University of Delaware researchers have identified a protein, hiding in plain sight, that acts like a bodyguard to help protect and stabilize another key protein, that when unstable, is involved in Crohn\u2019s disease. The fundamental research points to a possible pathway for developing an effective therapy for the inflammatory bowel disease. <\/p>\n
The research was conducted by Catherine Leimkuhler Grimes, assistant professor of chemistry and biochemistry at UD, and Vishnu Mohanan, doctoral student in biological sciences, <\/p>\n
As the scientists point out, our immune system provides the first line of defence against invading pathogens, a task even more challenging in the human gut, where over a trillion commensal bacteria live \u2014 resident microorganisms that help convert food into protein, vitamins and minerals.<\/p>\n
To distinguish \u201cbad\u201d versus \u201cgood\u201d bacteria, our bodies rely on a complex network of receptors that can sense patterns that are unique to bacteria, such as small fragments of bacterial cell wall. The receptors recognize and bind to these fragments, triggering an immune response to take out the \u201cbad guys\u201d or control the growth of the \u201cgood guys.\u201d <\/p>\n
However, when one of these receptors breaks down, or mutates, an abnormal immune response can occur, causing the body to mount an immune response against the \u201cgood\u201d bacteria. Chronic inflammatory disorders, such as Crohn\u2019s disease, are hypothesized to arise as a result.<\/p>\n
The UD team focused on a protein called NOD2 \u2014 nucleotide-binding oligomerisation domain containing protein 2. More than 58 mutations in the NOD2 gene have been linked with various diseases, and 80 percent of these mutations are connected specifically to Crohn\u2019s disease, according to Grimes. <\/p>\n
In experiments to unveil NOD2\u2019s signalling mechanisms and where they break down, \u201cwe stumbled on this chaperone molecule,\u201d says Mohanan, who was the lead author of the scientific article. <\/p>\n
The chaperone molecule was HSP70, which stands for \u201cheat shock protein 70.\u201d It assists with the folding of proteins into their correct three-dimensional shapes, even when cells are under stress from elevated body temperatures, such as a fever. <\/p>\n
Grimes said she was a little sceptical at first about pursuing studies with HSP70 because it is a commonly known protein, but she found Mohanan\u2019s initial data intriguing. <\/p>\n
\u201cVishnu found that if we increased the expression level of HSP70, the NOD2 Crohn\u2019s mutants were able to respond to bacterial cell wall fragments. A hallmark of the NOD2 mutations is inability to respond to these fragments. Essentially, Vishnu found a fix for NOD2, and we wanted to determine how we were fixing it.\u201d <\/p>\n
In further experiments, Mohanan created a tagged-wild-type NOD2 cell line in which NOD2 levels nearly matched the levels found in nature (versus \u201csuper\u201d levels that might stimulate an artificial response) and found that NOD2 became more stabilized and degraded more slowly when treated with HSP70. In fact, HSP70 increased the half-life of NOD2 by more than four hours.<\/p>\n
\u201cBasically, HSP70 keeps the protein around \u2014 it kind of watches over and protects NOD2, and keeps it from going in the cellular trash can,\u201d Grimes explains.<\/p>\n
The researchers tested three human cell lines in their study: kidney cells, colon cells and white blood cells. In the next phase of the study, patient tissue will be examined through a collaboration with Nemours\/A.I. duPont Hospital for Children to determine if NOD2 levels can be controlled via HSP70 expression. <\/p>\n
\u201cWe want to figure out why the mutation in NOD2 results in an increase in inflammation,\u201d says Mohanan. \u201cRight now, we have limited knowledge. Once the signalling mechanism is figured out, we will have the keystone.\u201d\nUniversity of Delaware<\/link>\n","protected":false},"excerpt":{"rendered":"
University of Delaware researchers have identified a protein, hiding in plain sight, that acts like a bodyguard to help protect and stabilize another key protein, that when unstable, is involved in Crohn\u2019s disease. The fundamental research points to a possible pathway for developing an effective therapy for the inflammatory bowel disease. The research was conducted […]<\/p>\n","protected":false},"author":2,"featured_media":0,"comment_status":"closed","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_monsterinsights_skip_tracking":false,"_monsterinsights_sitenote_active":false,"_monsterinsights_sitenote_note":"","_monsterinsights_sitenote_category":0,"footnotes":""},"categories":[35],"tags":[],"_links":{"self":[{"href":"https:\/\/clinlabint.com\/wp-json\/wp\/v2\/posts\/1597"}],"collection":[{"href":"https:\/\/clinlabint.com\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/clinlabint.com\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/clinlabint.com\/wp-json\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/clinlabint.com\/wp-json\/wp\/v2\/comments?post=1597"}],"version-history":[{"count":0,"href":"https:\/\/clinlabint.com\/wp-json\/wp\/v2\/posts\/1597\/revisions"}],"wp:attachment":[{"href":"https:\/\/clinlabint.com\/wp-json\/wp\/v2\/media?parent=1597"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/clinlabint.com\/wp-json\/wp\/v2\/categories?post=1597"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/clinlabint.com\/wp-json\/wp\/v2\/tags?post=1597"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}