Dr. Karhausen Awarded NIH Grant for Septic Shock Study

Jorn Karhausen, MDThe National Institutes of Health’s National Institute of General Medical Sciences has awarded Duke Anesthesiology’s Jorn Karhausen, MD, a four-year, $1,719,290 R01 grant for his project, “Platelet-Mast Cell Interactions as Determinants of the Vascular Pathology in Septic Shock.”

Development of shock in sepsis defines a dramatic deterioration of clinical status and is linked to a significant increase in morbidity and mortality rates. However, the cellular and molecular mechanisms determining the vascular pathology of septic shock remain undefined.

Karhausen’s previous work established mast cells (MC) as key effector cells of vascular pathology in different disease contexts. Because MC products are found in the plasma in shock, but not during sepsis alone, this supports that MC activation is a central event leading to septic shock.

Based on extensive preliminary work, they hypothesize that specific signaling interactions between platelets from within the blood stream and MCs, which are located close by, but outside of the blood vessels, drive the vascular pathology of septic shock. The objectives of this study are to 1) comprehensively define the mechanisms of MC-mediated vascular pathology in sepsis, 2) elucidate the specific mechanism by which platelets trigger MC responses and resultant vascular pathology and 3) better define the clinical sepsis phenotype using biomarkers of platelet-, vascular- and MC- activation in patients.

To provide first evidence how MCs shape key features of shock in sepsis, Karhausen and his co-investigators will employ state-of-the- art technologies ranging from dynamic photoacoustic imaging of the microvasculature to gene expression modeling from clinical samples. This comprehensive approach will be made possible through a strong collaborative team, including groups from the School of Engineering, the Center for Applied Genomics and Precision Medicine and the Department of Pathology at Duke, as well as the Department of Cell Biology and Physiology at UNC.

“Together, this project constitutes a key step towards our long-term goal to establish MC responses as a biomarker of sepsis biology,” says Karhausen, associate professor of anesthesiology, “and to develop novel therapeutic strategies that may directly target the mechanisms of disease progression in sepsis.”

Stacey HiltonDr. Karhausen Awarded NIH Grant for Septic Shock Study
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Dr. Privratsky Awarded NIH Grant to Develop Novel Therapeutic

Jamie Privratsky, MD, PhDThe National Institutes of Health’s National Institute of Diabetes and Digestive and Kidney Diseases has awarded Duke Anesthesiology’s Jamie Privratsky, MD, PhD, a five-year, $1,610,000 R01 grant for his project titled, “Novel Mitochondrial Protective Properties of Annexin A1.”

Acute kidney injury (AKI) is one of the most common forms of perioperative organ injury occurring in up to 30 percent of post-surgical patients, and it significantly increases morbidity and mortality. A number of vascular and transplant surgeries require interruption of blood flow to the kidney, rendering the kidney ischemic and causing significant metabolic stress. The timing of this kidney insult is known; thus, the possibility exists to intervene to protect the kidney. However, no treatment options exist to prevent or treat post-surgical AKI.

Privratsky’s research seeks to understand the cellular mechanism of a novel kidney protective therapeutic that could be given prior to surgery or kidney transplantation to protect the kidney from injury. The development of kidney protective therapeutics has the potential to greatly improve outcomes in the millions of people who undergo surgical operations and kidney transplants each year.

Privratsky and his co-investigators have characterized a novel peptide mimetic of the endogenous pro-resolving molecule annexin A1 that in their recently published data shows that it can ameliorate ischemic kidney injury in mice by augmenting mitochondrial function and limiting kidney tubular cell death. Despite the promise of their therapeutic to limit kidney injury, the novel mechanism by which it protects the kidney is not known. Thus, the objectives of his proposal are to determine the cellular receptor and signaling mechanism through which their therapeutic augments mitochondrial function and metabolism to limit AKI.

“Upon the completion of the study, we will be primed to pursue translational studies and further drug development,” says Privratsky, assistant professor of anesthesiology. “The development of our new therapeutic would not only help limit postoperative and transplant AKI but also have broad implications for protection of other organs following surgery and transplantation.”

Stacey HiltonDr. Privratsky Awarded NIH Grant to Develop Novel Therapeutic
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Dr. Achanta Awarded NIH Grant for Countermeasures Research

Satya Achanta, DVM, PhD, DABTThe National Institutes of Health’s National Institute of Environmental Health Services has awarded Duke Anesthesiology’s Satya Achanta, DVM, PhD, DABT, a two-year, $442,750 R21 grant for his project, titled “Inhibition of Soluble Epoxide Hydrolase Protects Against Phosgene-Induced Lung Injuries.”

The toxic effects of phosgene gas were first reported in 1899 by a group of anesthesiologists and surgeons due to the conversion of chloroform to phosgene. In modern times, phosgene is widely used as a chemical intermediate in the chemical manufacturing of pharmaceuticals, polymers, dyes, and other products. Despite the use of phosgene as a chemical weapon since World War I, there is no effective antidote.

Phosgene gas-exposed victims experience chest tightness and shortness of breath at about six to eight hours after inhalation, with progressive hypoxia and severe pulmonary edema leading to high mortality. The recovered individuals may experience long-term symptoms such as airway and pulmonary remodeling, and asphyxia. Currently, symptomatic treatment is provided to victims. Therefore, phosgene gas remains an important threat, potentially released in industrial accidents, diverted, or synthesized by terrorist groups.

In the funded proposal, Achanta and his team will identify and test novel therapeutic drugs that inhibit factors contributing to pulmonary injury and promote the resolution of the injury. The project is part of the portfolio of NIH’s Countermeasures against Chemical Threats (CounterACT) Program, a trans-agency initiative launched by the Department of Health and Human Services after the 9/11 attacks to improve the nation’s preparedness and to engage academia in countermeasures research. Achanta made significant contributions to the medical countermeasures research over the past nine years, in collaboration with Duke Anesthesiology’s Dr. Sven-Eric Jordt.

Stacey HiltonDr. Achanta Awarded NIH Grant for Countermeasures Research
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Grant Awarded for Immunoprofiling Study

Niccolò Terrando, BSc (hons), DIC, PhD

Niccolò Terrando, BSc (hons), DIC, PhD

The National Institutes of Health’s National Institute on Aging has awarded Duke Anesthesiology’s Niccolò Terrando, PhD, and University of Rochester’s Harris Gelbard, MD, PhD, a $239,843 multi-PI R21 grant for their project, “Immunoprofiling Postoperative Delirium During Aging and Neurodegeneration.”

Millions of elderly Americans live with cognitive impairment and require common surgical interventions, such as orthopedic surgery, that are frequently accompanied by delirium in the postoperative period. The proposed research will address this serious public health concern by providing key data about immune cell populations that are the likely cause of this type of delirium. This will help Terrando and Gelbard develop new therapies that target these immune cells for these high-risk patients.

With the R21 award, they will explore the use of the technique of mass cytometry (CyTOF) that is available through the Gelbard lab to identify immune cell subsets that mediate neuroinflammation in the central nervous system (CNS) using a well- established orthopedic mouse model of postoperative delirium developed by Terrando’s Neuroinflammation and Cognitive Outcomes Laboratory. This represents an ever-growing collaboration between these two labs, which over the past five years have been tackling questions on how surgery, and more recently infection akin to COVID-19, affect the vulnerable brain. “We are thrilled to be working with Dr. Gelbard and his team to expand our understanding on how surgery engages the immune system in contributing to complications such as delirium,” says Terrando, associate professor in anesthesiology.

Harris Gelbard, MD, PhD

Harris Gelbard, MD, PhD

Dysregulated immunity is a hallmark of normal aging; it is also recognized as a key feature of many neurological disorders, including dementia and perioperative complications like delirium as recently reviewed in Nature Immunology. No study has yet attempted to unbiasedly profile the immune subset specific response to orthopedic surgical trauma in the CNS. Terrando and Gelbard will conduct two specific aims: (1) to define how age differences between young adult and elderly male and female mice modulate immune cell subsets in the CNS and blood after orthopedic surgery; and (2) to determine the impact of Alzheimer’s (AD)-like pathologic features using 5xFAD transgenic male and female mice (an accelerated model to study key aspects of neurodegeneration) on immune cell subsets in the CNS and blood after orthopedic surgery. The ability to resolve immune cell subsets and align them with discrete repertoires of pro-inflammatory signaling molecules with CyTOF will be key to understanding whether delirium results from neuroinflammation due to peripherally migrating and/or CNS-resident immunocytes.

Findings from this research are expected to have an important, positive impact on the ADRD field to reduce the impact of delirium and dementia in the aging population by helping identify patients at greater risk for developing delirium and delirium superimposed on dementia. “We are grateful for the continuous support by the National Institute on Aging to advance this field of research,” adds Terrando.

Stacey HiltonGrant Awarded for Immunoprofiling Study
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