Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0034067 (emphysema)
 11,506 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The common fatal hereditary disorders, alpha 1-antitrypsin (alpha 1AT) deficiency and cystic fibrosis (CF), are clinical models for the common lung diseases, emphysema and chronic bronchitis, respectively. Both are potentially amenable to therapeutic intervention by gene therapy, in which the relevant gene is used to modify cells of the affected individual. Although the gene therapy strategies for these diseases are conceptually quite different, a promising approach for both is the in vivo administration of a recombinant replication deficient adenovirus vector containing a normal copy of the abnormal gene. If the goal is to express the normal extracellular anti-protease alpha 1 AT, the route of administration could be directly into the lung, liver or vascular endothelium. If the goal is to express the normal transmembrane protein defective in CF epithelial cells, the new gene will need to be delivered directly to the affected cells. The feasibility of these approaches has been demonstrated in vitro and in vivo in experimental animals.
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PMID:Gene therapy for pulmonary diseases. 829 Mar 11

Degradation of proteins that are retained in the quality control apparatus of the endoplasmic reticulum (ER) has been attributed to a third proteolytic system, distinct from the lysosomal and the cytoplasmic ubiquitin-dependent proteosomal proteolytic pathways. However, several recent studies have shown that ER degradation of a mutant membrane protein, CFTRdeltaF508, is at least in part mediated from the cytoplasmic side by the 26 S proteasome. In this study, we examined the possibility that ER degradation of mutant secretory protein alpha1-antitrypsin (alpha1-AT) Z, the mutant protein associated with infantile liver disease and adult-onset emphysema of alpha1-AT deficiency, is mediated by the proteasome. The results show that a specific proteasome inhibitor, lactacystin, inhibits ER degradation of alpha1-ATZ in transfected human fibroblast cell lines and in a cell-free microsomal translocation system. Although it is relatively easy to conceptualize how a transmembrane protein like CFTRDeltaF508 might be accessible on the cytoplasmic aspect of the ER membrane for ubiquitination and degradation by the proteasome, it is more difficult to conceptualize how this might occur for a luminal polypeptide. The results show that, once within the lumen of the ER, alpha1-ATZ interacts with the transmembrane molecular chaperone calnexin and specifically induces the polyubiquitination of calnexin. The results, therefore, provide evidence that the proteasome, from its cytoplasmic localization, induces the degradation of the luminal alpha1-ATZ molecule by first attacking the cytoplasmic tail of calnexin molecules that are associated with alpha1-ATZ.
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PMID:Degradation of a mutant secretory protein, alpha1-antitrypsin Z, in the endoplasmic reticulum requires proteasome activity. 879 55

Mice carrying a loss-of-function mutation in the klotho gene (KL(-/-) mice) develop ageing-like symptoms around 4 weeks after birth and suffer from multiple age-related disorders observed in humans, including osteoporosis, arteriosclerosis, and pulmonary emphysema. The klotho gene encodes a single-pass transmembrane protein that may function in signaling pathways that suppress ageing. To investigate the ability of Klotho to regulate the development of ageing-related disorders, we established an inducible Klotho expression system using KL(-/-) mice carrying an exogenous klotho gene fused to the mouse metallothionein-I promoter, in which Klotho expression was dependent on zinc water feeding. We demonstrate that many advanced ageing-like KL(-/-) phenotypes were restored to normal whenever Klotho expression was induced. Conversely, decreasing Klotho expression in these rescued KL(-/-) mice induced several ageing-like KL(-/-) phenotypes. Our data indicate that Klotho may be effective in the treatment of multiple age-related disorders and is essential for maintaining animals free of these disorders.
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PMID:Regulation of multiple ageing-like phenotypes by inducible klotho gene expression in klotho mutant mice. 1614 5