TRPM7

In a new study with obese mice, researchers say they have added to evidence that specialized channel proteins are possible therapeutic targets for sleep apnea and similar abnormally slow breathing disorders in obese people. In a new study with obese mice, Johns Hopkins Medicine researchers say they have added to evidence that specialized channel proteins are possible therapeutic targets for sleep apnea and similar abnormally slow breathing disorders in obese people. The protein, a cation channel known as TRPM7, is found in carotid bodies, tiny sensory organs in the neck that detect oxygen and carbon dioxide changes, and certain hormones such as leptin, in the bloodstream. TRPM7 proteins help transport and regulate the stream of positively charged molecules in and out of the carotid bodies' cells. The new research, carried out in the Johns Hopkins Medicine Polotsky Research Lab and led by postdoctoral fellow Lenise Kim, Ph.D., builds on previous findings from the lab that show that TRPM7 contributed to the development of high blood pressure in mice. The latest experiments, described in a report first published October 10 in The Journal of Physiology, revealed that TRPM7 plays a role in suppressing breathing in obese mice with symptoms of sleep-disordered breathing conditions. Sleep-disordered breathing is characterized by breathing that stops and starts throughout sleep and is estimated to affect up to 45% of obese Americans. Untreated, the condition can worsen heart disease progression and diabetes, cause significant fatigue, as well as death from poor oxygenation. Lifestyle changes such as weight loss and nightly use of continuous positive airway pressure devices, or CPAP, can alleviate sleep apnea, but CPAP treatment is often poorly tolerated by patients. "CPAP actually works for most patients, the fact is that most patients are not adherent to this treatment," says Kim. "So knowing that TRPM7 contributed to high blood pressure and sleep-disordered breathing, we wondered if blocking or eliminating that channel could offer a new treatment target." Using silencing RNA, the researchers knocked out the gene responsible for the production of the TRPM7 channel protein, reducing the number of TRPM7 channels in the carotid bodies of obese mice. Mice then underwent a sleep study, during which researchers observed their breathing patterns and blood oxygen levels. In obese mice with blocked TRPM7, the researchers noted large differences in their rates of minute ventilation, or the amount of air inhaled and exhaled by the lungs per minute. The obese mice showed a 14% increase in their minute ventilation, 0.83 milliliters of air per minute (mL/min/g) during sleep. Researchers say these data are a significant improvement in ventilation when compared to obese mice that had TRPM7, whose average minute ventilation was 0.73 mL/min/g. These findings indicate the ventilatory capacity in these mice was improved while they slept, effectively combating the decreased breathing patterns of sleep apnea. Notably, the researchers found that despite the increased ventilation in obese mice lacking TRPM7, their blood oxygen levels did not increase. For this finding, researchers exposed the mice to hypoxic -- or low-oxygen -- environments and then monitored their breathing patterns. Although the mice's minute ventilation increased by 20%, from 1.5 mL/min/g to 1.8 mL/min/g, their bloodstream oxygen levels decreased, meaning their additional inhalations did not help saturate the body with more oxygen. "This suggests that treatments designed to reduce or erase TRPM7 in carotid bodies would not be workable for people living in low-oxygen environments, such as those in very high altitudes, or for those with conditions that already limit blood oxygen saturation, such as lung disease," says Kim. The team's findings also illustrate that the hormone leptin -- which is produced in fat cells and is responsible for curbing appetite -- may cause an increase in TRPM7 channels. Leptin is already known to accelerate production and increase the concentration of TRPM7 in carotid bodies. In obese mice who possess more fat cells, the increased amount of leptin may lead to an oversaturation of TRPM7. These high levels of the cation channel in turn may lead to the low respiration rates observed in obese mice with TRPM7. "We have shown that the genetic knockdown of TRPM7 in carotid bodies reduces suppressed respiration in sleep-disordered breathing," says Vsevolod (Seva) Polotsky, M.D., Ph.D., director of sleep research and professor of medicine at the Johns Hopkins University School of Medicine. "While more research is needed, carotid body TRPM7 is a promising therapeutic target not only for hypertension in obesity, but also for abnormal breathing during sleep associated with obesity." Other researchers involved in this research include Mi-Kyung Shin, Huy Pho, Nishitha Hosamane, Frederick Anokye-Danso, Rexford Ahima, James Sham and Luu Pham of Johns Hopkins University School of Medicine, as well as Wan-Yee Tang of the University of Pittsburgh. This research was supported by National Heart, Lung, and Blood Institute grant NIH R01 HL128970, R01 HL133100 and R01 HL12892, American Academy of Sleep Medicine Foundation 238-BS-20, American Thoracic Society Unrestricted Award, American Heart Association (AHA) Postdoctoral Fellowship Award 828142 and AHA Career Development Award 19CDA34700025.

Every week there are numerous scientific studies published. Here’s a look at some of the more interesting ones. A Newly Identified Protein that Prevents Cancer Cells from Spreading in Blood Vessels Scientists at Johns Hopkins University identified a specialized protein that seems to stop tumor cells from entering the bloodstream and metastasizing to other parts of the body. The protein, TRPM7, has been known to regulate calcium in cells. But they found that TRPM7 senses the pressure of fluid flowing in circulation and prevents the cells from spreading through the vascular system, according to Kaustav Bera, a Johns Hopkins University Ph.D. candidate in chemical and biomolecular engineering and lead author of the study. It was conducted jointly with colleagues at the University of Alberta and Universitat Pompeu Fabra. “We found that metastatic tumors cells have markedly reduced levels of this sensor protein, and that is why they efficiently enter into the circulation rather than turning away from fluid flow.” The research was published in Science Advances. A separate analysis of data in osteosarcoma, breast, gastric, and liver cancers found that patients who expressed high levels of TRPM7 tended to live longer than those with low levels of the protein. They believe the results of their research could lead to new cancer therapies via CRISPR activation. “We’ll need further developments before we can take this to the clinical setting, but we believe we provide, for the first time, a definitive picture of the role of TRPM7 in a crucial step of tumor metastasis,” said senior author Konstantinos Konstantopoulos, professor of chemical and biomolecular engineering and member of the Johns Hopkins Kimmel Cancer Center. A 90-Year-Old Woman Died of Two Variant COVID-19 Infections Simultaneously Researchers from the OLV Hospital in Aalst, Belgium presented a paper at the European Congress of Clinical Microbiology & Infectious Diseases describing the case of a 90-year-old Belgian woman who was infected with two strains of COVID-19, the Alpha (UK) and Beta (South Africa) strains at the same time. The elderly woman was screened for SARS-CoV-2 and had a “strongly positive” result. Follow-up PCR testing for variants was conducted and found the two variants in her system, which were confirmed with secondary tests. This appears to be the first published report of multiple variant infections, although there have been reports of earlier double infections. And similar infections with influenza viruses have been reported. Single COVID-19 Shot Decreases COVID-19 Risk by About 2/3 in Elderly A study published in Clinical Infectious Diseases found that a single dose of the Pfizer-BioNTech or Moderna vaccines decrease COVID-19 risk by about two-thirds in the elderly. The research evaluated 16,993 sample specimens from British Columbia residents 70 years or older from April 4 to May 1, 2021. They found overall vaccine effectiveness for a single dose at 21 or more days after vaccination was 65%. Restoring Sense of Touch in Damaged Nerves Investigators from Tel Aviv University developed an implantable sensor that connects to another nerve that functions normally and can restore the sense of touch to injured nerves. This technology is biocompatible and does not require electricity, wires or batteries. Any time the limb touches an object, it activates the sensor, which conducts an electric current to the functioning nerve, which recreates the sensation of touch. The technology has been tested and is suitable for the human body. The research team says it can be implanted anywhere in the body once clinical trials are completed. The technology is called a triboelectric nanogenerator (TENG). The electric current comes directly from the healthy nerve and friction — whenever the device senses friction, it charges itself. How Fatty Liver Disease Progresses to NASH Non-alcoholic fatty liver disease is observed in about 25% of people around the world. Although it’s possible to have a fatty liver and continue having normal liver function, it can progress to non-alcoholic steatohepatitis (NASH), an aggressive type of non-alcoholic fatty liver disease that combines inflammation and scarring (fibrosis). Researchers at the Helmholtz Diabetes Center at Helmholtz Zentrum Munchen (Germany) leveraged comparative genomics to study mechanisms that control the development of hepatocytes in the liver and how they progress from fatty-liver disease to NASH. Hepatocyte reprogramming is controlled by a network of proteins that act as molecular switches. They found that in the progression to NASH, hepatocytes suffer from partial identity loss and are reprogrammed. This reprogramming causes hepatocyte dysfunction. The transcription factors also control progression of fibrosis. Inflammatory Clock Predicts Immunological Health and Aging Researchers at the Buck Institute for Research on Aging developed iAge, an inflammatory clock of aging. iAge measures inflammatory load and predicts multiple diseases of aging, frailty, immune health, cardiovascular aging, and it linked to exceptional longevity in people who lived 100 years or more. It leverages machine learning in assays of the blood immunome of 1,001 people. They also identified a modifiable chemokine linked with cardiac aging that can be the basis of an assay for early detection of age-related pathology. The study was published in Nature Aging. “Standard immune metrics which can be used to identify individuals most at risk for developing single or even multiple chronic diseases of aging have been sorely lacking,” said David Furman, Buck Institute Associate Professor, director of the 1001 Immunomes Project at Stanford University School of Medicine and senior author of the study. “Bringing biology to our completely unbiased approach allowed us to identify a number of metrics, including a small immune protein which is involved in age-related systemic chronic inflammation and cardiac aging. We now have means of detecting dysfunction and a pathway to intervention before full-blown pathology occurs.” The results of the individual analysis of 902 people were validated in an independent cohort of centenarians and all-cause mortality in the Framingham Heart Study. The “age” of the immune system appears to be a dominating factor over chronological age. Furman noted, “On average, centenarians have an immune age that is 40 years younger than what is considered ‘normal’ and we have one outlier, a super-healthy 105-year-old man (who lives in Italy) who has the immune system of a 25-year-old.”