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1.
PLoS Biol ; 16(5): e2003663, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29813050

RESUMO

Sleep science is entering a new era, thanks to new data-driven analysis approaches that, combined with mouse gene-editing technologies, show a promise in functional genomics and translational research. However, the investigation of sleep is time consuming and not suitable for large-scale phenotypic datasets, mainly due to the need for subjective manual annotations of electrophysiological states. Moreover, the heterogeneous nature of sleep, with all its physiological aspects, is not fully accounted for by the current system of sleep stage classification. In this study, we present a new data-driven analysis approach offering a plethora of novel features for the characterization of sleep. This novel approach allowed for identifying several substages of sleep that were hidden to standard analysis. For each of these substages, we report an independent set of homeostatic responses following sleep deprivation. By using our new substages classification, we have identified novel differences among various genetic backgrounds. Moreover, in a specific experiment with the Zfhx3 mouse line, a recent circadian mutant expressing both shortening of the circadian period and abnormal sleep architecture, we identified specific sleep states that account for genotypic differences at specific times of the day. These results add a further level of interaction between circadian clock and sleep homeostasis and indicate that dissecting sleep in multiple states is physiologically relevant and can lead to the discovery of new links between sleep phenotypes and genetic determinants. Therefore, our approach has the potential to significantly enhance the understanding of sleep physiology through the study of single mutations. Moreover, this study paves the way to systematic high-throughput analyses of sleep.

2.
Sci Rep ; 7(1): 17765, 2017 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-29259298

RESUMO

Circadian clock is known to adapt to environmental changes and can significantly influence cognitive and physiological functions. In this work, we report specific behavioral, cognitive, and sleep homeostatic defects in the after hours (Afh) circadian mouse mutant, which is characterized by lengthened circadian period. We found that the circadian timing irregularities in Afh mice resulted in higher interval timing uncertainty and suboptimal decisions due to incapability of processing probabilities. Our phenotypic observations further suggested that Afh mutants failed to exhibit the necessary phenotypic plasticity for adapting to temporal changes at multiple time scales (seconds-to-minutes to circadian). These behavioral effects of Afh mutation were complemented by the specific disruption of the Per/Cry circadian regulatory complex in brain regions that govern food anticipatory behaviors, sleep, and timing. We derive statistical predictions, which indicate that circadian clock and sleep are complementary processes in controlling behavioral/cognitive performance during 24 hrs. The results of this study have pivotal implications for understanding how the circadian clock modulates sleep and behavior.

3.
Genetics ; 204(3): 1129-1138, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27672097

RESUMO

Abnormal feeding behavior is one of the main symptoms of Prader-Willi syndrome (PWS). By studying a PWS mouse mutant line, which carries a paternally inherited deletion of the small nucleolar RNA 116 (Snord116), we observed significant changes in working-for-food behavioral responses at various timescales. In particular, we report that PWS mutant mice show a significant delay compared to wild-type littermate controls in responding to both hour-scale and seconds-to-minutes-scale time intervals. This timing shift in mutant mice is associated with better performance in the working-for-food task, and results in better decision making in these mutant mice. The results of our study reveal a novel aspect of the organization of feeding behavior, and advance the understanding of the interplay between the metabolic functions and cognitive mechanisms of PWS.


Assuntos
Comportamento Alimentar , Síndrome de Prader-Willi/fisiopatologia , Animais , Tomada de Decisões , Camundongos , Camundongos Endogâmicos C57BL , Síndrome de Prader-Willi/genética , RNA Nucleolar Pequeno/genética , Tempo de Reação
4.
Sleep ; 39(3): 637-44, 2016 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-26446116

RESUMO

STUDY OBJECTIVES: Sleep-wake disturbances are often reported in Prader-Willi syndrome (PWS), a rare neurodevelopmental syndrome that is associated with paternally-expressed genomic imprinting defects within the human chromosome region 15q11-13. One of the candidate genes, prevalently expressed in the brain, is the small nucleolar ribonucleic acid-116 (SNORD116). Here we conducted a translational study into the sleep abnormalities of PWS, testing the hypothesis that SNORD116 is responsible for sleep defects that characterize the syndrome. METHODS: We studied sleep in mutant mice that carry a deletion of Snord116 at the orthologous locus (mouse chromosome 7) of the human PWS critical region (PWScr). In particular, we assessed EEG and temperature profiles, across 24-h, in PWScr (m+/p-) heterozygous mutants compared to wild-type littermates. High-resolution magnetic resonance imaging (MRI) was performed to explore morphoanatomical differences according to the genotype. Moreover, we complemented the mouse work by presenting two patients with a diagnosis of PWS and characterized by atypical small deletions of SNORD116. We compared the individual EEG parameters of patients with healthy subjects and with a cohort of obese subjects. RESULTS: By studying the mouse mutant line PWScr(m+/p-), we observed specific rapid eye movement (REM) sleep alterations including abnormal electroencephalograph (EEG) theta waves. Remarkably, we observed identical sleep/EEG defects in the two PWS cases. We report brain morphological abnormalities that are associated with the EEG alterations. In particular, mouse mutants have a bilateral reduction of the gray matter volume in the ventral hippocampus and in the septum areas, which are pivotal structures for maintaining theta rhythms throughout the brain. In PWScr(m+/p-) mice we also observed increased body temperature that is coherent with REM sleep alterations in mice and human patients. CONCLUSIONS: Our study indicates that paternally expressed Snord116 is involved in the 24-h regulation of sleep physiological measures, suggesting that it is a candidate gene for the sleep disturbances that most individuals with PWS experience.


Assuntos
Encéfalo/fisiopatologia , Síndrome de Prader-Willi/genética , Síndrome de Prader-Willi/fisiopatologia , RNA Nucleolar Pequeno/genética , Deleção de Sequência/genética , Sono/genética , Adulto , Animais , Encéfalo/patologia , Estudos de Casos e Controles , Ritmo Circadiano/genética , Estudos de Coortes , Eletroencefalografia , Feminino , Genótipo , Substância Cinzenta/patologia , Substância Cinzenta/fisiopatologia , Hipocampo/patologia , Hipocampo/fisiopatologia , Humanos , Masculino , Camundongos , Obesidade/fisiopatologia , Herança Paterna/genética , Sono REM/genética , Ritmo Teta
5.
Clin Cancer Res ; 21(24): 5499-5510, 2015 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-26272063

RESUMO

PURPOSE: PI3K pathway activation occurs in concomitance with RAS/BRAF mutations in colorectal cancer, limiting the sensitivity to targeted therapies. Several clinical studies are being conducted to test the tolerability and clinical activity of dual MEK and PI3K pathway blockade in solid tumors. EXPERIMENTAL DESIGN: In the present study, we explored the efficacy of dual pathway blockade in colorectal cancer preclinical models harboring concomitant activation of the ERK and PI3K pathways. Moreover, we investigated if TP53 mutation affects the response to this therapy. RESULTS: Dual MEK and mTORC1/2 blockade resulted in synergistic antiproliferative effects in cell lines bearing alterations in KRAS/BRAF and PIK3CA/PTEN. Although the on-treatment cell-cycle effects were not affected by the TP53 status, a marked proapoptotic response to therapy was observed exclusively in wild-type TP53 colorectal cancer models. We further interrogated two independent panels of KRAS/BRAF- and PIK3CA/PTEN-altered cell line- and patient-derived tumor xenografts for the antitumor response toward this combination of agents. A combination response that resulted in substantial antitumor activity was exclusively observed among the wild-type TP53 models (two out of five, 40%), but there was no such response across the eight mutant TP53 models (0%). Interestingly, within a cohort of 14 patients with colorectal cancer treated with these agents for their metastatic disease, two patients with long-lasting responses (32 weeks) had TP53 wild-type tumors. CONCLUSIONS: Our data support that, in wild-type TP53 colorectal cancer cells with ERK and PI3K pathway alterations, MEK blockade results in potent p21 induction, preventing apoptosis to occur. In turn, mTORC1/2 inhibition blocks MEK inhibitor-mediated p21 induction, unleashing apoptosis. Clin Cancer Res; 21(24); 5499-510. ©2015 AACR.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Mutação , Inibidores de Proteínas Quinases/farmacologia , Proteína Supressora de Tumor p53/genética , Animais , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Inibidor de Quinase Dependente de Ciclina p21/genética , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Modelos Animais de Doenças , Sinergismo Farmacológico , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , Feminino , Humanos , Alvo Mecanístico do Complexo 1 de Rapamicina , Alvo Mecanístico do Complexo 2 de Rapamicina , Camundongos , Complexos Multiproteicos/antagonistas & inibidores , Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/antagonistas & inibidores , Proteína Supressora de Tumor p53/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Proteína X Associada a bcl-2/metabolismo
6.
Philos Trans R Soc Lond B Biol Sci ; 369(1637): 20120471, 2014 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-24446504

RESUMO

Sleep homoeostasis refers to a process in which the propensity to sleep increases as wakefulness progresses and decreases as sleep progresses. Sleep is tightly organized around the circadian clock and is regulated by genetic and epigenetic mechanisms. The homoeostatic response of sleep, which is classically triggered by sleep deprivation, is generally measured as a rebound effect of electrophysiological measures, for example delta sleep. However, more recently, gene expression changes following sleep loss have been investigated as biomarkers of sleep homoeostasis. The genetic background of an individual may affect this sleep-dependent gene expression phenotype. In this study, we investigated whether parental genetic background differentially modulates the expression of genes following sleep loss. We tested the progeny of reciprocal crosses of AKR/J and DBA/2J mouse strains and we show a parent-of-origin effect on the expression of circadian, sleep and neuronal plasticity genes following sleep deprivation. Thus, we further explored, by in silico, specific functions or upstream mechanisms of regulation and we observed that several upstream mechanisms involving signalling pathways (i.e. DICER1, PKA), growth factors (CSF3 and BDNF) and transcriptional regulators (EGR2 and ELK4) may be differentially modulated by parental effects. This is the first report showing that a behavioural manipulation (e.g. sleep deprivation) in adult animals triggers specific gene expression responses according to parent-of-origin genomic mechanisms. Our study suggests that the same mechanism may be extended to other behavioural domains and that the investigation of gene expression following experimental manipulations should take seriously into account parent-of-origin effects.


Assuntos
Ritmo Circadiano/genética , Regulação da Expressão Gênica/fisiologia , Plasticidade Neuronal/genética , Privação do Sono/fisiopatologia , Análise de Variância , Animais , Ritmo Circadiano/fisiologia , Cruzamentos Genéticos , Padrões de Herança/genética , Padrões de Herança/fisiologia , Camundongos , Plasticidade Neuronal/fisiologia , Reação em Cadeia da Polimerase em Tempo Real , Especificidade da Espécie
7.
J Clin Invest ; 123(6): 2551-63, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23635776

RESUMO

The PI3K signaling pathway regulates diverse cellular processes, including proliferation, survival, and metabolism, and is aberrantly activated in human cancer. As such, numerous compounds targeting the PI3K pathway are currently being clinically evaluated for the treatment of cancer, and several have shown some early indications of efficacy in breast cancer. However, resistance against these agents, both de novo and acquired, may ultimately limit the efficacy of these compounds. Here, we have taken a systematic functional approach to uncovering potential mechanisms of resistance to PI3K inhibitors and have identified several genes whose expression promotes survival under conditions of PI3K/mammalian target of rapamycin (PI3K/mTOR) blockade, including the ribosomal S6 kinases RPS6KA2 (RSK3) and RPS6KA6 (RSK4). We demonstrate that overexpression of RSK3 or RSK4 supports proliferation upon PI3K inhibition both in vitro and in vivo, in part through the attenuation of the apoptotic response and upregulation of protein translation. Notably, the addition of MEK- or RSK-specific inhibitors can overcome these resistance phenotypes, both in breast cancer cell lines and patient-derived xenograft models with elevated levels of RSK activity. These observations provide a strong rationale for the combined use of RSK and PI3K pathway inhibitors to elicit favorable responses in breast cancer patients with activated RSK.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/enzimologia , Imidazóis/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Quinolinas/farmacologia , Proteínas Quinases S6 Ribossômicas 90-kDa/metabolismo , Aminopiridinas/farmacologia , Animais , Apoptose/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Sobrevivência Celular/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos , Sinergismo Farmacológico , Feminino , Expressão Gênica , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Células MCF-7 , Camundongos , Camundongos Nus , Terapia de Alvo Molecular , Morfolinas/farmacologia , Fases de Leitura Aberta , Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Proteínas Quinases S6 Ribossômicas 90-kDa/antagonistas & inibidores , Proteínas Quinases S6 Ribossômicas 90-kDa/genética , Transdução de Sinais , Transcriptoma , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Cancer Discov ; 2(11): 1036-47, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22915752

RESUMO

UNLABELLED: PARP inhibitors are active in tumors with defects in DNA homologous recombination (HR) due to BRCA1/2 mutations. The phosphoinositide 3-kinase (PI3K) signaling pathway preserves HR steady state. We hypothesized that in BRCA-proficient triple-negative breast cancer (TNBC), PI3K inhibition would result in HR impairment and subsequent sensitization to PARP inhibitors. We show in TNBC cells that PI3K inhibition leads to DNA damage, downregulation of BRCA1/2, gain in poly-ADP-ribosylation, and subsequent sensitization to PARP inhibition. In TNBC patient-derived primary tumor xenografts, dual PI3K and PARP inhibition with BKM120 and olaparib reduced the growth of tumors displaying BRCA1/2 downregulation following PI3K inhibition. PI3K-mediated BRCA downregulation was accompanied by extracellular signal-regulated kinase (ERK) phosphorylation. Overexpression of an active form of MEK1 resulted in ERK activation and downregulation of BRCA1, whereas the MEK inhibitor AZD6244 increased BRCA1/2 expression and reversed the effects of MEK1. We subsequently identified that the ETS1 transcription factor was involved in the ERK-dependent BRCA1/2 downregulation and that knockdown of ETS1 led to increased BRCA1/2 expression, limiting the sensitivity to combined BKM120 and olaparib in 3-dimensional culture. SIGNIFICANCE: Treatment options are limited for patients with TNBCs. PARP inhibitors have clinical activity restricted to a small subgroup of patients with BRCA mutations. Here, we show that PI3K blockade results in HR impairment and sensitization to PARP inhibition in TNBCs without BRCA mutations, providing a rationale to combine PI3K and PARP inhibitors in this indication. Our findings could greatly expand the number of patients with breast cancer that would benefit from therapy with PARP inhibitors. On the basis of our findings, a clinical trial with BKM120 and olaparib is being initiated in patients with TNBCs.


Assuntos
Proteína BRCA1/biossíntese , Proteína BRCA2/biossíntese , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/enzimologia , Inibidores Enzimáticos/uso terapêutico , Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Inibidores de Poli(ADP-Ribose) Polimerases , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Feminino , Humanos , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Poli(ADP-Ribose) Polimerases/genética , Poli(ADP-Ribose) Polimerases/metabolismo , Prognóstico , Transdução de Sinais
9.
Clin Cancer Res ; 18(9): 2603-12, 2012 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-22407832

RESUMO

PURPOSE: The PI3K/Akt/mTOR pathway is an attractive target in HER2-positive breast cancer that is refractory to anti-HER2 therapy. The hypothesis is that the suppression of this pathway results in sensitization to anti-HER2 agents. However, this combinatorial strategy has not been comprehensively tested in models of trastuzumab and lapatinib resistance. EXPERIMENTAL DESIGN: We analyzed in vitro cell viability and induction of apoptosis in five different cell lines resistant to trastuzumab and lapatinib. Inhibition of HER2/HER3 phosphorylation, PI3K/Akt/mTOR, and extracellular signal-regulated kinase (ERK) signaling pathways was evaluated by Western blotting. Tumor growth inhibition after treatment with lapatinib, INK-128, or the combination of both agents was evaluated in three different animal models: two cell-based xenograft models refractory to both trastuzumab and lapatinib and a xenograft derived from a patient who relapsed on trastuzumab-based therapy. RESULTS: The addition of lapatinib to INK-128 prevented both HER2 and HER3 phosphorylation induced by INK-128, resulting in inhibition of both PI3K/Akt/mTOR and ERK pathways. This dual blockade produced synergistic induction of cell death in five different HER2-positive cell lines resistant to trastuzumab and lapatinib. In vivo, both cell line-based and patient-derived xenografts showed exquisite sensitivity to the antitumor activity of the combination of lapatinib and INK-128, which resulted in durable tumor shrinkage and exhibited no signs of toxicity in these models. CONCLUSIONS: The simultaneous blockade of both PI3K/Akt/mTOR and ERK pathways obtained by combining lapatinib with INK-128 acts synergistically in inducing cell death and tumor regression in breast cancer models refractory to anti-HER2 therapy.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Proteínas/antagonistas & inibidores , Receptor ErbB-2/antagonistas & inibidores , Fatores de Transcrição/antagonistas & inibidores , Ensaios Antitumorais Modelo de Xenoenxerto , Animais , Anticorpos Monoclonais Humanizados/farmacologia , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Benzoxazóis/farmacologia , Western Blotting , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Ciclo Celular/efeitos dos fármacos , Sinergismo Farmacológico , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Humanos , Lapatinib , Alvo Mecanístico do Complexo 1 de Rapamicina , Camundongos , Camundongos Nus , Complexos Multiproteicos , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Proteínas/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Pirimidinas/farmacologia , Quinazolinas/farmacologia , Receptor ErbB-2/metabolismo , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo , Fatores de Transcrição/metabolismo , Trastuzumab , Células Tumorais Cultivadas
10.
Biochem Pharmacol ; 79(6): 853-63, 2010 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-19896469

RESUMO

The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a TNF superfamily member that is being considered as a new strategy in anticancer therapy because of its ability to induce apoptosis, alone or in combination with other stimuli, in many cancer cells. AMP-activated protein kinase (AMPK) is an evolutionarily conserved key regulator of cellular energy homeostasis that protects the cell from energy depletion and stress by activating several biochemical pathways that lead to the conservation, as well as generation, of ATP. Here we report that a number of AMPK activators, including the small molecule activator A-769662, markedly sensitize TRAIL-resistant breast cancer cells to TRAIL-induced apoptosis. However, silencing AMPKalpha1 expression with siRNA or over-expression of DN-AMPKalpha1 does not inhibit AICAR, glucose deprivation, phenformin or A-769662-induced sensitization to TRAIL. Furthermore, the expression of constitutively active AMPK subunits does not sensitize resistant breast cancer cells to TRAIL-induced apoptosis. The cellular FLICE-inhibitory proteins (cFLIP(L) and cFLIP(S)) were significantly down-regulated following exposure to AMPK activators through an AMPK-independent mechanism. Furthermore, in cells over-expressing cFLIP(L), sensitization to TRAIL by AMPK activators was markedly reduced. In summary, our results indicate that AMPK activators facilitate the activation by TRAIL of an apoptotic cell death program through a mechanism independent of AMPK and dependent on the down-regulation of cFLIP levels.


Assuntos
Adenilato Quinase/metabolismo , Neoplasias da Mama/tratamento farmacológico , Proteína Reguladora de Apoptosis Semelhante a CASP8 e FADD/metabolismo , Regulação para Baixo , Ativadores de Enzimas/farmacologia , Ligante Indutor de Apoptose Relacionado a TNF/farmacologia , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Apoptose , Proteína Reguladora de Apoptosis Semelhante a CASP8 e FADD/genética , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica/fisiologia , Inativação Gênica , Humanos , Subunidades Proteicas
11.
EMBO J ; 28(6): 677-85, 2009 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-19197243

RESUMO

The capacity of tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) to trigger apoptosis preferentially in cancer cells, although sparing normal cells, has motivated clinical development of TRAIL receptor agonists as anti-cancer therapeutics. The molecular mechanisms responsible for the differential TRAIL sensitivity of normal and cancer cells are, however, poorly understood. Here, we show a novel signalling pathway that activates cytoprotective autophagy in untransformed human epithelial cells treated with TRAIL. TRAIL-induced autophagy is mediated by the AMP-activated protein kinase (AMPK) that inhibits mammalian target of rapamycin complex 1, a potent inhibitor of autophagy. Interestingly, the TRAIL-induced AMPK activation is refractory to the depletion of the two known AMPK-activating kinases, LKB1 and Ca(2+)/calmodulin-dependent kinase kinase-beta, but depends on transforming growth factor-beta-activating kinase 1 (TAK1) and TAK1-binding subunit 2. As TAK1 and AMPK are ubiquitously expressed kinases activated by numerous cytokines and developmental cues, these data are most likely to have broad implications for our understanding of cellular control of energy homoeostasis as well as the resistance of untransformed cells against TRAIL-induced apoptosis.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Autofagia/efeitos dos fármacos , Citoproteção/efeitos dos fármacos , Células Epiteliais/citologia , Células Epiteliais/enzimologia , MAP Quinase Quinase Quinases/metabolismo , Ligante Indutor de Apoptose Relacionado a TNF/farmacologia , Animais , Mama/citologia , Quinase da Proteína Quinase Dependente de Cálcio-Calmodulina/metabolismo , Ativação Enzimática/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Humanos , Interleucina-1beta/farmacologia , Alvo Mecanístico do Complexo 1 de Rapamicina , Camundongos , Modelos Biológicos , Complexos Multiproteicos , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas , Epitélio Pigmentado da Retina/citologia , Serina-Treonina Quinases TOR , Fatores de Transcrição/antagonistas & inibidores
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