The National Heart, Lung, and Blood Institute of the National Institutes of Health (NIH) recently awarded a team of researchers at Weill Cornell Medicine a $2.1 million, four-year grant to study the mechanisms that cause scar tissue in the lungs and kidneys. The project aims to discover new molecular targets for the diagnosis and treatment of lung and kidney fibrosis-related diseases.
Fibrosis is an essential process of normal wound repair. But excessive fibrosis results in out-of-control tissue accumulation, leading to debilitating symptoms and risking organ failure.
The mechanisms behind aberrant fibrosis appear to be very similar across different organ systems. For this reason, the NIH opened a call for “Collaborative Projects to Accelerate Research in Organ Fibrosis,” based on the belief that work shared among various fibrosis researchers would accelerate medical knowledge. The competitive award given the Weill Cornell team was one of three distributed this year.
Co-principal investigators of the awarded project are Mary and Augustine Choi, a nephrologist and a pulmonologist, respectively.
“Almost any chronic disease that progresses to an end stage, such as lung or kidney disease, leads to fibrosis that is ultimately responsible for organ failure,” Mary Choi said in a Cornell news release. “Still, there are very limited treatment options specifically targeting this. So we want to address that by investigating what leads to progressive fibrosis in chronic disease.”
The couple will focus on the receptor-interacting protein kinase 3 (RIPK3) gene and its role in the development of lung and kidney fibrosis.
RIPK3, a regulator of a type of programmed cell death called necroptosis, is known to have a critical role in promoting injury-induced reparative inflammation. It is highly expressed during wound healing.
Preliminary studies performed by the team showed that RIPK3 is important in fibrosis formation and progression. The absence of the RIPK3 gene in mice protected them against kidney fibrosis, although they were still susceptible to pulmonary fibrosis. The researchers believe these differences may be due to distinct signaling pathways through which RIPK3 acts.
They want to characterize RIPK3 function and its targets in kidney and lung fibrosis. They also plan to analyze the effect of RIPK3 suppression in fibrosis formation using chemical inhibitors and low-dose carbon monoxide — found to regulate RIPK3-controlled necroptosis.
Human samples will be examined to uncover the molecules involved in this process and to assess if they can be used as disease biomarkers.
“There are two avenues for potential human therapy — the specific inhibitor for this protein or the use of carbon monoxide gas to target this pathway,” said Augustine Choi.
“Ultimately we want to make a difference in patients by discovering innovative treatments” he concluded.
End-stage lung diseases are frequently characterized by lung fibrosis. Idiopathic pulmonary fibrosis (IPF) is a pulmonary condition characterized by thickening and fibrosis of lung tissue, making breathing difficult. Fibrosis is also the hallmark of progressive chronic kidney diseases as a common response to injury.
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