Self-Transducible Bimodal PDX1-FOXP3 Protein Lifts Insulin Secretion and Curbs Autoimmunity, Boosting Tregs in Type 1 Diabetic Mice

Amatya, Christina; Radichev, Ilian; Ellefson, Jacob; Williams, Mark S.; Savinov, Alexei Y.

doi:10.1016/j.ymthe.2017.08.014

Cited by 3 publications

(3 citation statements)

References 83 publications

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“…Each independent sample was normalized to the level of Gapdh , as this gene was not altered in R6/1 brains 20,23 . The following primer pair sequences were obtained from previous works: Gapdh (5′-CATGGACTGTGGTCATGAGCC-3′, 5′-CTTCACCACCATGGAGAAGGC-3′), Penk (5′-GGCGTGCACACTGGAATGT-3′, 5′-TCCCAGATTTTGAAAGAAGGCA-3′), Plk5 (5′-CACCTGTGTTTGCCTTTCCC-3′, 5′-TTTTGAGGTAAAGGGACAAGGTG-3′), Itpka (5′-TACACTCGGCTTTCGCATTG-3′, 5′-CAAAGACACGGGTCACTTGCT-3′), Rin1 (5′-GCGGCTGCCAGAAGCTAGT-3′, 5′-CCTGGAACATGAGCTCTGAGC-3′), Gabrd (5′-ATTGGAGGTGCTCCTGTGAAT-3′, 5′-CCATGTTTGCCTCTGAGATAT-3′), Pde10a (5′-TAACAATGCGAGTTGCTTCC-3′, 5′-CAGCCACTTTTCCACAGTCTC-3′), Nfya (5′-ACAAGGGACGGTCACTGTGAC-3′, 5′-TTTGGATAGCAGGCACAGAGC-3′), Bcl2 (5′-CACACCTGGATCCAGGATAAC-3′, 5′-GAGAAATCAAACAGAGGTCGCA-3′) 20,23,24 , Gfap (5′-GGACAACTTTGCACAGGACCTC-3′, 5′-TCCAAATCCACACGAGCCA-3′), H2Q7/8/9 (5′-AGGAGCAGAATTACACATGCCA-3′, 5′-CGCCATGTTGGAGAGAGTGTAT-3′) 53 , Arg1 (5′-TGGCTTGCGAGACGTAGAC-3′, 5′-GCTCAGGTGAATCGGCCTTTT-3′) 54 , Bax (5′-TGAAGACAGGGGCCTTTTTG-3′, 5′-AATTCGCCGGAGACACTCG-3′) 55 , Scn4b (5′-CATGGTTTAGTCCTCTGGCTTGG-3′, 5′-CACGGCCCACCACTGTATTG-3′) 56 , Tac1 (5′-ATGAAAATCCTCGTGGCCGT-3′, 5′-GTTCTGCATCGCGCTTCTTT-3′) 57 , and Mbd2 (5′-CCTTAGCAGTTTTGACTTCAGG-3′, 5′-TGGCAATGTTGTGTTCAGGT-3′) 58 . Other sequences were: Hsp90b1 (5′-GATGATCTCCCCCTCAATGTT-3′, 5′-ATATTCGTGCCGAACTCCTTC-3′), Nfyb (5′-GACAGCTACGTGGAGCCTCTG-3′, 5′-AGTCCATCTGTGGCGGAGAC-3′) and Trpc4 (5′-TGAGAAGGAAGCCAGAAAGCTTCG-3′, 5′-CCTTAACATTCTCCTCCGTCAAGCC-3′).…”

Section: Methodsmentioning

confidence: 99%

Transcriptional correlates of the pathological phenotype in a Huntington’s disease mouse model

Gallardo-Orihuela

Hervás-Corpión

Hierro-Bujalance

et al. 2019

Sci Rep

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Huntington disease (HD) is a fatal neurodegenerative disorder without a cure that is caused by an aberrant expansion of CAG repeats in exon 1 of the huntingtin (HTT) gene. Although a negative correlation between the number of CAG repeats and the age of disease onset is established, additional factors may contribute to the high heterogeneity of the complex manifestation of symptoms among patients. This variability is also observed in mouse models, even under controlled genetic and environmental conditions. To better understand this phenomenon, we analysed the R6/1 strain in search of potential correlates between pathological motor/cognitive phenotypical traits and transcriptional alterations. HD-related genes (e.g., Penk, Plk5, Itpka), despite being downregulated across the examined brain areas (the prefrontal cortex, striatum, hippocampus and cerebellum), exhibited tissue-specific correlations with particular phenotypical traits that were attributable to the contribution of the brain region to that trait (e.g., striatum and rotarod performance, cerebellum and feet clasping). Focusing on the striatum, we determined that the transcriptional dysregulation associated with HD was partially exacerbated in mice that showed poor overall phenotypical scores, especially in genes with relevant roles in striatal functioning (e.g., Pde10a, Drd1, Drd2, Ppp1r1b). However, we also observed transcripts associated with relatively better outcomes, such as Nfya (CCAAT-binding transcription factor NF-Y subunit A) plus others related to neuronal development, apoptosis and differentiation. In this study, we demonstrated that altered brain transcription can be related to the manifestation of HD-like symptoms in mouse models and that this can be extrapolated to the highly heterogeneous population of HD patients.

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Section: Methodsmentioning

confidence: 99%

Transcriptional correlates of the pathological phenotype in a Huntington’s disease mouse model

Gallardo-Orihuela

Hervás-Corpión

Hierro-Bujalance

et al. 2019

Sci Rep

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“…Several interventions have been developed based on this finding (40, 41). Amatya et al demonstrated the possibility of anti-T1D therapy by constructing a cell-permeable PDX1-FOXP3-TAT fusion protein (FP) to stabilize Tregs for the purpose of anti-autoimmune and insulin production (42). The protein was tested both in vitro and in vivo (nonobese diabetic mouse T1D model).…”

Section: Current Immunotherapy Strategiesmentioning

confidence: 99%

Autoimmune CD8+ T cells in type 1 diabetes: from single-cell RNA sequencing to T-cell receptor redirection

Yang,

Zhang,

Ding

et al. 2024

Front. Endocrinol.

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Type 1 diabetes (T1D) is an organ-specific autoimmune disease caused by pancreatic β cell destruction and mediated primarily by autoreactive CD8+ T cells. It has been shown that only a small number of stem cell-like β cell-specific CD8+ T cells are needed to convert normal mice into T1D mice; thus, it is likely that T1D can be cured or significantly improved by modulating or altering self-reactive CD8+ T cells. However, stem cell-type, effector and exhausted CD8+ T cells play intricate and important roles in T1D. The highly diverse T-cell receptors (TCRs) also make precise and stable targeted therapy more difficult. Therefore, this review will investigate the mechanisms of autoimmune CD8+ T cells and TCRs in T1D, as well as the related single-cell RNA sequencing (ScRNA-Seq), CRISPR/Cas9, chimeric antigen receptor T-cell (CAR-T) and T-cell receptor-gene engineered T cells (TCR-T), for a detailed and clear overview. This review highlights that targeting CD8+ T cells and their TCRs may be a potential strategy for predicting or treating T1D.

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“…2). 20 Contudo, não teve impacto no controlo da glicemia nestes ratinhos. Por fim, apenas existem estudos acerca da administração deste fator em modelos de ratinhos, pelo que estes resultados carecem de corroboração em pessoas com DM1.…”

Section: Alterações Nas Células Treg Na Dm1unclassified

The role of regulatory T cells in type 1 diabetes

Vieira¹,

Neves²,

Carvalho³

2021

Revista Portuguesa de Endocrinologia, Diabetes e Metabolismo

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A diabetes mellitus tipo 1 (DM1) é uma doença autoimune causada por um desequilíbrio entre as células T reguladoras (Treg), que controlam o mecanismo de tolerância imunológica, e os restantes subtipos de células T, que ao reagirem contra o próprio organismo levam à destruição das células beta dos ilhéus pancreáticos. A DM1 é uma das doenças crónicas mais comuns no mundo, com taxas de incidência e prevalência a aumentar a cada ano. Contudo, os tratamentos atualmente disponíveis para a DM1 não garantem a resolução da patologia, e por isso, atualmente, grande parte dos doentes evolui com o passar dos anos para complicações graves, o que aumenta a sua morbilidade e mortalidade. A medicina tem caminhado cada vez mais no sentido de personalizar os tratamentos dirigidos a cada patologia, e os estudos na área das doenças autoimunes, em particular da DM1, não são exceção. Terapêuticas dirigidas às alterações celulares observadas em doentes diabéticos estão em constante estudo e evolução, nomeadamente com foco no reequilíbrio da função das células Treg. Estas células expressam marcadores à superfície que as distinguem estruturalmente de todas as outras e que são essenciais para a sua ação imunossupressora. Por esta razão são também chamadas células CD4+ CD25+ CD127-FOXP3+. Estudos focados no papel que cada um destes marcadores desempenha na função das células Treg e, consequentemente, na progressão da DM1, são abordados nesta revisão, assim como o seu potencial uso no tratamento desta doença. Uma outra área de investigação promissora é o isolamento e expansão in vitro de células Treg de doentes com DM1, com fatores que potenciam o seu crescimento e eficácia, seguidamente introduzidas na circulação do doente, com o intuito de aumentar o número de células Treg capazes de combater o desequilíbrio autoimune subjacente. Neste sentido, têm também surgido vários estudos na procura de antigénios que marquem especificamente as células Treg que atuam no pâncreas, de modo a tornar o tratamento o mais dirigido possível para o local da doença. As várias técnicas atualmente desenvolvidas nesta área, assim como futuras recomendações e limitações das mesmas serão discutidas neste trabalho.

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Self-Transducible Bimodal PDX1-FOXP3 Protein Lifts Insulin Secretion and Curbs Autoimmunity, Boosting Tregs in Type 1 Diabetic Mice

Cited by 3 publications

References 83 publications

Transcriptional correlates of the pathological phenotype in a Huntington’s disease mouse model

Transcriptional correlates of the pathological phenotype in a Huntington’s disease mouse model

Autoimmune CD8+ T cells in type 1 diabetes: from single-cell RNA sequencing to T-cell receptor redirection

The role of regulatory T cells in type 1 diabetes

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