A5082063678- Protease and Inhibitor Mechanisms
- Endoplasmic Reticulum Stress and Disease
- Cellular transport and secretion
- Peptidase Inhibition and Analysis
- Signaling Pathways in Disease
- Blood Coagulation and Thrombosis Mechanisms
- Ubiquitin and proteasome pathways
- Calpain Protease Function and Regulation
- Immune Response and Inflammation
- Insect Resistance and Genetics
- Lysosomal Storage Disorders Research
- Pluripotent Stem Cells Research
- Pulmonary Hypertension Research and Treatments
- Autophagy in Disease and Therapy
- CRISPR and Genetic Engineering
- interferon and immune responses
- S100 Proteins and Annexins
- Antimicrobial Peptides and Activities
- Coagulation, Bradykinin, Polyphosphates, and Angioedema
- Wnt/β-catenin signaling in development and cancer
- Alzheimer's disease research and treatments
- Neurological diseases and metabolism
- Heat shock proteins research
- RNA regulation and disease
- Enzyme Production and Characterization
Sapienza University of Rome
2015-2025
Istituto Pasteur
2012-2022
University College London
2022
Universität Hamburg
2021
University Medical Center Hamburg-Eppendorf
2021
Institut Pasteur
2014-2015
University of Cambridge
2004-2013
Wellcome Trust
2005-2013
Medical Research Council
2009-2013
Charles Darwin University
2010-2012
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...
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]...
Serine protease inhibitors (serpins), the acute phase reactants and regulators of proteolytic processing proteins, have been recognized as potential contributors to pathogenesis Alzheimer disease (AD). We measured plasma CSF levels serpins in controls patients with dementia.Using rocket immunoelectrophoresis, ELISA, Luminex xMAP technology, we analyzed alpha(1)-antichymotrypsin alpha(1)-antitrypsin, alpha(1)-antichymotrypsin, neuroserpin along three standard biomarkers (total tau, tau...
To the Editor: Most individuals carry two wild-type M alleles of SERPINA1 gene which encodes α1-antitrypsin. 95% severe deficiency α1-antitrypsin is associated with Z allele (Glu342Lys; denoted PiZZ in homozygote), and retention polymerisation within hepatocytes [1]. These polymers are contained periodic acid–Schiff-positive, diastase-resistant inclusions that neonatal hepatitis, cirrhosis hepatocellular carcinoma. The concomitant lack circulating predisposes homozygote to early-onset...
The dementia familial encephalopathy with neuroserpin inclusion bodies (FENIB) is caused by the accumulation of mutant within neurons (Davis, R. L., Shrimpton, A. E., Holohan, P. D., Bradshaw, C., Feiglin, Sonderegger, P., Kinter, J., Becker, L. M., Lacbawan, F., Krasnewich, Muenke, Lawrence, D. A., Yerby, M. S., Shaw, C.-M., Gooptu, B., Elliott, R., Finch, J. T., Carrell, W., and Lomas, (1999) Nature 401, 376–379), but little known about trafficking wild type neuroserpins. We have...
Familial encephalopathy with neuroserpin inclusion bodies (FENIB) is an autosomal dominant dementia that characterized by the retention of polymers as inclusions within endoplasmic reticulum (ER) neurons. We have developed monoclonal antibodies detect polymerized and used COS-7 cells, stably transfected PC12 cell lines transgenic Drosophila melanogaster to characterize cellular handling all four mutant forms cause FENIB. show a direct correlation between severity disease-causing mutation...
The autosomal dominant dementia familial encephalopathy with neuroserpin inclusion bodies is characterized by the accumulation of ordered polymers mutant within endoplasmic reticulum neurones. We show here that intracellular activate NF-kappaB a pathway independent IRE1, ATF6, and PERK limbs canonical unfolded protein response but dependent on calcium. This provides mechanism for cells to sense react folded structures serpins reticulum. Our results provide strong support overload being response.
Background Small studies have linked α1 antitrypsin (α1AT) deficiency to patients with antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV). Objective To test the validity and mechanism of this association between α1AT AAV. Methods The distribution alleles Z S was compared 856 White Europeans AAV 1505 geographic ethnically matched healthy controls. Genotyping performed by allelic discrimination assay. Results were cases controls using χ 2 tests. serum renal biopsies for...
DnaK/Hsp70 chaperones form oligomers of poorly understood structure and functional significance. Site-specific proteolysis crosslinking were used to probe the architecture formed by endoplasmic reticulum (ER) Hsp70, BiP. These found consist adjacent protomers engaging interdomain linker one molecule in substrate binding site another, attenuating chaperone function oligomeric Native gel electrophoresis revealed a rapidly-modulated reciprocal relationship between burden unfolded proteins BiP...
ABSTRACT Familial encephalopathy with neuroserpin inclusion bodies (FENIB) is a neurodegenerative pathology caused by accumulation of mutant (NS) polymers inside the endoplasmic reticulum (ER) neurons, leading to cellular toxicity and neuronal death. To date, there no cure for FENIB, only palliative care available FENIB patients, underlining urgency develop therapeutic strategies. The purpose this work was create system designed testing small molecules able reduce formation NS polymers. Our...
Abstract Forward and reverse signaling mediated by EphB tyrosine kinase receptors their transmembrane ephrin‐B ligands play important roles in axon pathfinding, yet little is known about the intracellular pathways involved. Here we have used growth cones from ventral (EphB receptor‐bearing) dorsal (ephrin‐B‐bearing) embryonic Xenopus retina to investigate mechanisms both forward directions. We report that unclustered, but not clustered, EphB2 ectodomains trigger fast (5–10 min) transient...
Because most cases of secondary dengue virus infection are associated with an increased level platelet-associated IgG, a high dose intravenous immunoglobulin (IVIG) may have effect on the development severe thrombocytopenia in this disease. A randomized, controlled study was conducted two treatment groups consisting group (n = 15) and non-treatment (non-IVIG) 16) to determine whether IVIG is effective hastening recovery from patients infection. No significant difference found baseline...
Mutant Z α1-antitrypsin (E342K) accumulates as polymers within the endoplasmic reticulum (ER) of hepatocytes predisposing to liver disease, whereas low levels circulating lead emphysema by loss inhibition neutrophil elastase. The ideal therapy should prevent polymer formation while preserving inhibitory activity. Here we used mAb technology identify interactors with that comply both requirements. We report generation an (4B12) blocked polymerization in vitro at a 1:1 molar ratio, causing...
The serpinopathies are among a diverse set of conformational diseases that involve the aberrant self-association proteins into ordered aggregates. α1-Antitrypsin deficiency is archetypal serpinopathy and results from formation deposition mutant forms α1-antitrypsin as "polymer" chains in liver tissue. No detailed structural analysis has been performed this material. Moreover, there little information on relevance well-studied artificially induced polymers to these disease-associated...
Chimeric antigen receptor (CAR)-T cells can induce powerful immune responses in patients with hematological malignancies but have had limited success against solid tumors. This is part due to the immunosuppressive tumor microenvironment (TME) which limits activity of tumor-infiltrating lymphocytes (TILs) including CAR-T cells. We developed a next-generation armored CAR (F i-CAR) targeting tyrosine kinase-like orphan 1 (ROR1), expressed at high levels range aggressive tumors poorly prognostic...