CIRBP

Researchers have identified the protein that enables mammals to sense cold, filling a long-standing knowledge gap in the field of sensory biology. University of Michigan researchers have identified the protein that enables mammals to sense cold, filling a long-standing knowledge gap in the field of sensory biology. The findings, published in Nature Neuroscience, could help unravel how we sense and suffer from cold temperature in the winter, and why some patients experience cold differently under particular disease conditions. "The field started uncovering these temperature sensors over 20 years ago, with the discovery of a heat-sensing protein called TRPV1," said neuroscientist Shawn Xu, a professor at the U-M Life Sciences Institute and a senior author of the new research. "Various studies have found the proteins that sense hot, warm, even cool temperatures -- but we've been unable to confirm what senses temperatures below about 60 degrees Fahrenheit." In a 2019 study, researchers in Xu's lab discovered the first cold-sensing receptor protein in Caenorhabditis elegans, a species of millimeter-long worms that the lab studies as a model system for understanding sensory responses. Because the gene that encodes the C. elegans protein is evolutionarily conserved across many species, including mice and humans, that finding provided a starting point for verifying the cold sensor in mammals: a protein called GluK2 (short for Glutamate ionotropic receptor kainate type subunit 2). For this latest study, a team of researchers from the Life Sciences Institute and the U-M College of Literature, Science, and the Arts tested their hypothesis in mice that were missing the GluK2 gene, and thus could not produce any GluK2 proteins. Through a series of experiments to test the animals' behavioral reactions to temperature and other mechanical stimuli, the team found that the mice responded normally to hot, warm and cool temperatures, but showed no response to noxious cold. GluK2 is primarily found on neurons in the brain, where it receives chemical signals to facilitate communication between neurons. But it is also expressed in sensory neurons in the peripheral nervous system (outside the brain and spinal cord). "We now know that this protein serves a totally different function in the peripheral nervous system, processing temperature cues instead of chemical signals to sense cold," said Bo Duan, U-M associate professor of molecular, cellular, and developmental biology and co-senior author of the study. While GluK2 is best known for its role in the brain, Xu speculates that this temperature-sensing role may have been one of the protein's original purposes. The GluK2 gene has relatives across the evolutionary tree, going all the way back to single-cell bacteria. "A bacterium has no brain, so why would it evolve a way to receive chemical signals from other neurons? But it would have great need to sense its environment, and perhaps both temperature and chemicals," said Xu, who is also a professor of molecular and integrative physiology at the U-M Medical School. "So I think temperature sensing may be an ancient function, at least for some of these glutamate receptors, that was eventually co-opted as organisms evolved more complex nervous systems." In addition to filling a gap in the temperature-sensing puzzle, Xu believes the new finding could have implications for human health and well-being. Cancer patients receiving chemotherapy, for example, often experience painful reactions to cold. "This discovery of GluK2 as a cold sensor in mammals opens new paths to better understand why humans experience painful reactions to cold, and even perhaps offers a potential therapeutic target for treating that pain in patients whose cold sensation is overstimulated," Xu said. The research was supported by the National Institutes of Health. All procedures performed in mice were approved by the Institutional Animal Care and Use Committee and performed in accordance with the institutional guidelines. Study authors are: Wei Cai, Wenwen Zhang, Chia Chun Hor, Tong Pan, Mahar Fatima, Bo Duan and X.Z. Shawn Xu of the University of Michigan; and Qin Zheng and Xinzhong Dong of the Johns Hopkins University School of Medicine

The study, published in the Journal of Clinical Investigation, hopes to lead to new sepsis therapies MANHASSET, N.Y.--(BUSINESS WIRE)-- Sepsis is one of the leading causes of in-hospital deaths worldwide and is often known as a silent killer. Despite claiming the lives of more than 11 million people globally each year, there is no one treatment. In a potential therapeutic breakthrough, investigators at The Feinstein Institutes for Medical Research have identified a type of white blood cell that can worsen inflammation in sepsis and opens up new avenues of research to treat the deadly condition. This press release features multimedia. View the full release here: Drs. Monowar Aziz, Ping Wang and Max Brenner recently published the study in the Journal of Clinical Investigation. (Credit: Feinstein Institutes) Results of the study, led by Ping Wang, MD, professor and chief scientific officer at the Feinstein Institutes, were published today in the Journal of Clinical Investigation. The paper outlines how Dr. Wang and his colleagues, Monowar Aziz, PhD, and Max Brenner, MD, PhD, discovered a new subset of neutrophils – which are typically regarded as the first line of immune defense against infection as one of the main cell types involved in the initiation of the inflammatory response – called antigen-presenting aged neutrophils (APANs). These specific neutrophils proved to be extremely inflammatory. Upon activation, APANs can cause severe tissue damage. “APANs, when triggered, can result in devastating circumstances for patients who have sepsis,” said Dr. Wang, senior author of the paper. “The discovery of these neutrophils will help researchers and doctors to better understand sepsis and develop new therapies to tackle this condition.” Sepsis occurs when the body’s immune system triggers inflammation to help fight against infection. If out of control, this inflammatory response can cause damage to multiple organ systems and often leads to death. Patients with sepsis often exhibit the simultaneous occurrence of pro- and anti-inflammatory pathways, which can lead them to suffer from immunosuppression, the inability to eradicate invading bacteria and eventually become susceptible to secondary infections. This paper builds off Dr. Wang’s previous research which showed that extracellular cold-inducible RNA-binding protein (eCIRP) is a new inflammatory mediator. eCIRPs are an alarm molecule released during sepsis that could cause immune dysfunction. They also disrupt the cells within the immune system, which ingest bacteria and secrete both pro-inflammatory and antimicrobial mediators, known as macrophages. In this new research, the frequency of APANs was significantly increased in the blood, spleen and lungs in septic mouse models, as well as in the blood of sepsis patients. APAN-transferred septic mice had increased levels of injury and inflammatory markers, exacerbated acute lung injury and eventually lowered survival odds, concluding that eCIRPs released during sepsis induced APANs that could potentially be harmful. Last year, Dr. Wang and co-principal investigators at the Feinstein Institutes received $3.8 million from the National Institute of Health to study sepsis and radiation exposure. About the Feinstein Institutes The Feinstein Institutes for Medical Research is the home of the research institutes of Northwell Health, the largest health care provider and private employer in New York State. Encompassing 50 research labs, 3,000 clinical research studies and 5,000 researchers and staff, the Feinstein Institutes raises the standard of medical innovation through its five institutes of behavioral science, bioelectronic medicine, cancer, health system science, and molecular medicine. We make breakthroughs in genetics, oncology, brain research, mental health, autoimmunity, and are the global scientific leader in bioelectronic medicine – a new field of science that has the potential to revolutionize medicine. For more information about how we produce knowledge to cure disease, visit and follow us on LinkedIn.

MANHASSET, N.Y.--( BUSINESS WIRE )--Sepsis often leads to shock and multiple organ failure, making it one of the leading causes of in-hospital deaths worldwide. While much of the mystery surrounding sepsis remains, Feinstein Institutes for Medical Research scientists published in Cellular & Molecular Immunology the discovery of a protein that inhibits the body’s ability to clear bacteria, opening new avenues of therapeutic research. The new study explores how extracellular cold-inducible RNA-binding protein (eCIRP) – an alarm molecule released during sepsis – causes immune dysfunction. Specifically, eCIRP disrupts the cells within the immune system, which ingest bacteria and secrete both pro-inflammatory and antimicrobial mediators, known as macrophages. Macrophages play an important role in eliminating invading bacteria and damaged or dead cells from the body; however, new research shows how eCIRP dysregulates its normal function and contributes to sepsis progression. The research, led by Feinstein Institutes’ Ping Wang, MD , explains how eCIRP disrupts the cytoskeleton – the structure that maintains a cell’s shape – in lab mice, ultimately leading to the impairment of macrophage bacterial digestion during sepsis. Conversely, eCIRP-deficient, or eCIRP-neutralizing antibody-treated mice restored the macrophage function and reduced bacterial load. Indeed, the mice without eCIRP proteins displayed better survival outcomes. “There is no single specific treatment for patients with sepsis and it remains an enigmatic disease for researchers globally,” said Dr. Wang, professor and chief scientific officer at the Feinstein Institutes. “By reducing eCIRP molecules, we can lower the bacteria in septic patients and improve their outcome. This new information opens new avenues of research for effective therapies.” Sepsis impacts at least 1.7 million Americans annually , leading to the death of 270,000 patients and accounting for 30 percent of all hospital deaths. Sepsis occurs when the body’s immune system triggers inflammation to help fight against infection. If out of control, this inflammatory response can cause damage to multiple organ systems and often leads to death. Septic patients often exhibit the simultaneous occurrence of pro- and anti-inflammatory pathways, which can lead them to suffer from immunosuppression, the inability to eradicate invading bacteria and eventually become susceptible to secondary infections. Macrophages clear pathogens in the body, but during sepsis, the macrophage’s bacterial phagocytic ability is compromised. This results in bacterial overgrowth that can ultimately cause tissue injury and death. The study suggests that because of these findings, new therapies for sepsis could be provided. Currently, targeting sepsis-induced immunosuppression is one of the most striking therapeutic directions being studied. Correcting the function of macrophages for efficient clearance of pathogens could be an important therapeutic strategy to safeguard patients from sepsis. It could also provide a new therapeutic avenue to restore host defense against pathogens to improve the outcomes of sepsis, and potentially other inflammatory disease conditions. “Sepsis affects millions of people annually, and effective therapies are needed,” said Kevin J. Tracey, MD , president and CEO of the Feinstein Institutes. “The discoveries from Dr. Wang, and his lab, pave the way to exploring new mechanisms that may one day lead to new treatments.” The Feinstein Institutes continues to lead research studying the molecular mechanisms of sepsis to develop treatments. Most recently, Dr. Wang and co-principal investigators received $3.8 million from the National Institute of Health to study sepsis and radiation exposure. About the Feinstein Institutes The Feinstein Institutes for Medical Research is the home of the research institutes of Northwell Health, the largest health care provider and private employer in New York State. Encompassing 50 research labs, 3,000 clinical research studies and 5,000 researchers and staff, the Feinstein Institutes raises the standard of medical innovation through its five institutes of behavioral science, bioelectronic medicine, cancer, health system science, and molecular medicine. We make breakthroughs in genetics, oncology, brain research, mental health, autoimmunity, and are the global scientific leader in bioelectronic medicine – a new field of science that has the potential to revolutionize medicine. For more information about how we produce knowledge to cure disease, visit http://feinstein.northwell.edu and follow us on LinkedIn .