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Curative and beta cell regenerative effects of alpha1 antitrypsin treatment in autoimmune diabetic NOD mice

ABSTRACT: In this study, we performed the gene expression analysis of the Normal, Diabetic and AAT treated NOD mice to elucidate the transcriptional changes induced by AAT. This will assist in identifying the biological processes / pathways involved in curative mechanism of AAT. Keywords: alpha1 antitrypsin treatment

ORGANISM(S): Mus musculus

PROVIDER: GSE10478 | GEO | 2008/12/31

SECONDARY ACCESSION(S): PRJNA108039

REPOSITORIES: GEO

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Transcription profiling of mouse autoimmune and diabetic NOF animals reveals the curative and beta cell regenerative effects of alpha1 antitrypsin treatment

Project description:In this study, we performed the gene expression analysis of the Normal, Diabetic and AAT treated NOD mice to elucidate the transcriptional changes induced by AAT. This will assist in identifying the biological processes / pathways involved in curative mechanism of AAT. Experiment Overall Design: Duplicate samples of Normal, Diabetic and AAT treated NOD mice were analyzed.

2009-01-14 | E-GEOD-10478 | biostudies-arrayexpress

Mice inflammatory responses to inhaled aerosolized LPS: effects of various forms of human alpha1-antitrypsin

Project description:Characterize how Balb/c mice responses to aerosolized LPS (lipopolysaccharide) alone or with intraperitoneal (i.p.) delivery of alpha1-antitrypsin (AAT)

2022-09-30 | GSE214249 | GEO

Transcription profiling of mouse (6 wk) inducibly expresssing human alpha1-antitrypsin in the liver

Project description:In the classical form of Î±1antitrypsin deficiency a mutant protein accumulates in a polymerized form in the ER of liver cells causing liver damage and carcinogenesis by a gain-of-toxic function mechanism. Recent studies have indicated that the accumulation of mutant Î±1antitrypsin Z in the ER specifically activates the autophagic response but not the unfolded protein response and that autophagy plays a critical role in disposal of insoluble Î±1antitrypsin Z. In this study, we used genomic analysis of the liver in a novel transgenic mouse model with inducible expression to screen for changes in gene expression that would potentially define how the liver responds to accumulation of this mutant protein. Experiment Overall Design: Liver RNA from juvenile (6 wk old) male mice inducibly expressing human alpha1-antitrypsin wild type (M) or mutant (Z) form exclusively in the liver was subjected to genomic analysis. Groups: mutant AAT (Z), wild type AAT (M), expressing (4), non-expressing (1); 3 biological replicates/each group. Experiment Overall Design: Groups: mutant AAT (Z), wild type AAT (M), expressing (4), non-expressing (1); 3 biological replicates/each group, all males, 6 weeks of age

2008-06-16 | E-GEOD-8600 | biostudies-arrayexpress

Transcription profiling of mouse transgenics (3 mo) inducibly expresssing human alpha1-antitrypsin in the liver

Project description:In the classical form of Î±1antitrypsin deficiency a mutant protein accumulates in a polymerized form in the ER of liver cells causing liver damage and carcinogenesis by a gain-of-toxic function mechanism. Recent studies have indicated that the accumulation of mutant Î±1antitrypsin Z in the ER specifically activates the autophagic response but not the unfolded protein response and that autophagy plays a critical role in disposal of insoluble Î±1antitrypsin Z. In this study, we used genomic analysis of the liver in a novel transgenic mouse model with inducible expression to screen for changes in gene expression that would potentially define how the liver responds to accumulation of this mutant protein. Experiment Overall Design: Liver RNA from adult (3 mo old) male mice inducibly expressing human alpha1-antitrypsin wild type (M) or mutant (Z) form exclusively in the liver was subjected to genomic analysis. Groups: mutant AAT (Z), wild type AAT (M), expressing (4), non-expressing (1), wild type littermates (WT); 3 biological replicates/each group

2008-06-16 | E-GEOD-8599 | biostudies-arrayexpress

Curative and beta cell regenerative effects of alpha1-antitrypsin treatment in autoimmune diabetic NOD mice.

Project description:Invasive insulitis is a destructive T cell-dependent autoimmune process directed against insulin-producing beta cells that is central to the pathogenesis of type 1 diabetes mellitus (T1DM) in humans and the clinically relevant nonobese diabetic (NOD) mouse model. Few therapies have succeeded in restoring long-term, drug-free euglycemia and immune tolerance to beta cells in overtly diabetic NOD mice, and none have demonstrably enabled enlargement of the functional beta cell mass. Recent studies have emphasized the impact of inflammatory cytokines on the commitment of antigen-activated T cells to various effector or regulatory T cell phenotypes and insulin resistance and defective insulin signaling. Hence, we tested the hypothesis that inflammatory mechanisms trigger insulitis, insulin resistance, faulty insulin signaling, and the loss of immune tolerance to islets. We demonstrate that treatment with alpha1-antitrypsin (AAT), an agent that dampens inflammation, does not directly inhibit T cell activation, ablates invasive insulitis, and restores euglycemia, immune tolerance to beta cells, normal insulin signaling, and insulin responsiveness in NOD mice with recent-onset T1DM through favorable changes in the inflammation milieu. Indeed, the functional mass of beta cells expands in AAT-treated diabetic NOD mice.

| S-EPMC2570971 | biostudies-literature

Calreticulin enhances the secretory trafficking of a polymerogenic alpha1-antitrypsin

Project description:α-1-antitrypsin (AAT) regulates protease activity in the lungs and liver. The presence of one or more copies of a mutant Z allele (AAT (E342K), called ATZ), results in low serum levels of ATZ along with intracellular inclusions of polymeric forms, causing lung emphysema and liver cirrhosis. Our experiments show that calreticulin (CRT), an endoplasmic reticulum (ER) glycoprotein chaperone, promotes the secretory trafficking of ATZ, enhancing the media to cell ratio. This effect is more specific for ATZ compared with AAT, and is only partially dependent on the glycan-binding site of CRT. The CRT-related chaperone calnexin (CNX) does not promote enhanced ATZ secretory trafficking, despite the higher cellular abundance of CNX-ATZ complexes. CRT deficiency alters the distributions of ATZ-ER chaperone complexes, increasing ATZ-BiP binding and inclusion body (IB) formation, and reducing ATZ interactions with components required for ER-Golgi trafficking. These findings indicate a novel role for CRT in promoting the secretory trafficking of a polymerogenic protein. Inefficient secretory trafficking of ATZ in the absence of CRT is coincident with enhanced accumulation of ER-derived ATZ IBs.

2020-09-24 | PXD020562 | Pride

The delivery of alpha1-antitrypsin therapy through transdermal route: is this worse to explore?

Project description:Human α1-antitrypsin (AAT) is an abundant acute phase glycoprotein performing anti-protease, anti-apoptotic and immunomodulatory functions. Purified human plasma AAT used as a specific therapy for patients with lung emphysema and panniculitis due to inherited AAT deficiency, and it is beneficial in treating of other disorders. This therapy administered intravenously although other routes of administration are tested. Herein, we examined the transdermal application of native or recombinant AAT by using epiCS®, the 3D human epidermis equivalent reconstructed from human primary epidermal keratinocytes. Topically applied AAT protein (50µl, prepared in Hank`s balance solution, HBSS) freely diffused across epidermis layers in a concentration and time-dependent manner. We concluded that within 18 hours topically added 0.2 mg AAT well penetrates the stratum corneum and can be detected inside the cytosol of keratinocytes. Importantly, treatments with AAT did not induce obvious morphological changes in keratinocyte layers. Next, we supplemented culture medium with 100µg/ml of combined bacterial lipopolysaccharide (LPS) and peptidoglycan (PNG) mixture and incubated epiCS for 18h with or without the topical application of 0.2 mg AAT. Under these conditions, LPS/PNG triggered a strongly activation of epidermis model. Even though AAT exhibited a limited capacity to neutralize the effect of LPS/PNG, it lowered expression of IL-18 and IL-8, and preserved levels of filaggrin, an important protein for maintaining the epidermal barrier integrity. Our results suggest that the transdermal route for delivering AAT is worth exploration. If successful, this approach may offer easy-to-use therapy with AAT.

2020-05-21 | GSE150946 | GEO

Candida albicans: control vs. alpha1-antitrypsin (AAT) treatment

Project description:Transcriptional profiling of Candida albicans SC5314 comparing C. albicans grown in RPMI1640 or in RPMI1640 with 100ug/ml AAT. Goal was to determine the effects of AAT on global C. albicans gene expression.

2023-01-01 | GSE165326 | GEO

Expression data from transgenic mice (3 mo) inducibly expressing human alpha1-antitrypsin in the liver

Project description:In the classical form of α1antitrypsin deficiency a mutant protein accumulates in a polymerized form in the ER of liver cells causing liver damage and carcinogenesis by a gain-of-toxic function mechanism. Recent studies have indicated that the accumulation of mutant α1antitrypsin Z in the ER specifically activates the autophagic response but not the unfolded protein response and that autophagy plays a critical role in disposal of insoluble α1antitrypsin Z. In this study, we used genomic analysis of the liver in a novel transgenic mouse model with inducible expression to screen for changes in gene expression that would potentially define how the liver responds to accumulation of this mutant protein. Keywords: genomic analysis, alpha1-antitrypsin deficiency, comparative study, adult animals, inducible expression, liver specific

2007-07-26 | GSE8599 | GEO

Alpha-1-antitrypsin binds to the glucocorticoid receptor with anti-inflammatory and anti-mycobacterial significance in macrophages

Project description:Alpha-1-antitrypsin (AAT), a serine protease inhibitor produced mainly by the liver, is the third most abundant protein in plasma. Individuals who possess homozygous Z-AAT genotype have severe AAT deficiency and are at risk for early-onset emphysema, bronchiectasis, cirrhosis, panniculitis, and vasculitis. While a canonical receptor for AAT has not been identified, AAT can be internalized into the cytoplasm and is known to affect gene regulation. Since AAT has significant anti-inflammatory properties affecting many cell types including macrophages, we examined whether AAT binds the cytoplasmic glucocorticoid receptor (GR) in macrophages. We report the novel finding that AAT binds to GR in macrophages using several approaches, including co-immunoprecipitation, mass spectrometry, microscale thermophoresis, and in silico molecular modeling. We further demonstrate that AAT induction of angiopoietin-like 4 protein and AAT inhibition of lipopolysaccharide-induced nuclear factor-kappa B activation and interleukin-8 production are mediated, in part, through AAT–GR interaction. Furthermore, this interaction contributes to a host-protective role against Mycobacterium tuberculosis in macrophages. The interaction of AAT and GR described in this study identifies a mechanism for the anti-inflammatory and host-protective properties of AAT.

2022-08-24 | PXD030989 | Pride

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