A5036734448- Protease and Inhibitor Mechanisms
- Peptidase Inhibition and Analysis
- Blood Coagulation and Thrombosis Mechanisms
- Endoplasmic Reticulum Stress and Disease
- Signaling Pathways in Disease
- Cellular transport and secretion
- Chronic Obstructive Pulmonary Disease (COPD) Research
- Metabolism and Genetic Disorders
- Calpain Protease Function and Regulation
- Long-Term Effects of COVID-19
- Insect Resistance and Genetics
- Asthma and respiratory diseases
- Lysosomal Storage Disorders Research
- Coagulation, Bradykinin, Polyphosphates, and Angioedema
- Neurological diseases and metabolism
- Intensive Care Unit Cognitive Disorders
- Enzyme Production and Characterization
- Pediatric health and respiratory diseases
- Genetics and Neurodevelopmental Disorders
- Biochemical and Molecular Research
- Ubiquitin and proteasome pathways
- Silk-based biomaterials and applications
- Amino Acid Enzymes and Metabolism
- Pulmonary Hypertension Research and Treatments
- Protein Hydrolysis and Bioactive Peptides
University College London
2016-2025
Institute of Structural and Molecular Biology
2015-2025
Queen Elizabeth Hospital
2024
University College Hospital
2020-2024
Birkbeck, University of London
2013-2024
University Hospitals Birmingham NHS Foundation Trust
2024
University of Birmingham
2023
National Institute for Health Research
2021-2023
Imperial College London
2023
Newcastle University
2023
Human induced pluripotent stem (iPS) cells hold great promise for advancements in developmental biology, cell-based therapy, and modeling of human disease. Here, we examined the use iPS inherited metabolic disorders liver. Dermal fibroblasts from patients with various diseases liver were used to generate a library patient-specific cell lines. Each line was differentiated into hepatocytes using what believe be novel 3-step differentiation protocol chemically defined conditions. The resulting...
The mutation in the Z deficiency variant of α<sub>1</sub>-antitrypsin perturbs structure protein to allow a unique intermolecular linkage. These loop-sheet polymers are retained within endoplasmic reticulum hepatocytes form inclusions that associated with neonatal hepatitis, juvenile cirrhosis, and hepatocellular carcinoma. process polymer formation has been investigated here by intrinsic tryptophan fluorescence, fluorescence polarization, circular dichroic spectra extrinsic...
<h3>Background:</h3> Circulating levels of Clara cell secretory protein-16 (CC-16) have been linked to toxicity. It has therefore suggested that this protein may be a useful marker chronic obstructive pulmonary disease (COPD). <h3>Methods:</h3> Serum CC-16 were measured in 2083 individuals aged 40–75 years with COPD and smoking history ⩾10 pack-years, 332 controls pack-years normal lung function 237 non-smoking controls. <h3>Results:</h3> had coefficient repeatability 2.90 over 3 months...
The serine proteinase inhibitors, or serpins, are a superfamily of proteins that found in wide range species, including plants, viruses, and humans.The family includes as diverse α 1 -antichymotrypsin, C1 inhibitor, antithrombin, plasminogen activator inhibitor-1, which have key regulatory functions the inflammatory, complement, coagulation, fibrinolytic cascades.Members serpin characterized by more than 30% sequence homology with -antitrypsin conservation tertiary structure.The structure is...
Abstract Alpha1-antitrypsin is the most abundant circulating protease inhibitor. The severe Z deficiency allele (Glu342Lys) causes protein to undergo a conformational transition and form ordered polymers that are retained within hepatocytes. This neonatal hepatitis, cirrhosis, hepatocellular carcinoma. We have developed conformation-specific monoclonal antibody (2C1) recognizes pathological formed by α1-antitrypsin. was used characterize variant novel shutter domain mutant (His334Asp;...
The serpinopathies result from the ordered polymerization of mutants members serine proteinase inhibitor (serpin) superfamily. These polymers are retained within cell synthesis where they cause a toxic gain function. exemplified by inclusions that form with common severe Z mutant α 1 -antitrypsin associated liver cirrhosis. There is considerable controversy as to pathway serpin and structure pathogenic disease. We have used synthetic peptides, limited proteolysis, monoclonal antibodies, ion...
Point mutants of alpha1-antitrypsin (α1AT) form ordered polymers that are retained as inclusions within the endoplasmic reticulum (ER) hepatocytes in association with neonatal hepatitis, cirrhosis, and hepatocellular carcinoma. These cause cell damage predispose to ER stress absence classical unfolded protein response (UPR). The pathophysiology underlying this was explored by generating models conditionally express wild-type (WT) α1AT, two polymer-mediated liver disease (E342K [the Z allele]...
Neutrophil elastase (NE) is released by activated neutrophils during an inflammatory response and exerts proteolytic activity on elastin other extracellular matrix components. This protease rapidly inhibited the plasma serine inhibitor alpha‐1‐antitrypsin (AAT), importance of this protective lung tissue highlighted development early onset emphysema in individuals with AAT deficiency. As a serpin, presents surface‐exposed reactive centre loop (RCL) whose sequence mirrors target specificity....
The serpins are a family of proteinase inhibitors that play central role in the control proteolytic cascades. Their inhibitory mechanism depends on intramolecular insertion reactive loop into β-sheet A after cleavage by target proteinase. Point mutations within protein can allow aberrant conformational transitions characterized β-strand exchange between one molecule and another. These loop-sheet polymers result diseases as varied cirrhosis, emphysema, angio-oedema, thrombosis, we recently...
Conformational diseases such as amyloidosis, Alzheimer's disease, prion diseases, and the serpinopathies are all caused by structural rearrangements within a protein that transform it into pathological species. These typified Z variant of α<sub>1</sub>-antitrypsin (E342K), which causes retention hepatocytes inclusion bodies associated with neonatal hepatitis cirrhosis. The result from mutation perturbing conformation protein, facilitates sequential interaction between reactive center loop...