Nature Communications<\/a> study, the same team discovered a signaling pathway that may be mediating fibrosis and could be a target for future therapies.<\/p>\n\u201cTreatments for fibrosis are an enormously unmet need,\u201d says Richard Flavell, a professor of immunobiology at Yale School of Medicine (YSM) and co-principal investigator of the studies. \u201cBetter understanding these conditions will likely yield new medicines to help patients.\u201d<\/p>\n
Previous research has linked the upregulation of a protein called epidermal growth factor receptor (EGFR)\u2014which helps control how cells grow and multiply\u2014with fibrotic diseases. Typically, this protein helps promote wound healing. But when it becomes overactivated, it can produce excessive scar tissue associated with fibrosis.<\/p>\n
In 2022, the YSM researchers found that skin samples from patients with scleroderma\u2014a rare autoimmune disease that causes fibrosis of the skin and sometimes internal organs\u2014had increased levels of epiregulin, a signaling molecule that binds to EGFR. They hypothesized that more epiregulin could be driving the overactivation of EGFR, leading to fibrosis in scleroderma. To test this idea, they used an antibody to target and reduce epiregulin in animal models and found that it reversed fibrosis.<\/p>\n
Based on these findings, in their latest study, the team developed a new human anti-epiregulin therapeutic antibody and tested its ability to mitigate graft-versus-host-disease, a complication of stem cell or bone marrow transplants in which donor immune cells attack the body and, in some cases, cause fibrosis. First, the researchers compared single-cell RNA sequencing data from patients with scleroderma and graft-versus-host disease to identify the shared mechanisms driving fibrosis in both diseases and they confirmed that upregulated epiregulin was a common pathology.<\/p>\n
\u201cWhat really stood out was that the epiregulin signal, like we had seen before in scleroderma, was really highlighted in patients with this fibrotic graft-versus-host disease,\u201d says Ian Odell, assistant professor of dermatology at YSM and co-principal investigator of the studies.<\/p>\n
Then, the team tested their anti-EREG antibody in humanized mouse models and skin biopsies from patients and found that inhibiting epiregulin reduced biomarkers associated with fibrosis. These findings suggest that the therapeutic antibody could be a promising new therapy for patients with various types of fibrotic conditions.<\/p>\n
In future studies, the researchers plan to test the therapy in other fibrotic diseases such as lupus and hidradenitis suppurativa.<\/p>\n
In a second recent study, the researchers aimed to further understand mechanisms that differentiate fibrotic and non-fibrotic skin diseases. The team compared single-cell RNA sequencing data from seven different inflammatory skin diseases. Some of the diseases, like atopic dermatitis and psoriasis, were associated with redness and scaling, but not fibrosis. They also analyzed data from patients with fibrotic diseases such as scleroderma, graft-versus-host disease, and lupus.<\/p>\n
Their analyses revealed that fibrotic diseases were associated with greater activity of a protein called STAT1 in fibroblasts, the key cell type that\u2019s hyperactivated in fibrotic diseases. To better understand how STAT1 interacts with the EGFR signaling pathway to drive fibrosis, the researchers developed mouse models that lacked STAT1. When the team activated EGFR, they found that mice without STAT1 showed less fibrosis compared to regular animal models.<\/p>\n
\u201cIf we activate EGFR by inducing injury when there\u2019s no STAT1 present, none of the fibrotic genes are activated,\u201d says Odell.<\/p>\n
The researchers conducted further experiments on cultured fibroblasts in vitro which confirmed that STAT1 was required for the onset of fibrosis.<\/p>\n
Current therapies for skin diseases include Janus kinases (JAK) inhibitors, which target the JAK-STAT pathway. Previous research shows that the activation of JAKs can trigger activity of STAT proteins like STAT1. While JAK inhibitors can successfully treat skin diseases like atopic dermatitis and psoriasis, they are less effective in mitigating fibrosis.<\/p>\n
The current study shows that EGFR signaling can activate STAT1 independent of JAKs, which could explain why JAK inhibitors don\u2019t work as well for fibrotic diseases. This EGFR-STAT1 pathway is a promising new target for potential therapies, the researchers say.<\/p>\n
Importantly, the upregulation of epiregulin activation of EGFR-STAT1 pathway isn\u2019t always active\u2014it\u2019s only switched on under specific conditions such as the presence of injury or inflammation.<\/p>\n
\u201cThese are not targets required for living your daily life\u2014we\u2019re not expecting significant side effects by inhibiting them,\u201d says Odell. \u201cWe\u2019re expecting a very safe profile.\u201d<\/p>\n
The new studies highlight two promising therapeutic avenues for treating fibrotic diseases. The researchers are optimistic that they will lead to new tools that will greatly improve patients\u2019 quality of life.<\/p>\n
\u201cThere\u2019s a lot of hope for the future,\u201d Flavell says.<\/p>\n
Source: Yale<\/a><\/p>\n","protected":false},"excerpt":{"rendered":"Share this Article You are free to share this article under the Attribution 4.0 International license. Researchers have…\n","protected":false},"author":2,"featured_media":159491,"comment_status":"","ping_status":"","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[10],"tags":[38026,103,61,60,60887],"class_list":["post-159490","post","type-post","status-publish","format-standard","has-post-thumbnail","category-health","tag-cystic-fibrosis","tag-health","tag-ie","tag-ireland","tag-pulmonary-fibrosis"],"_links":{"self":[{"href":"https:\/\/www.newsbeep.com\/ie\/wp-json\/wp\/v2\/posts\/159490","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.newsbeep.com\/ie\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.newsbeep.com\/ie\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.newsbeep.com\/ie\/wp-json\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/www.newsbeep.com\/ie\/wp-json\/wp\/v2\/comments?post=159490"}],"version-history":[{"count":0,"href":"https:\/\/www.newsbeep.com\/ie\/wp-json\/wp\/v2\/posts\/159490\/revisions"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/www.newsbeep.com\/ie\/wp-json\/wp\/v2\/media\/159491"}],"wp:attachment":[{"href":"https:\/\/www.newsbeep.com\/ie\/wp-json\/wp\/v2\/media?parent=159490"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.newsbeep.com\/ie\/wp-json\/wp\/v2\/categories?post=159490"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.newsbeep.com\/ie\/wp-json\/wp\/v2\/tags?post=159490"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}