Awards
Department of Internal Medicine 2014
Faculty Research Award
Western American Federation for Medical Research (AFMR) 2013-2014
Outstanding Investigator Award
American Federation for Medical Research (AFMR) 2012
Henry Christian Award
NIH/NHLBI K08 Award (PI: A Zeki) 01/01/14 – 1/31/17
The Modulation of Eotaxin Expression by Statins: Implications for Asthma Therapy
To understand the mechanisms by which statins regulate gene expression of the eotaxins, potent eosinophil chemokines, and in doing so elucidate general underlying principles of the statin effect on a wider array of genes involved in TH2 lung inflammation relevant to allergic asthma and COPD. Aim 3 is a cross-over clinical trial to evaluate whether simvastatin added to inhaler therapy can reduce asthma exacerbations in patients with severe asthma.
Tobacco-Related Disease Research Program (PI: B. Davis) 07/01/09 – 06/30/13
Novel Treatments for COPD with Statins
To investigate whether tobacco smoke-induced chronic lung inflammatory and structural changes correlate with pulmonary function measurements in a model of spontaneously
hypertensive rats, and whether treatment with statins can mitigate COPD pathogenesis.
American Thoracic Society (PI: A Zeki) 07/01/09 – 06/30/10
Fellows Career Development Award
The Role of Statins in Modulating Airway Hyperreactivity and Remodeling
To determine the mechanisms whereby statins modulate asthmatic inflammation, airway hyperreactivity, and airway remodeling.
Yeganeh B, Wiechec E, Ande SR, Sharma P, Moghadam AR, Post M, Freed DH, Hashemi M, Shojaei S, Zeki AA, Ghavami S. Targeting the mevalonate cascade as a new therapeutic approach in heart disease, cancer and pulmonary disease. Pharmacol Ther. 2014 Feb 26. [Epub ahead of print]
Zeki AA. Statins and asthma: where we stand, and the next critical steps in research.
Curr Med Res Opin. 2014 Jan 30. [Epub ahead of print]
Zeki AA, Oldham J, Wilson M, Fortenko O, Goyal V, Last M, Last A, Patel A, Last JA, Kenyon NJ. Statin Use and Asthma Control in Patients with Severe Asthma. BMJ Open. 2013 Aug 13;3(8).
Kenyon NJ, Bratt JM, Lee J, Luo J, Franzi LM, Zeki AA, Lam KS. Self-assembling nanoparticles containing dexamethasone as a novel therapy in allergic airways inflammation.
PLoS One. 2013 Oct 25;8(10):e77730.
Davis BB, Zeki AA, Bratt JM, Wang L, Filosto S, Walby WF, Kenyon NJ, Goldkorn T, Schelegle ES, Pinkerton KE. Simvastatin Inhibits Tobacco Smoke-Induced Acute Lung Inflammation and Airway Injury: Implications for the Treatment of COPD. Eur Respir J. 2013 Aug;42(2):350-61.
Zeki AA, Thai P, Kenyon NJ, Wu R. Differential Effects of Simvastatin on IL-13-Induced Cytokine Gene Expression in Mouse Primary Tracheal Epithelial Cells. Respir Res. 2012 May 14;13:38.
Zeki AA, Bratt JM, Rabowsky M, Last JA, Kenyon NJ. Simvastatin Inhibits Goblet Cell Hyperplasia and Lung Arginase in a Mouse Model of Allergic Asthma: A Novel Treatment for Airway Remodeling? Transl Res. 2010 Dec;156(6):335-49.
Zeki AA, Franzi L, Last J, Kenyon NJ. Simvastatin Inhibits Airway Hyperreactivity: Implications for the Mevalonate Pathway and Beyond. Am J Respir Crit Care Med. 2009 Oct 15;180(8):731-40.
RESEARCH SPOTLIGHT ON JAY V. SOLNICK, M.D., PH.D.
In 1993, while an Infectious Disease fellow at Stanford University, Dr. Solnick had the opportunity work in the laboratory of Dr. Agnes Labigne at the Pasteur Institute in Paris. "At the time, she was the only scientist in the world who was able to genetically manipulate Helicobacter pylori, and I went there to learn how. The work was hard and the initial results were disappointing. Agnes told me that 'the most important lesson I ever learned in my scientific career was just keep going'. I did, the experiments eventually worked, and I never forgot this lesson, which I have repeated to my students many times."
Dr. Solnick’s lab has been funded by the NIH since shortly after his arrival at UC Davis in 1995. "The funding climate at NIH has become extraordinarily difficult, and even very accomplished investigators are finding themselves without NIH support. I was very gratified recently to learn that our most recent R01 application was scored in the top 2%, which assures that we will be able to continue our work for another 5 years."
Dr. Solnick’s laboratory studies Helicobacter pylori, a bacterial pathogen that commonly infects the human stomach and sometimes leads to peptic ulcers or gastric cancer. They use mouse and non-human primate models, as well as in vitro cell culture, to understand how H. pylori causes disease. They also perform translational studies. For example, his lab recently led an international collaboration to use mass spectrometry to identify serum glycans that might identify those H. pylori-infected patients who are at increased risk of gastric cancer.
His lab recently discovered a novel strategy that H. pylori uses to dial up or dial down its capacity to cause inflammation—a sort of "molecular rheostat" that tunes the host response, presumably for the benefit of the pathogen. "The implication is that inflammation, the host response to control infection, is actually co-opted to serve the interests of the bacterium. They aren’t as smart as we are, but there are a lot more of them, and there is strength in numbers!"
Dr. Solnick enjoys exercising in the morning and rides his bike everywhere that he can. He also enjoys working in the garden, cooking, and playing the guitar. "My wife and I recently bought a small cabin in Mt. Shasta, and we love to hike with our devoted golden retriever, Cooper. I also have a longstanding interest in learning Spanish, which began as a medical student working in Spanish Harlem in New York. I attend a weekly conversation class at the International House in Davis and try to do the homework when I have time."
Ozcan S, Barkauskas DA, Ruhaak LR, Javier Torres J, Cooke CL, An H, Hua S, Williams CC, Dimapasoc LM, Kim J, Camorlinga-Ponce M, Rocke DM, Lebrilla C, Solnick J.V. Serum glycan signatures of gastric cancer. Cancer Prev Res, 2013 Dec 10. [Epub ahead of print]
Moore ME, Lam A, Bhatnagar S, Solnick JV. Environmental determinants of transformation efficiency in Helicobacter pylori. J Bacteriol. 2014 Jan;196(2):337-44. doi: 10.1128/JB.00633-13.
Martin, ME, Bhatnagar, S, George, MD, Paster, BJ, Canfield, DR, Eisen, JA, and Solnick, JV. The impact of Helicobacter pylori infection on the gastric mic robiota of the rhesus macaque. 2013, PLoS ONE 8(10): e76375.
Cooke CL, Torres J, Solnick JV. Biomarkers of Helicobacter pylori-associated gastric cancer. Gut Microbes. 2013 Jul 12;4(6).
Barrozo, RM, Cooke, CL, Hansen, LM, Lam, AM, Gaddy, JA, Johnson, EM, Cariaga, TA, Suarez, G, Peek, RM Jr, Cover, TL, and Solnick, JV. Functional plasticity in the type IV secretion system of Helicobacter pylori. PLoS Pathogens, 2013, Feb;9(2):e1003189. Reviewed in Faculty of 1000
Martin, ME, Dieter, JA, Luo, Z, Baumgarth, N and Solnick, JV. Predicting the outcome of infectious diseases: Variability among inbred mice as a new and powerful tool for biomarker discovery. mBio, 2012 Oct 16;3(5):e00199-12.
Jay V. Solnick, M.D., Ph.D.
Professor of Medicine and Microbiology and Immunology
Department of Internal Medicine
Division of Infectious Diseases
Staff Scientist, California National Primate Research Center
Core Faculty Member, Center for Comparative Medicine
Research Funding News
American Federation for Medical Research
The AFMR works to support the careers of academic physician-scientists and to develop and encourage young academic and clinical researchers. Some of the ways that the AFMR works toward this mission are Professional Opportunities and Advocacy.
Additional benefits for your residents and fellows are the opportunity to present their research at a regional meeting and be eligible to apply for travel and trainee awards. Many of the academic leaders in our region attend this meeting so it is an excellent opportunity for your trainees to network as they are looking for a fellowship or faculty position. It is also an excellent chance for mentees and mentors to attend the meeting together to showcase their work. We hope you will accept our invitation to attend this meeting and encourage your faculty and trainees to submit abstracts and attend the meeting in Carmel, CA.
Please note the call for abstracts deadline is October 1, 2013. For details: http://bit.ly/14gBxf3
Furthermore, please connect with us through the AFMR LinkedIn Group, and join our Discussion Forum here: http://linkd.in/14gAxrc.
CALL FOR FELLOWSHIP APPLICATIONS:
Eligibility: Graduate students, postdoctoral fellows, and medical students and residents at member MMPC institutions
Requirements: One-page abstract application; Poster presentation on the day of the Symposium
Fellowship: Will support travel expenses and poster presentations up to $1,500
Deadline: 5PM PT, September 27, 2013. Please send the one-page abstract to Sasha Wirth (SSWirth@ucdavis.edu)
November 8, 2013
7:30 AM-12 Noon
AGR Hall, Buehler Alumni & Visitor Center