A faulty protein folds into the wrong shape, sticks to itself in long chains, and kills the cells that make it—causing liver cirrhosis, dementia, or lung damage in people with alpha-1-antitrypsin deficiency. This matters because current treatments only manage symptoms; there is no way to stop the protein from polymerising in the first place. The researchers have already identified small molecules that block polymer formation in the test tube and reduce protein buildup in cell models. They now need to understand exactly how polymers form and how they kill cells, and to develop new antibodies that can detect the harmful latent shape of the protein in human tissues. If successful, this work could lead to the first drugs that prevent the protein from misfolding, rather than just treating the damage afterward. The new antibodies could also be used to image pathological polymers inside patients’ lungs, giving doctors a way to track disease progression and see whether experimental treatments are clearing the toxic clumps. This is fundamental science with a clear path toward a diagnostic tool and, eventually, a therapy for a currently untreatable genetic disease.
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The serine proteinase inhibitors or serpins are a family of proteins that play an important role in controlling enzymes within the human body. Naturally occurring mutations cause the protein to change shape and accumulate as chains of polymers within the cell of synthesis. This causes cell death and hence either cirrhosis (if the protein accumulates within the liver) or dementia (if it accumulates within the brain). We propose to assess the mechanism by which polymers form and their effect on the cells in which they are synthesised. We also propose to determine the mechanism of action of small molecules that we have identified that can block polymer formation in the test tube and reduce the accumulation of mutant protein in a cell model of disease. We have shown that mutations that favour the formation of polymers also favour the formation of an inactive latent conformation. We propose to develop new monoclonal antibodies to the latent conformation of the serpins alpha-1-antitrypsin and neuroserpin so that we can identify them in biological tissues and so evaluate their role in disease. Polymers of alpha-1-antitrypsin form spontaneously within the lungs of individuals with alpha-1-antitrypsin deficiency where they inactivate alpha-1-antitrypsin as a proteinase inhibitor as well as acting as a chemoattractant to recruit inflammatory cells to the lung. We will use our antibody to polymers of alpha-1-antitrypsin to develop a new assay to image pathological polymers within the lung. This will provide useful information on the clearance of polymers from the lung and perhaps the progression of lung disease in individuals with alpha-1-antitrypsin deficiency.
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