Category: News (Page 3 of 3)

Drs. Haj and Bettaieb among group of scientists who find key mechanism that causes neuropathic pain

haj-bettaieb-articleScientists at the University of California, Davis, have identified a key mechanism in neuropathic pain. The discovery could eventually benefit millions of patients with chronic pain from trauma, diabetes, shingles, multiple sclerosis or other conditions that cause nerve damage.

A biological process called endoplasmic reticulum stress, or ER stress, is the significant driver of neuropathic pain, said lead researchers Bora Inceoglu of the UC Davis Department of Entomology and Nematology and UC Davis Comprehensive Cancer Center, and Ahmed Bettaieb, Department of Nutrition. The work is published July 6 in the journal Proceedings of the National Academy of Sciences.

“This is a fundamental discovery that opens new ways to control chronic pain,” said co-author Bruce Hammock, distinguished professor at the UC Davis Department of Entomology and Nematology and the UC Davis Comprehensive Cancer Center.

“We can now specifically search for agents to control ER stress and its downstream pathways,” Hammock said. “This search is already underway in a number of laboratories working on cancer and other diseases.”

Working with Professor Fawaz Haj of the UC Davis nutrition department, Bettaieb found that key molecular signatures associated with diabetes and diabetic pain were linked to ER stress. Neuropathic pain is a common consequence of both Type 1 and Type 2 diabetes, affecting up to 70 percent of patients.

Inceoglu, working in Hammock’s laboratory, showed that neuropathic pain could be initiated by compounds that cause ER stress and reversed by agents that block it.

The researchers had previously shown that a class of natural bioactive lipids has powerful analgesic effects in the body. These analgesic lipids are broken down in the body by an enzyme, soluble epoxide hydrolase. The team was able to show that blocking soluble epoxide hydrolase blocks ER stress and associated neuropathic pain.

The work sheds new light onto at least one biological process that mediates neuropathic pain, Inceoglu said. With this knowledge, researchers can now test ER-stress blocking drugs in the clinic, and carry out fundamental research on how different types of pain grouped under the name “neuropathic” differ from each other and respond to new drugs.

The study provides convincing evidence for a novel concept as to what causes neuropathic pain said John Imig, professor of pharmacology and toxicology at the Medical College of Wisconsin, Milwaukee, who was not involved in the study. The work provides new opportunities for drugs or drug combinations to treat chronic pain, he said.

Additional authors on the paper are Kin Sing Stephen Lee and Carlos Trindade da Silva, both at the UC Davis Department of Entomology and Nematology and the UC Davis Comprehensive Cancer Center.

The research was supported by grants from the National Institute of Environmental Health Sciences and NIEHS Superfund Basic Research Program grant, National Institutes of Health, and the National Institute of Arthritis and Musculoskeletal and Skin Disease.

Additional information:

Media contact(s):

From UC Davis News

Dr. Fawaz Haj to collaborate on new NIH grant to fund mouse-based research center at UC Davis

Dr. Haj will be a collaborator on a new National Institutes of Health grant that awarded $3.8 million to the University of California, Davis, to fund a new mouse-based research center devoted to studies of the physiology and genetics of obesity, diabetes and cardiovascular health.

A major focus for the new Mouse Metabolic Phenotyping Center will be cardiovascular disease, which affects more than 82 million Americans, costs an estimated $444 billion annually and is the nation’s leading cause of death.

The new center will provide scientists worldwide with complete physiologic characterizations of mice that have been genetically altered for metabolic studies. It will be one of only six such centers in the United States, and the only one that can create the mice for researchers.

Collaborating in the new center are UC Davis School of Medicine researchers Craig Warden, scientific director of the Mouse Metabolic Phenotyping Center and a professor of pediatrics, and neurobiology, physiology and behavior; Amparo Villablanca and Nipavan Chiamvimovat, both professors of cardiovascular medicine; Liming Jin, an assistant professor of endocrinology; and Thomas Huser, an adjunct professor of endocrinology.

Collaborators from the School of Veterinary Medicine include clinical professor Stephen Griffey; Peter Havel, a professor of molecular bioscience; Philip Kass, a professor of statistics; Jon Ramsey, an associate professor of molecular bioscience; Helen Raybould, a professor of physiology; and assistant clinical professor Katherine Wasson.

Other collaborators include adjunct assistant nutrition professor Sean H. Adams, a supervisory research physiologist at the USDA-Agricultural Research Service’s Western Human Nutrition Research Center at UC Davis; and Mari Golub, an adjunct professor of toxicology.

Dr. Fawaz Haj is co-author on article suggesting leptin may offer Type 2 diabetes treatment

The hormone leptin, naturally produced by fat cells and long known to play an important role in regulating appetite and fat metabolism, may prove to be successful in treating Type 2 diabetes, a disease that affects more than 21 million people in the United States, reports a team of scientists led by researchers at the University of California, Davis.

The findings from their study, involving rats predisposed to Type 2 diabetes — formerly known as adult-onset diabetes — appear in the Aug. 30 issue of the journal the Proceedings of the National Academy of Sciences.

“One of leptin’s important effects is in signaling the brain to decrease food intake, and recent animal studies have shown that the hormone also lowers blood sugar in Type 1 diabetes,” said lead author Peter Havel, a veterinary endocrinologist.

“Our study, however, is the first to demonstrate that twice-daily injections of leptin lower blood sugar levels and circulating triglycerides in an animal model with the more common form of diabetes — Type 2 diabetes,” Havel said.

Triglycerides are compounds containing three fatty acids; they primarily circulate in the bloodstream and, at high levels, can increase the risk of heart disease.

“The data from this study indicate that leptin improves blood sugar control, in part, by increasing the animals’ sensitivity to insulin, the hormone responsible for maintaining normal blood sugar levels,” said co-author Bethany Cummings, a veterinary molecular physiologist in the Havel laboratory.

The results suggest that the improved insulin sensitivity may be due to reduced stress in a specialized part of the cell called the endoplasmic reticulum. Previous studies have shown that stress to the endoplasmic reticulum can cause insulin resistance, which can lead to Type 2 diabetes.

The study also showed that the leptin treatments resulted in decreased levels of circulating glucagon, a hormone produced in the pancreas that stimulates an increase in blood-sugar levels and works in opposition to insulin.

Other co-authors of this study are: postdoctoral fellow Ahmed Bettaieb, Associate Professor Fawaz G. Haj, and undergraduate assistant Riva Dill, all of the UC Davis Department of Nutrition; research scientists James L. Graham and Kimber L. Stanhope, both of the School of Veterinary Medicine and the Department of Nutrition; and Research Assistant Professor Gregory J. Morton of the University of Washington School of Medicine.

Funding for the study was provided by the National Institutes of Health and UC Davis’ Center for Nutrition and Health Research.

Dr. Fawaz Haj selected as Hellman Fellow

UC Davis awarded Hellman Faculty Foundation awards to 13 up and coming scholars on August 18th, 2008. Dr. Haj was selected as a Hellman Fellow and was awarded $26,000 for his work on the role of protein-tyrosine phosphatase 1B in diabetes.

“These grants are for newer professors who show the capacity for great distinction in their research,” said Bruce White, interim vice provost for academic personnel. “It’s an extraordinary opportunity for younger faculty, many of whom can use it as a springboard to larger funding in the years ahead.”

This spring, the foundation notified UC Davis it would receive $1.25 million in grant funding during the next five years. The goal is to provide support for the research of promising faculty at the assistant professor rank. At this career stage, faculty often do not have the research track record to establish themselves in the all-important grant world.

“There is less money available at this level, and many professors are competing for it,” White said.

Under the guidelines, the Hellman Fellows must have completed at least two years as an assistant professor and submitted a compelling research proposal. All the foundation asks in return — beyond adding to society’s knowledge base, of course — is that the recipients have lunch next spring with Warren and Chris Hellman, the philanthropists behind the foundation. Warren is an investment banker and UC Berkeley alumnus.

The foundation has supported similar programs at UC Berkeley, UC San Francisco and UC San Diego — but not every university is chosen for this kind of support. What does getting Hellman funding mean for UC Davis? Above all, White said, it reflects highly on the institution’s academic pedigree.

“UC Davis is in the big leagues of attracting world-class young faculty,” he said. “We attribute this to the intellectual draw of the campus itself and the fact that the city of Davis is a very attractive place to live.”

One benefit of the funding is that UC Davis decides how to allocate it. The university, not the foundation, chose the specific research to be supported, White explained. The Academic Senate was instrumental in establishing a review panel to sift through 48 research proposals and select recipients and how much they would receive from the Hellman Foundation. “Everybody moved efficiently to make all this possible,” he noted.

And everybody on the receiving end welcomed the grants with great fanfare. The professors found out via e-mail that they had been selected as Hellman fellows.

UC Davis Nutrition Department Welcomes Faculty Member Dr. Fawaz Haj

The Department of Nutrition recently welcomed faculty member, Dr. Fawaz Haj with a reception held in his honor (photo at right). After receiving his doctorate from Oxford, Dr. Haj spent six years as a post doctorial fellow at Harvard. Dr. Haj brings a wealth of experience with him to UC Davis especially in the area of cell signaling, which is viewed as one of the essential components (along with system analysis/metabolomics) for understanding nutrition-related mechanisms in a 21st century context.

Dr. Haj is currently conducting research to understand the molecular signals responsible for metabolic diseases such as obesity and diabetes.  He is particularly interested in protein-tyrosine phosphatases, or PTPs, enzymes which up- or down-regulate intracellular signals via dephosphorylation.

“For a long time, these enzymes were ignored,” Dr. Haj says.  “People had the misconception that phosphatases were boring.”

Each phosphatase has numerous substrates.  Studying such promiscuous enzymes, the thinking went, couldn´t possibly yield useful insight into metabolic regulation.  But then, two independent labs generated knockout mice deficient in protein-tyrosine phosphatase 1B.  Surprisingly, given that PTP1B has so many substrates, the two independently derived knockout strains shared the same phenotype of increased insulin sensitivity and resistance to diet-induced obesity.  PTP1B thus appeared to have very specific intracellular targets.  Additional work using knockout and RNAi approaches revealed the specificity of other phosphatases as well.

“This raised the hope that you could inhibit PTP1B in humans to increase insulin response and energy expenditure,” says Dr. Haj.  In 1999, he began exploring the workings of PTP1B as a postdoctoral scholar in the laboratory of Harvard´s Dr. Benjamin Neel.  Now, as a recently appointed Assistant Professor of Nutrition, he´s bringing his research to UC Davis.

To understand how phosphatases can be inhibited, Dr. Haj needs to understand their actions both at the whole-body level and within each cell.  “We´re using tissue-specific knockouts of PTPs to see what these enzymes do in a physiological setting,” he says.  His team will test the PTPs´ regulatory roles in peripheral insulin-responsive tissues.  They´ve already demonstrated that the liver is a site of PTP1B action.  Future work will let them see the level of communication and redundancy between tissues with respect to these enzymes.

In close collaboration with the laboratory of Dr. Philippe Bastiaens in Germany, Dr. Haj is using fluorescence resonance energy transfer (FRET) to examine PTP regulation inside each cell.  This technique will help determine how enzymes with many substrates target their actions.  “We know that localizing PTPs within the cell controls which substrates they can access,” Dr. Haj says.  PTP1B is tethered to the endoplasmic reticulum, where it must wait for substrates to come to it.  This system of enzymatic regulation is rather like having sit-down service in a restaurant instead of a buffet.  FRET will show what “meals” arrive at the enzyme and which “waiters” bring them.

Although Dr. Haj is very busy setting up his lab and building collaborative relationships with scientists from Europe to China, he is keen to explore sit-down and buffet service in Davis at the macroscopic level.  He grew up in Lebanon and has lived in the UK and Boston, so he eats “everything” – but sushi is his favorite.

Shortly after joining the UC Davis Nutrition Department Dr. Haj was selected to be a 2008-2009 Hellman Fellow, which involves an award of funds to support his research on the role of protein-tyrosine phosphatase 1B in diabetes. The Hellman Family Foundation established the UC Davis Hellman Fellowship program to provide support and encouragement for the research of promising faculty at the Assistant Professor rank who exhibit potential for great distinction in their research.

By Erin Digitale

Newer posts »

© 2023 Haj Lab

Theme by Anders NorenUp ↑