Jamey Marth Archives - Sanford Burnham Prebys
Institute News

Team led by Jamey Marth awarded $12.8M to develop new ways to prevent sepsis

AuthorJessica Moore
Date

July 26, 2016

A multidisciplinary team of scientists led by Jamey Marth, PhD, professor in the NCI-designated Cancer Center and director of UC Santa Barbara’s Center for Nanomedicine, is poised to undertake a major biomedical research initiative focused on the escalating problem of sepsis, the body’s abnormal response to severe infections.

The multi-investigator program will be supported by a five-year, $12.8 million research grant from the National Institutes of Health (NIH).

“Millions of people are diagnosed with sepsis each year worldwide, and on average 30 percent die from the complications of sepsis. No new effective treatments have been developed in decades,” said Marth.

Playing a lead role in the translational component is Jeffrey Fried, MD, an acute care physician at Santa Barbara Cottage Hospital and an expert in sepsis. Fried and Marth have collaborated over the past four years.

“With Dr. Fried’s expertise, we have already made unexpected discoveries pertaining to human sepsis,” Marth said.

“While we have made great strides at our hospital in reducing the mortality of sepsis by two-thirds over the past 11 years, we have reached a plateau of what we can accomplish without new treatments,” Fried explained. “Marth and his co-investigators have done seminal work in investigating the molecular basis of sepsis. This work should translate into the development of radically different and more effective approaches to treating sepsis in the future.”

Additional contributing biomedical scientists and clinicians include UC San Diego faculty member Jeffrey Esko, PhD, an expert in the mechanisms of blood-based diseases, and Dzung Le, MD, PhD, head of the clinical hematology and coagulation laboratory at UC San Diego’s Hillcrest and Thornton hospitals. Jeffrey Smith, PhD, also a professor in SBP’s NCI-designated Cancer Center, brings leading expertise in mass spectrometry methods applied to blood systems.

“I look forward to contributing to this potentially transformative research,” said Smith. “The proteomics analyses at SBP will link regulation of specific blood proteins to disease states, which should point to targets for future therapeutic development.”

The program will also benefit from the involvement of renowned scientists and clinicians on its advisory board. “Sepsis remains the leading killer of patients in intensive care units and there are no approved medications,” said advisory board member Victor Nizet, MD, PhD, chief of the Division of Host-Microbe Systems and Therapeutics at UC San Diego’s School of Medicine. “The highly innovative discoveries by Jamey Marth and his team have inspired a rethinking of how blood components respond to severe infection and suggest new ways to restore normal function and protect vital organs from injury.”

Marth noted the program’s potential to reduce the frequency of disability and death in patients diagnosed with sepsis. “We have an extraordinary opportunity to achieve major advances in the understanding and treatment of sepsis,” he said.

This post is based on a press release from UC Santa Barbara.

Venn diagram portraying relationships among causes, risk factors, and conditions related to sepsis. "SIRS" refers  to systemic inflammatory response syndrome. Diagram provided by Jamey Marth.

Venn diagram portraying relationships among causes and risk factors for sepsis. “SIRS” refers to systemic inflammatory response syndrome. Diagram provided by Jamey Marth.

 

Institute News

How proteins age

Authorsgammon
Date

October 19, 2015

SBP researchers and colleagues discover a mechanism that regulates the aging and abundance of secreted proteins.

Physiological processes in the body are in large part determined by the composition of secreted proteins found in the circulatory systems, including the blood. Each of the hundreds of proteins in the blood has a specific life span that determines its unique range of abundance. In fact, measurements of their quantities and activities contribute to many clinical diagnoses. However, the way in which normal protein concentrations in the blood are determined and maintained has been a mystery for decades.

Biomedical scientists at Sanford Burnham Prebys Medical Discovery Institute (SBP) and UC Santa Barbara (UCSB) have now discovered a mechanism by which secreted proteins age and turnover at the end of their life spans. Their findings, which shed light on a crucial aspect of health and disease, appear today in the Proceedings of the National Academy of Sciences (PNAS).

“This is a fundamental advance that is broadly applicable and provides an understanding of how secreted proteins, which are involved in many important physiological processes, normally undergo molecular aging and turnover,” said senior author Jamey Marth, PhD, professor in SBP’s NCI-designated Cancer Center.

“When a secreted protein is made, it has a useful life span and then it must be degraded — the components are then basically recycled,” added Marth, also director of UCSB’s Center for Nanomedicine and a professor in the campus’s Department of Molecular, Cellular, and Developmental Biology. “We can now see how the regulation and alteration of secreted protein aging and turnover is able to change the composition of the circulatory system and thereby maintain health as well as contribute to various diseases.”

This newly discovered mechanism encompasses multiple factors, including circulating enzymes called glycosidases. These enzymes progressively remodel N-glycans, which are complex structures of monosaccharide sugars linked together and attached to virtually all secreted proteins.

It is the N-glycan structure itself that identifies the protein as nearing the end of its life span. Subsequently, multiple receptors known as lectins — carbohydrate-binding proteins — recognize these aged proteins and eliminate them from circulation.

Marth and colleagues identified more than 600 proteins in the bloodstream that exhibit molecular signs of undergoing this aging and turnover process. Many of these proteins are regulators of proteolysis (the breakdown of proteins), blood coagulation and immunity.

Honing in on individual examples, the researchers were able to track each of them through time and watch the process unfold. “In these studies we further saw that the different life spans of distinct proteins are accounted for by the different rates of aging due to N-glycan remodeling,” said lead author Won Ho Yang, PhD, a postdoctoral associate at SBP and at UCSB’s Center for Nanomedicine.

“Altering this aging and turnover mechanism is the fastest way to change the abundance of a secreted protein, which we increasingly note is occurring at the interface of health and disease,” Marth explained. “In retrospect from published literature and from studies in progress, we can now see how sepsis, diabetes and inflammatory bowel disorders can arise by the targeted acceleration or deceleration of secreted protein aging and turnover.”

“The discovery of this mechanism provides a unique window into disease origins and progression,” Marth added. “It has been known that circulating glycosidase enzyme levels are altered in diseases such as sepsis, diabetes, cancer and various inflammatory conditions. The resulting changes in the composition and function of the circulatory systems, including the blood and lymphatic systems, can now be identified and studied. We are beginning to see previously unknown molecular pathways and connections in the onset and progression of disease.”