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An inhibitor to the enzyme, soluble epoxide hydrolase (sEH), discovered in the Hammock lab, prevented the eye disease in diabetic mice, Fleming said.
The paper, “Inhibition of Soluble Epoxide Hydrolase Prevents Diabetic Retinopathy,” involving six years of research and 22 scientists, is published today (Dec. 6) in the journal Nature.
"This has been a long but exciting project where Dr. Fleming's team used tools developed to study the biology of fatty acid epoxides to probe the fundamental mechanism of diabetic retinopathy,” said co-author Hammock, a distinguished professor of entomology who holds a joint appointment with the UC Davis Department of Entomology and Nematology and the UC Davis Comprehensive Cancer Center “This work has targeted many possible sites for intervention that could preserve vision, and one such target is using inhibitors of the soluble epoxide hydrolase which block diabetic retinopathy in mice.”
The eye generates a dihydroxy metabolite from polyunsaturated fatty acids that initiates pericyte loss and breakdown of the endothelial barrier function in the eye, the scientists said. This leads to vascular edema and ultimately to a proliferation of new blood vessels and loss of vision.
The small molecule which initiates this process is a diol of a long chain poly unsaturated fatty acid produced by sEH, the researchers said. The enzyme converts an anti-inflammatory epoxy fatty acid into the pro inflammatory and in this case, toxic diol. The research team demonstrated this process and the cellular mechanism involved in diabetic mice and in transgenic mice that over-produce the sEH enzyme.
They were able to block the process by inhibiting the sEH enzyme. The expression of the sEH enzyme also increased with severity of diabetic retinopathy in human patients.
“The expression of the soluble epoxide hydrolase gene was shown to increase in the retinas of human patients with the severity of the disease with non-proliferative diabetic retinopathy,” Hammock said. “Thus, there appears a connection to human medicine.”
Diabetic retinopathy is the most common diabetic eye disease and a leading cause of adult blindness. Chronically high blood sugar from diabetes damages the tiny blood vessels in the retina, leading to diabetic retinopathy, according to the National Eye Institute (NEI) of the National Institutes of Health. The blood vessels can leak fluid or hemorrhage, distorting vision. NEI officials predict that the number of Americans with diabetic retinopathy will nearly double from 7.7 million in 2010 to 14.5 million by 2050.
Fleming said the sEH enzyme generates a toxic metabolite, but when the enzyme is inhibited, eye disease is prevented.
Earlier work reported in the Proceedings of the National Academy of Sciences from the Kip Connor laboratory at Harvard University showed that inhibiting the soluble epoxide hydrolase preserves fatty acid epoxides which reduce the late or proliferative stages of diabetic retinopathy and macular degeneration. Now the Fleming team used the same soluble epoxide hydrolase inhibitors to block production of a pro inflammatory mediator that initiates the early stages of vascular permeability and inflammation of the retina.
Connor, an assistant professor of ophthalmology at Harvard Medical School, praised the work as bringing to light ”a previously unknown mechanism of action.” Said Connor: “The identification by the laboratories of Drs. Fleming and Dr. Hammock that 19,20-dihydroxydocosapentaenoic acid, a product of soluble epoxide hydrolase (sEH) activity, as a key regulator of pericyte loss and endothelial barrier breakdown has brought to light a previously unknown mechanism of action in the induction of diabetic retinopathy. Moreover, the authors clearly show that inhibition of sEH blocks formation of this degenerative lipid metabolite thereby halting disease progression, which is of vital interest for the potential management of this blinding disease.
Mehran Moghaddam and David Grant, then with the Hammock lab, demonstrated that the diol of the fatty acid linoleate produced by the soluble epoxide hydrolase was highly toxic to cells leading to vascular permeability and sepsis. They published their work in 1997 in Nature Medicine.
"It is interesting how discoveries of years ago resurface as a critical lead in another disease indication,” commented Moghaddam. “It certainly seems hopeful we will be able to treat blindness resulting from severe diabetes."
The Hammock laboratory has published almost 900 peer-reviewed papers on the sEH enzyme, discovered while Hammock and Sarjeet Gill (now of UC Riverside) were researching insect developmental biology and green insecticides at UC Berkeley. The work, begun in 1969, led to the discovery that many regulatory molecules are controlled as much by degradation as by biosynthesis, Hammock said. These epoxy fatty acid chemical mediators control blood pressure, fibrosis, immunity, tissue growth, pain and inflammation to name a few processes, and now Fleming's team has shown the diols products from these epoxides can cause diabetic retinopathy.
For many years Gill and Hammock were alone in studying this enzyme but today its importance is well recognized in mammalian biology, with more than 17,000 peer-reviewed papers in the area. Hammock credits the National Institute of Environmental Health Sciences (NIEHS) for supporting research in this area since the 1970s.
A Davis-based company, EicOsis, has received a large grant from the U.S. National Institutes of Health to move inhibitors to the clinic to treat diabetic neuropathic pain. “We are developing a non opiate analgesic to treat the chronic pain often associated with diabetes,” said William Schmidt, vice president of clinical development at EicOsis. "It would be wonderful if the came drug also could be used to prevent the blindness driven by diabetes.
Bruce Hammock at email@example.com
Ingrid Fleming at Fleming@vrc.uni-frankfurt.de
Newly published research by an international team of scientists, headed by the Jun-Yan Liu lab of Tongji University, Shanghai, China, and the Bruce Hammock lab at the University of California, Davis, may provide promising therapeutic strategies for those suffering from acute kidney injury (AKI), formerly called acute renal failure.
AKI, common in hospitalized patients—especially among older adults in intensive care--occurs when the kidneys suddenly fail to filter waste products from the blood. Many of these patients do not recover or require dialysis or transplantation, or partly recover and are thus at risk for worsening kidney disease.
The paper, published in the current edition of the Proceedings of the National Academy of Sciences, found that a small molecule inhibitor of soluble epoxide hydrolase developed in the Hammock lab at UC Davis, helped alleviate AKI in mice and prolonged their lives.
“The soluble epoxide hydrolase or sEH degrades chemically stable fatty acid epoxides,” explained Hammock, a UC Davis distinguished professor who holds a joint appointment in the Department of Entomology and Nematology and the UC Davis Comprehensive Cancer Center. “But sometimes it can be useful to block the function of sEH, so that beneficial fatty acid epoxides, like those from omega-3 and omega-6 fatty acids, are not degraded. These fatty acid epoxides have been found to protect the kidney, reduce inflammation, inflammatory pain, and even chronic or neuropathic pain.”
In general, the epoxides of docosahexaenoic acid (DHA) from fish oil make the soluble epoxide hydrolase inhibitors even more effective, the Hammock lab has found. “However, in this case, the fish oil seemed to be deleterious rather than beneficial when combined with the sEH inhibitors with kidney injury,” Hammock said. This was unexpected and the investigators caution that fish oil may not always have beneficial effects.
Professor Jun-Yan Liu, a former postgraduate researcher and assistant project scientist in the Hammock lab, related that the lipid mediators that preserve the kidney in AKI are termed EETs. “Their levels can be changed by altering their degradation or biosynthesis with selective inhibitors. This increase in EET resulted in anticipated decreases in the plasma level of creatinine and urea nitrogen—both biomarkers for kidney injury.” He added that they are looking forward to the epoxide hydrolase inhibitors finishing phase I clinical trials in humans so they can be evaluated for preventing or treating AKI.
Specifically, the researchers discovered that a 14(15)-EET mitigated kidney injury and prolonged life, while another epoxide, 19(20)-EDP from fish oil, exacerbated the kidney injury and shortened life. “We found that epoxides of docosahexaenoic acid (DHA) and DHA-enriched fish oil worsened kidney injury prophylactically and therapeutically in multiple animal models of AKI,” wrote Liu, pointing out that fish oil has proven beneficial in a number of other investigations.
Statistics show that “the incidence of AKI in hospitalized patients increased dramatically from 4.9 percent in 1983 to 20 percent in 2012,” the researchers wrote in their paper. “The mortality from AKI is greater than 50 percent; worldwide, approximately 2 million people die of AKI every year. Therefore, novel, safe and effective approaches are urgently needed to prevent and treat AKI.”
“Because AKI has no specific effective therapy and treatment is merely supportive frequently requiring hemodialysis any new treatment or therapeutic paradigm would be welcome in the nephrology community and has the potential to improve the lives of many patients with AKI,” said kidney expert Dr. Robert Weiss, a professor of medicine in the UC Davis Division of Nephrology, who was not involved in the research.
Kidney injury expert Alan Parrish of the University of Missouri's School of Medicine, Columbia, also not involved in the research, called the findings “significant.”
“The collaborative studies between Dr. Liu's and Hammock's group are an elegant, and timely, contribution to our understanding of acute kidney injury (AKI),” said Parrish, vice chair for education and director of Graduate Studies for Medical Pharmacology at the medical school. “AKI has potentially devastating short-term consequences - high mortality - as well as the detrimental long-term impact on renal function. Importantly, specific interventions to treat AKI in patients have not yet been identified. These results are significant in that they provide a unique mechanistic insight into pathways targeted by soluble epoxide hydrolase inhibitors that attenuate AKI, providing a powerful rationale for future clinical trials in AKI patients.”
The paper is the work of scientists led by Jun-Yan Liu from the Center for the Nephrology and Metabolomics and Division of Nephrology and Rheumatology, Tongji University School of Medicine, Shanghai, China: Bing-Qing Deng, Ying Luo, Xin Kang, Chang-Bin Li, Jian Huang, Da-Yong Hu, Ming-Yu Wu, and Ai Peng; and Hammock and his lab researchers Jun Yang, Christophe Morrisseau, Kin Sing Stephen Lee at UC Davis.
CBP supports students engaged in pre-doctoral training at the chemistry-biology interface, preparing them for careers in the biomedical workforce. McReynolds is one of four students selected for the 2017-18 CBP training grant program.
“We are very proud of her,” said Hammock, distinguished professor of entomology, UC Davis Department of Entomology and Nematology, who holds a joint appointment with the UC Davis Comprehensive Cancer Center.
A member of the Pharmacology and Toxicology Graduate Group, McReynolds focuses her research on “developing chemical tools to elucidate the biological relevance of chemical compounds (dihydroxy diols) in biological systems.”
Hammock is her major professor. "Cindy has more than 12 years of experience in research and project management, extensive research experience and advanced knowledge of drug development,” Hammock said.
Prior to enrolling in the doctoral program, McReynolds served as the program administrator of UC Davis/National Institute of Environmental Health Sciences Superfund Research Program, directed by Hammock. She is the project manager of EicOsis, a Davis-based company founded by Hammock to develop a small molecule inhibitor to treat pain in humans and animals.
A native of Louisville, KY, McReynolds received her bachelor of science degree in animal science from UC Davis in 1999, and her master's degree in animal science in 2001 from Washington State University, Pullman, Wash., where she was named Outstanding Graduate Student, Teaching Assistant of the Year and recipient of the Dr. Ralph Erb Outstanding Graduate Student Award. Her master's thesis involved how dietary carotenoids inhibit tumor growth.
McReynolds then joined a project development team at Celera Corporation--an Alameda-based company involved in genetic sequencing and related technologies--that led to the selection of Vorinostat, a cancer treatment. She served as a team leader of the Tumor Development Team at Celera, tasked with developing new models of drug-resistant cancer and analyzing newly generated data from the Human Genome Project to identify new cancer therapies.
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.