The research, published in the current edition of the Proceedings of the National Academy of Sciences, shows that bioactive products from a major family of enzymes discovered in the UC Davis lab of Bruce Hammock, reduced the eye disease severity in an animal model with neovascular AMD. The compounds regulated inflammatory immune cells both locally—in the retina--and systemically.
Previous research has largely ignored the role of immune cells, “which likely are a major contributor in this pathologic process,” said corresponding author Kip Connor, a vision scientist at the Massachusetts Eye and Ear Infirmary and an assistant professor of ophthalmology at Harvard Medical School.
The chronic, progressive disease affects as many as 11 million Americans but that number is expected to double by 2020, said Connor, one of the nine international experts in lipid biology and AMD involved in the study. Globally, some 196 million are projected to get AMD by 2020. The risk of getting AMD increases from 2 percent for those ages 50-59, to nearly 30 percent for those over the age of 75, according to the Bright Focus Foundation, which helped fund the research.
Hammock, a distinguished professor who holds a joint appointment with the UC Davis Department of Entomology and Nematology and the UC Davis Comprehensive Cancer Center, expressed hope that the team “that Dr. Connor's laboratory will find a solution to this devastating human health problems."
The study, based in Connor's laboratory at Harvard, “shows how rapidly fundamental knowledge of physiology and regulatory biology can be translated to practical solutions for a major type of blindness,” Hammock said. “I was at Harvard several years ago and saw a poster outside a laboratory on AMD. This resulted in me meeting Eiichi Hasegawa, a doctorial fellow in the Connor lab, and through him, Kip, which has led to a long-term collaboration.”
“I also see the compounds that I made moving to human clinical trials with the hope of treating pain and inflammatory diseases such as AMD,” Hammock added.
“In patients with advanced AMD, abnormal blood vessels start to develop from underneath the light-sensing layer of the eye in a process known as choroidal neovascularization (CNV),” Connor explained. “Such cases, termed neovascular or “wet” AMD, account for 10 to 15 percent of AMD cases,develop abruptly, and rapidly lead to substantial vision loss.”
“Although we do not fully understand how and why AMD develops, identifying additional mechanisms that regulate abnormal blood vessel growth in the eye beyond what we currently know could open up a range of possibilities for new research and treatments for AMD,” Connor noted.
The team demonstrated that “specific bioactive products from the cytochrome P450 (CYP) pathway, a major family of enzymes, can influence CNV and vascular leakage by changing how immune cells are recruited to areas of disease and injury,” lead author Eiichi Hasegawa said. “Specifically, we isolated and characterized two key mediators of disease resolution generated from the CYP pathway: 17,18-epoxyeicosatetraenoic acid (EEQ) and 19,20-epoxydocosapentaenoic acid (EDP). “
“Our study offers new insights into bioactive lipid metabolites as regulators of systemic inflammatory immune cells and mediators in CNV resolution,” Connor said, noting that current treatments for AMD do not fully address the underlying causes of this disease. “Given the high prevalence and progressive nature of neovascular eye disease, the ability to stabilize bioactive lipids that mitigate or halt disease is of great and increasing therapeutic significance. It is our hope that emerging technologies and future studies will expand on our work and ultimately lead to safe, targeted, and cost-effective therapies that markedly improve visual outcomes and quality of life for patients suffering from these debilitating ocular diseases.”
Said co-author Kin Sing Stephen "Sing" Lee, who worked on the initial enzyme project as a postdoctoral researcher in the Hammock lab at UC Davis, and is now an assistant professor of pharmacology and toxicology at Michigan State University: “It was so exciting at UC Davis to be involved with basic research on inflammation but also see the compounds that I made moving to human clinical trials with the hope of treating pain and inflammatory diseases such as AMD. It was also a thrill to develop collaborations with scientists throughout the world like Eiichi Hasegawa and Kip Connor
In addition to Connor, Hammock, Lee and Hasegawa, co-authors of the publication, “Cytochrome P450 Monooxygenase Lipid Metabolites are Significant Second Messengers in the Resolution of Choroidal Neovascularization" include Saori Inafuku, Lama Mulki, M.D., Yoko Okunuki, M.D., Ph.D., Ryoji Yanai, M.D., Ph.D., Kaylee E. Smith, Clifford B. Kim, Garrett Klokman, Deeba Husain, M.D., and Joan W. Miller, M.D., of Massachusetts Eye and Ear/Harvard Medical School, as well as Diane R. Bielenberg, Ph.D., of Boston Children's Hospital/Harvard Medical School, Narender Puli, Ph.D., and John R. Falck, Ph.D., of the University of Texas Southwestern, Wolf-Hagen Schunck, Ph.D., of the Max Delbruch Center for Molecular Medicine in Germany, Matthew L. Edin, Ph.D., and Darryl Zeldin, M.D., of the National Institutes of Health's National Institute of Environmental Health Sciences (NIH/NIEHS).
The research was supported in part by the NIH NIEHS, Research to Prevent Blindness, Massachusetts Lion Eye Research Fund, BrightFocus Foundation, Harvard Department of Opthalmology and Massachusetts Eye and Ear Infirmary; the Japan Society for the Promotion of Science Postdoctoral Fellowships for Research Abroad; the Robert A. Welch Foundation, and by a scholar award and a medical student fellowship grant. (Follow the Connor lab on Twitter @ConnorLab and the Bruce Hammock lab on Facebook at https://www.facebook.com/hammocklab/)
Ready for 15 minutes of aim? Not fame--aim?
The 14th annual Bruce Hammock Lab Water Balloon Battle is set for 3 p.m., Friday, July 21 on the Briggs Hall lawn.
Last year 40 participants, including professors, researchers, graduate students, staff, students and family members, tossed 3000 water balloons in 15 minutes on the thirsty Briggs Hall lawn, as the temperature soared to 97 degrees. As the supply dwindled, they dumped the remaining water from the buckets on each other.
Bruce Hammock, a distinguished professor who holds a joint appointment with the UC Davis Department of Entomology and Nematology and the UC Davis Comprehensive Cancer Center, launched the annual event in 2003 as a form of camaraderie and as a means of rewarding the lab members for their hard work. The international Hammock lab researchers, postdoctorates, graduate students, visiting scholars, staff and undergraduates.
Coordinator Christophe Morisseau says 2000 water balloons will be filled and tossed. Balloon filling starts at 1 p.m. on the north side of Briggs Hall. "Our policy: no filling, no throwing! BYOB--bring your own balloons!" Morisseau said.
Highly honored by his peers (but a target at the annual water balloon battle), Hammock is a fellow of the National Academy of Inventors, which honors academic invention and encourages translations of inventions to benefit society. He is a member of the U.S. National Academy of Sciences, a fellow of the Entomological Society of America, and the recipient of the Bernard B. Brodie Award in Drug Metabolism, sponsored by the America Society for Pharmacology and Experimental Therapeutics. He directs the campuswide Superfund Research Program, National Institutes of Health Biotechnology Training Program, and the National Institute of Environmental Health Sciences (NIEHS) Combined Analytical Laboratory.
For more information, contact Morisseau at firstname.lastname@example.org.
Earlier research by the Judah Folkman laboratory of Harvard Medical School showed that cutting off blood vessels that feed a cancerous tumor can stop its growth.
The seven-member research team—five from the Bruce Hammock laboratory of UC Davis—“characterized a novel lipid signaling molecule that can change fundamental biological processes involved in our health and disease,” said lead author and researcher Amy Rand. “We've found that a novel product derived from the metabolism of omega-6 fatty acids stimulates angiogenesis, which may contribute to enhanced tumor growth by providing tumors with oxygen and nutrients.”
“As a highly regulated process, angiogenesis is critical for wound healing and development, but many diseases result in unregulated angiogenesis, including cancer,” explained Rand, a postdoctoral fellow in the lab of Bruce Hammock, a distinguished professor who holds a joint appointment with UC Davis Department of Entomology and Nematology and the UC Davis Comprehensive Cancer Center. “We may be able to control angiogenesis to stimulate wound healing when necessary, but also block tumor growth in patients. Diseases that rely on angiogenesis may be able to be treated in part by changes in dietary lipid exposure or by controlling levels of these metabolites through enzyme inhibitors that block their formation.”
The research, published April 10 in the Proceedings of the Natural Academy of Sciences (PNAS), explains, in part, why inhibiting the soluble epoxide hydrolase (sEH) in some systems is angiogenic whereas combining sEH inhibition with the inhibition of cyclooxygenase (COX) enzymes is dramatically antiangiogenic, which in turn may suppress tumor growth.
“There's uncertainty regarding the link between unsaturated fats and cancer, due to ongoing conflicts between scientific studies and insufficient data,” Rand said. “Because of this, there is a major gap in our understanding of how these essential dietary fats affect our health. We used tools to detect and characterize unknown metabolites from omega-6 unsaturated fats and determined their effect on angiogenesis, to address at least a small part of this uncertainty by focusing on how these fats contribute to cancer tumor growth.”
Hammock, who holds a joint appointment in the UC Davis Department of Entomology and Nematology and the UC Davis Comprehensive Cancer Center, said the research, titled “Cyclooxygenase-Derived Proangiogenic Metabolites of Epoxyeicosatrienoic Acids
Holds long term hope for cancer patients and those afflicted with heart, eye and other diseases. The team also included Christophe Morisseau, Bogdan Barnych, and Kin Sing Stephen Lee all of the UC Davis Department of Entomology and Nematology and UC Davis Comprehensive Cancer Center; Tomas Cajka of the UC Davis Genome Center; and Dipak Panigraphy of Harvard Medical School. Lee is now an assistant professor at Michigan State University.
“Pro and anti-angiogenic therapy can potentially help millions of people worldwide in various diseases such as heart, ulcers, eye and cancer as first demonstrated by Dr. Judah Folkman and his colleagues,” said Panigraphy, formerly of the Hammock lab and now with the Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, and the school's Department of Pathology.
“While the COX and sEH pathways can be targeted with drugs, their interaction is poorly understood,” Panigraphy said. “These studies by Rand et al demonstrate for the first time new specific mechanisms whereby targeting the sEH pathway can be both pro- and anti-angiogenic and has the potential to help patients with devastating diseases such as in the eye and cancer where blocking angiogenesis is desired.”
Rand, who received her doctorate in chemistry from the University of Toronto, Canada, in 2013, the same year she joined Hammock's biological analytical chemistry lab, said she's “always been interested in research that combines chemistry and biology to enhance our understanding of human health.”
Future work? “We aim to understand the direct involvement of these omega-6 fatty acid metabolites with cancer tumor growth and metastasis.”
Rand last year received the $100,000 Judah Folkman Fellowship for Angiogenesis Research from the American Association for Cancer Research. She won the highly competitive international award for her proposal, “Regulation of Cancer Angiogenesis from the Metabolism of Epoxy Omega-6 Fats.” Rand joined Hammock's biological analytical chemistry lab in 2013 and was a fellow on the Oncogenic Signals and Chromosome Biology T32 Training Grant, UC Davis Department of Microbiology and Molecular Genetics.
The late Judah Folkman (1933-2008), a Harvard Medical School professor considered the father of angiogenesis research, “is best known for pioneering the concept of blocking angiogenesis (the development of blood vessels) to control cancer growth," Hammock said. "This concept has resulted in a number of anti-cancer drugs and has had a major impact on cancer treatment. Of course, blood vessel development is also critical for survival."
Folkman discovered that cutting off the blood vessels that feed the tumor can stop cancer tumor growth. His revolutionary work has led to the discovery of a number of therapies based on inhibiting or stimulating neovascularization. Inhibitors of the sEH pathway are moving toward human trials to control neuropathic pain, but if combined with nonsteroidal anti-inflammatory drugs can block tumor growth by blocking angiogenesis. So Dr. Sung Hee Hwang combined inhibitors of both pathways into one molecule which is being investigated in cancer models at the UC Davis Cancer Center by Dr. Paul Henderson and Northwestern University Medical School by Dr. Guang-yu Yang.
Hammock directs the campuswide Superfund Research Program, National Institutes of Health Biotechnology Training Program, and the National Institute of Environmental Health Sciences (NIEHS) Combined Analytical Laboratory.
This work was supported by NIEHS and the NIEHS Superfund Program; and two of Rand's grants: the Oncogenic Signals and Chromosome Biology T32 Training Grant, NIH/NIEHS; and her 2016 AACR Judah Folkman Fellowship for Angiogenesis Research.
Researchers at the Huazhong University of Science and Technology, Wuhan China, used the drug developed at UC Davis to show that the neurofibrillary pathology of an Alzheimer's disease-related protein could be dramatically reduced. Their work was published in December in the Journal of Huazhong University of Science and Technology.
“They further demonstrated the mechanism of action of the UC Davis drug in blocking the oxidative stress-driven phosphorylation events associated with Alzheimer's disease,” Hammock said. The UC Davis drug stabilizes natural anti-inflammatory mediators by inhibiting an enzyme called soluble epoxide hydrolase (sEH) discovered at UC Davis and recently spotlighted in the Proceedings of the National Academy of Sciences and the National Institutes of Health's PubMed.
“I was thrilled to see this paper on tau phosphorylation from Huazhong University shows that our drug could block a key event and a key enzyme called GSK-3 beta thought critical in the development of Alzheimer's disease,” said Hammock, who holds a joint appointment in the UC Davis Department of Entomology and Nematology and the UC Davis Comprehensive Cancer Center.
“We were planning to do this study, but having another laboratory do it with our compound was even better,” he said. “Since our publication last year in PNAS that showed UC Davis soluble epoxide hydrolase inhibitors both prevented and reversed depression, we have been excited about trying to block the development of Alzheimer's disease.”
The PNAS paper, “Gene Deficiency and Pharmacological Inhibition of Soluble Epoxide Hydrolase Confers Resilience to Repeated Social Defeat Stress,” was co-authored by a 13-member research team led by Hammock and Kenji Hashimoto of Chiba University Center's Division of Clinical Neuroscience, Japan. They found that sEH plays a key role in the pathophysiology of depression, and that epoxy fatty acids, their mimics, as well as sEH inhibitors could be potential therapeutic or prophylactic drugs for depression and several other disorders of the central nervous system. Co-authors of the paper included Hammock lab researchers Christophe Morisseau, Jun Yang and Karen Wagner.
Hammock credited several UC Davis colleagues for their work leading to the publications. Research from the labs of Liang Zhang and Qing Li at the University of Hawaii--Qing is a former UC Davis doctoral student--pointed out some of the mechanisms involved in cognitive decline which associate professor Aldrin Gomes of the UC Davis Department of Neurobiology, Physiology and Behavior and Fawaz Haj of the UC Davis Department of Nutrition “have shown to be blocked by the natural metabolites stabilized by the UC Davis drugs,” Hammock said.
One of the Hammock lab drugs is moving toward human clinical trials for neuropathic pain through a Davis-based company, EicOsis, LLC, and the financial support of the Blueprint Program through NIH's National Institute of Neurological Disorders and Stroke. Hammock founded the company to develop inhibitors to the soluble epoxide hydrolase, a key regulatory enzyme involved in the metabolism of fatty acids, to treat unmet medical needs in human and animals.
“The clinical back-up candidate at EicOsis penetrates the blood brain barrier and should be a perfect compound to test if this class of chemistry can prevent cognitive decline and Alzheimer's disease,” Hammock said.
The National Institute of Environmental Health Sciences, National Institutes of Health, funded the research.
Highly honored by his peers, Hammock is a fellow of the National Academy of Inventors, which honors academic invention and encourages translations of inventions to benefit society. He is a member of the U.S. National Academy of Sciences, a fellow of the Entomological Society of America, and the recipient of the Bernard B. Brodie Award in Drug Metabolism, sponsored by the America Society for Pharmacology and Experimental Therapeutics. He directs the campuswide Superfund Research Program, National Institutes of Health Biotechnology Training Program, and the National Institute of Environmental Health Sciences (NIEHS) Combined Analytical Laboratory.
Xu, professor of agro-ecology at the China Agricultural University (CAU), is on a yearlong sabbatical in the Hammock lab. He received assistance in obtaining the grant from project manager Bruce Hammock and program manager Shirley Gee, now retired, both co-investigators.
“This is a highly competitive program and this grant is a huge honor for Ting and for Shirley Gee,” said Hammock, who holds joint appointments in the UC Davis Department of Entomology and Nematology and the UC Davis Comprehensive Center.
The $330,000 grant, funded by China, is a cooperative agreement between UC Davis and China. “The grant is quite timely, as UC Davis is working to increase scientific exchange with China,” Hammock said. “We have been collaborating with Ting's group for several years on nanobody-based immunoassays to improve human and environmental health.”
Two previous students from Professor Xu's laboratory have studied in Davis and the funds will allow additional senior Ph.D. students from Xu's laboratory to join the Hammock lab.
Xu described immunoassays as “a rapid, sensitive and cost effective method of analysis for pesticides.” Technically, engineering antibodies “such as a variable domain of heavy chain antibody (VHH) from camelids and a single-chain antibody variable fragment (scFv) from chickens have advantages over monoclonal and polyclonal antibodies in the respect of small size, thermal stability, solubility and easy generation,” Xu explained. “The objectives of this project focus on the production of specific VHHs and scFvs for several pesticides and the development of engineering antibodies based immunoassays for pesticide environmental exposure and food safety. The novel pesticide antibodies are expected to improve the assay sensitivity and stability.”
“Nanobodies are revolutionizing immunoassay development and possibly disease therapy,” explained Shirley Gee, UC Davis collaborator on the proposal. “It was thrilling over the last few months to have Ting and his student here at the same time as Gualberto Gonzalez from Uruguay and his students since we are three of the major labs developing this technology for analyzing environmental and food toxins.”
Among other benefits, the research can aid farm workers, who would be monitored for pesticides in their urine. The assay could distinguish between exposed and unexposed populations and provide useful information about relative exposure related to crop or use of personal protective equipment.
Xu's publications directly address the fact that the immunoassay method, especially ELISA, is an effective screen tool for the agrochemicals and pollutants in the environment. His main contributions to science are associated with design of novel haptens, production of tradition (monoclonal and polyclonal) and engineering antibodies, and development of competitive and non-competitive enzyme-linked immunosorbent assays (ELISA) for small molecules.
Xu received his doctorate in agro-ecology in 2003 from CAU, and did postdoctoral research in immunoassays in 2007 at the University of Hawaii. He joined the CAU faculty in 2003 as a lecturer and advanced to associate professor in 2007, and professor in 2013. Twice honored by Chinese governments, Xu received third prize for the Agriculture Science and Technology Award by the China Ministry of Agriculture in 2009, and second prize for the Technological Invention Award by the China Ministry of Education in 2013.