Seeking a Better NET Result—NIH grants $1.7 million to Jyotika Sharma

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School of Medicine & Health Sciences


GRAND FORKS, N.D.—The National Institutes of Health has granted $1.7 million to Assistant Professor Jyotika Sharma, Ph.D., in the Department of Basic Sciences at the University of North Dakota School of Medicine and Health Sciences, to pursue research on a possible mechanism that causes a life-threatening reaction in pneumonia patients. The five-year R01 grant is the highest level of research supported by the NIH.

Funded by two R21 grants, an American Heart Association grant and a UND Faculty Research Seed grant since she joined UND in August 2011, Sharma’s research focuses on sepsis, which is a life-threatening medical condition that results from a systemic inflammatory response by the body to fend off a severe infection or to recover from a traumatic injury.

“Sepsis is a medical condition where your immune system gets overactivated,” said Sharma, a microbial immunologist.

The patient’s immune system reacts to the body’s signal of impending peril with a defense that goes horribly wrong—it doesn’t distinguish between molecular friend and foe. The onslaught of sepsis is frighteningly fast; it can progress from simple sepsis to severe sepsis to septic shock sometimes within hours. Blood vessels are particularly affected by the hyperinflammation that accompanies sepsis. Extensive blood clotting occurs in vessels as a result of the ongoing inflammation, which disrupts blood flow and thus oxygen supply to the organs. Patients suffer a fever or hypothermia, a rapid heart rate, rapid respiration, and multiple organ failure because vital tissues lack perfusion with oxygen as a result of low blood pressure.

“The mortality rate is very, very high: 20 to 50 percent of people admitted to an ICU with sepsis are at risk of dying,” she said. “Half of the ICU resources in this country are spent on these patients. The annual expenditure is around $20 billion.”

Sharma’s work in this R01 grant examines the most common type of infection-fighting white blood cell—neutrophils—that are the first responders for combatting bacterial infections like pneumonia. Neutrophils fight pneumonic bacteria in two ways. Primarily, they engulf and destroy the bacteria. Or they can form NETs outside of cells. NETs are neutrophil extracellular traps in which the neutrophils expel DNA fibrils with molecules attached that can trap and kill bacteria. But the factors controlling NET formation are not well understood.

Sharma’s team has identified a molecule called “Mincle,” which is acting as a central regulator of NET formation in pneumonia and sepsis. In the absence of Mincle, the neutrophils don’t form NETs, which allows the bacteria to grow unchecked, ultimately leading to hyperinflammation and sepsis.

“Our observation of Mincle-mediated NET formation through a novel signaling pathway presents an exciting opportunity to understand NET formation and its role in sepsis at an unprecedented level.”

However, NET formation comes at a cost. Uncontrolled NET formation can also lead to collateral damage from inflammation. Hyperactive immune response because of too many NETs has now been identified in many diseases like lupus, COPD (chronic obstructive pulmonary disease), arthritis and even Alzheimer’s disease.

“In the future, when we are equipped with the understanding of NET formation from this work along with unique ways to manipulate NET formation that we are trying to develop currently, we will be able to harness the beneficial outcome of NETs while avoiding their potentially harmful effects. It’s a goal that has remained elusive so far.”

Assisting Sharma with this project has been her postdoctoral fellow Atul Sharma, Ph.D. (not related). Sharma’s project will have a clinical component as well. Associate Professor Mary Aaland, M.D., who is the director of rural surgery and the director of clinical research in the UND SMHS Department of Surgery, will be coordinating the acquisition of patient samples from Altru Clinic in Grand Forks with the help of UND SMHS Associate Professor of Surgery and Altru Hospital Surgeon Randy Szlabick, M.D.

“Determining the relevance of NET formation in a clinically relevant pneumonic sepsis model as well as in sepsis patients will not only provide possible therapeutic interventions for this deadly immune disorder,” Sharma said, “but it also may possibly provide treatments for a variety of disease conditions where unregulated NET formation is an underlying cause.”