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1.
Circulation ; 145(6): 448-464, 2022 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-35034472

RESUMO

BACKGROUND: The nuclear receptor Rev-erbα/ß, a key component of the circadian clock, emerges as a drug target for heart diseases, but the function of cardiac Rev-erb has not been studied in vivo. Circadian disruption is implicated in heart diseases, but it is unknown whether cardiac molecular clock dysfunction is associated with the progression of any naturally occurring human heart diseases. Obesity paradox refers to the seemingly protective role of obesity for heart failure, but the mechanism is unclear. METHODS: We generated mouse lines with cardiac-specific Rev-erbα/ß knockout (KO), characterized cardiac phenotype, conducted multi-omics (RNA-sequencing, chromatin immunoprecipitation sequencing, proteomics, and metabolomics) analyses, and performed dietary and pharmacological rescue experiments to assess the time-of-the-day effects. We compared the temporal pattern of cardiac clock gene expression with the cardiac dilation severity in failing human hearts. RESULTS: KO mice display progressive dilated cardiomyopathy and lethal heart failure. Inducible ablation of Rev-erbα/ß in adult hearts causes similar phenotypes. Impaired fatty acid oxidation in the KO myocardium, in particular, in the light cycle, precedes contractile dysfunctions with a reciprocal overreliance on carbohydrate utilization, in particular, in the dark cycle. Increasing dietary lipid or sugar supply in the dark cycle does not affect cardiac dysfunctions in KO mice. However, obesity coupled with systemic insulin resistance paradoxically ameliorates cardiac dysfunctions in KO mice, associated with rescued expression of lipid oxidation genes only in the light cycle in phase with increased fatty acid availability from adipose lipolysis. Inhibition of glycolysis in the light cycle and lipid oxidation in the dark cycle, but not vice versa, ameliorate cardiac dysfunctions in KO mice. Altered temporal patterns of cardiac Rev-erb gene expression correlate with the cardiac dilation severity in human hearts with dilated cardiomyopathy. CONCLUSIONS: The study delineates temporal coordination between clock-mediated anticipation and nutrient-induced response in myocardial metabolism at multi-omics levels. The obesity paradox is attributable to increased cardiac lipid supply from adipose lipolysis in the fasting cycle due to systemic insulin resistance and adiposity. Cardiac molecular chronotypes may be involved in human dilated cardiomyopathy. Myocardial bioenergetics downstream of Rev-erb may be a chronotherapy target in treating heart failure and dilated cardiomyopathy.


Assuntos
Ritmo Circadiano/fisiologia , Miocárdio/patologia , Obesidade/fisiopatologia , Animais , Relógios Circadianos , Cardiopatias , Humanos , Camundongos , Camundongos Knockout
2.
Am J Pathol ; 189(1): 200-213, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30339838

RESUMO

Acute lung injury and its more severe form, acute respiratory distress syndrome, are life-threatening respiratory disorders. Overwhelming pulmonary inflammation and endothelium disruption are commonly observed. Endothelial cells (ECs) are well recognized as key regulators in leukocyte adhesion and migration in response to bacterial infection. Prolyl hydroxylase domain (PHD)-2 protein, a major PHD in ECs, plays a critical role in intracellular oxygen homeostasis, angiogenesis, and pulmonary hypertension. However, its role in endothelial inflammatory response is unclear. We investigated the role of PHD2 in ECs during endotoxin-induced lung inflammatory responses with EC-specific PHD2 inducible knockout mice. On lipopolysaccharide challenge, PHD2 depletion in ECs attenuates lipopolysaccharide-induced increases of lung vascular permeability, edema, and inflammatory cell infiltration. Moreover, EC-specific PHD2 inducible knockout mice exhibit improved adherens junction integrity and endothelial barrier function. Mechanistically, PHD2 knockdown induces vascular endothelial cadherin in mouse lung microvascular primary endothelial cells. Moreover, PHD2 knockdown can increase hypoxia-inducible factor/vascular endothelial protein tyrosine phosphatase signaling and reactive oxygen species-dependent p38 activation, leading to the induction of vascular endothelial cadherin. Data indicate that PHD2 depletion prevents the formation of leaky vessels and edema by regulating endothelial barrier function. It provides direct in vivo evidence to suggest that PHD2 plays a pivotal role in vascular inflammation. The inhibition of endothelial PHD2 activity may be a new therapeutic strategy for acute inflammatory diseases.


Assuntos
Lesão Pulmonar Aguda/imunologia , Permeabilidade Capilar/efeitos dos fármacos , Endotélio Vascular/imunologia , Prolina Dioxigenases do Fator Induzível por Hipóxia/imunologia , Lipopolissacarídeos/toxicidade , Vasculite/imunologia , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/genética , Lesão Pulmonar Aguda/patologia , Células Epiteliais Alveolares/imunologia , Células Epiteliais Alveolares/patologia , Animais , Caderinas/genética , Caderinas/imunologia , Permeabilidade Capilar/genética , Permeabilidade Capilar/imunologia , Adesão Celular/efeitos dos fármacos , Adesão Celular/genética , Adesão Celular/imunologia , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Movimento Celular/imunologia , Células Endoteliais/imunologia , Células Endoteliais/patologia , Endotélio Vascular/patologia , Humanos , Prolina Dioxigenases do Fator Induzível por Hipóxia/genética , Inflamação/induzido quimicamente , Inflamação/genética , Inflamação/imunologia , Inflamação/patologia , Leucócitos/imunologia , Leucócitos/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/genética , Sistema de Sinalização das MAP Quinases/imunologia , Masculino , Camundongos , Camundongos Transgênicos , Proteínas Tirosina Fosfatases/genética , Proteínas Tirosina Fosfatases/imunologia , Estados Unidos , Vasculite/induzido quimicamente , Vasculite/genética , Vasculite/patologia , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/imunologia
3.
Am J Physiol Heart Circ Physiol ; 317(4): H793-H810, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31441691

RESUMO

Gravin, an A-kinase anchoring protein, is known to play a role in regulating key processes that lead to inflammation and atherosclerosis development, namely, cell migration, proliferation, and apoptosis. We investigated the role of gravin in the development of high-fat diet (HFD)-induced atherosclerosis and hyperlipidemia. Five-week-old male wild-type (WT) and gravin-t/t mice were fed a normal diet or an HFD for 16 wk. Gravin-t/t mice showed significantly lower liver-to-body-weight ratio, cholesterol, triglyceride, and very low-density lipoprotein levels in serum as compared with WT mice on HFD. Furthermore, there was less aortic plaque formation coupled with decreased lipid accumulation and liver damage, as the gravin-t/t mice had lower levels of serum alanine aminotransferase and aspartate aminotransferase. Additionally, gravin-t/t HFD-fed mice had decreased expression of liver 3-hydroxy-3-methyl-glutaryl-CoA reductase, an essential enzyme for cholesterol synthesis and lower fatty acid synthase expression. Gravin-t/t HFD-fed mice also exhibited inhibition of sterol regulatory element binding protein-2 (SREBP-2) expression, a liver transcription factor associated with the regulation of lipid transportation. In response to platelet-derived growth factor receptor treatment, gravin-t/t vascular smooth muscle cells exhibited lower intracellular calcium transients and decreased protein kinase A- and protein kinase C-dependent substrate phosphorylation, notably involving the Erk1/2 signaling pathway. Collectively, these results suggest the involvement of gravin-dependent regulation of lipid metabolism via the reduction of SREBP-2 expression. The absence of gravin-mediated signaling lowers blood pressure, reduces plaque formation in the aorta, and decreases lipid accumulation and damage in the liver of HFD mice. Through these processes, the absence of gravin-mediated signaling complex delays the HFD-induced hyperlipidemia and atherosclerosis.NEW & NOTEWORTHY The gravin scaffolding protein plays a key role in the multiple enzymatic pathways of lipid metabolism. We have shown for the first time the novel role of gravin in regulating the pathways related to the initiation and progression of atherosclerosis. Specifically, an absence of gravin-mediated signaling decreases the lipid levels (cholesterol, triglyceride, and VLDL) that are associated with sterol regulatory element binding protein-2 downregulation.


Assuntos
Proteínas de Ancoragem à Quinase A/deficiência , Aorta/metabolismo , Doenças da Aorta/prevenção & controle , Aterosclerose/prevenção & controle , Proteínas de Ciclo Celular/deficiência , Dieta Hiperlipídica , Hiperlipidemias/prevenção & controle , Lipídeos/sangue , Placa Aterosclerótica , Proteínas de Ancoragem à Quinase A/genética , Animais , Aorta/patologia , Doenças da Aorta/sangue , Doenças da Aorta/etiologia , Doenças da Aorta/genética , Aterosclerose/sangue , Aterosclerose/etiologia , Aterosclerose/genética , Proteínas de Ciclo Celular/genética , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Modelos Animais de Doenças , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Hidroximetilglutaril-CoA Redutases/genética , Hidroximetilglutaril-CoA Redutases/metabolismo , Hiperlipidemias/sangue , Hiperlipidemias/etiologia , Hiperlipidemias/genética , Fígado/enzimologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Músculo Liso Vascular/metabolismo , Fosforilação , Proteína Quinase C/metabolismo , Transdução de Sinais , Proteína de Ligação a Elemento Regulador de Esterol 2/genética , Proteína de Ligação a Elemento Regulador de Esterol 2/metabolismo
4.
Arterioscler Thromb Vasc Biol ; 37(8): 1524-1535, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28596374

RESUMO

OBJECTIVE: Bacterial endotoxin (lipopolysaccharide)-mediated sepsis involves dysregulated systemic inflammation, which injures the lung and other organs, often fatally. Vascular endothelial cells act as both targets and mediators of lipopolysaccharide-induced inflammatory responses. Dysfunction of endothelium results in increases of proinflammatory cytokine production and permeability leakage. BMPER (bone morphogenetic protein-binding endothelial regulator), an extracellular modulator of bone morphogenetic protein signaling, has been identified as a vital component in chronic endothelial inflammatory responses and atherosclerosis. However, it is unclear whether BMPER also regulates inflammatory response in an acute setting such as sepsis. To address this question, we investigated the role of BMPER during lipopolysaccharide-induced acute lung injury. APPROACH AND RESULTS: Mice missing 1 allele of BMPER (BMPER+/- mice used in the place of BMPER-/- mice that die at birth) were used for lipopolysaccharide challenge. Lipopolysaccharide-induced pulmonary inflammation and injury was reduced in BMPER+/- mice as shown by several measures, including survival rate, infiltration of inflammatory cells, edema, and production of proinflammatory cytokines. Mechanistically, we have demonstrated that BMPER is required and sufficient for the activation of nuclear factor of activated T cells c1. This BMPER-induced nuclear factor of activated T cells activation is coordinated by multiple signaling pathways, including bone morphogenetic protein-independent low-density lipoprotein receptor-related protein 1-extracellular signal-regulated kinase activation, calcineurin signaling, and low-density lipoprotein receptor-related protein 1ß-mediated nuclear factor 45 nuclear export in response to BMPER treatment. CONCLUSIONS: We conclude that BMPER plays a pivotal role in pulmonary inflammatory response, which provides new therapeutic options against sepsis shock. The new signaling pathway initiated by BMPER/low-density lipoprotein receptor-related protein 1 axis broadens our understanding about BMPER's role in vascular homeostasis.


Assuntos
Lesão Pulmonar Aguda/metabolismo , Proteínas de Transporte/metabolismo , Células Endoteliais/metabolismo , Endotoxinas , Pulmão/irrigação sanguínea , Pneumonia/metabolismo , Receptores de LDL/metabolismo , Transdução de Sinais , Proteínas Supressoras de Tumor/metabolismo , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/genética , Lesão Pulmonar Aguda/patologia , Animais , Apoptose , Permeabilidade Capilar , Proteínas de Transporte/genética , Células Cultivadas , Citocinas/metabolismo , Modelos Animais de Doenças , Células Endoteliais/patologia , Predisposição Genética para Doença , Haploinsuficiência , Mediadores da Inflamação/metabolismo , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade , Pulmão/metabolismo , Pulmão/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fatores de Transcrição NFATC/metabolismo , Proteína do Fator Nuclear 45/metabolismo , Fenótipo , Pneumonia/induzido quimicamente , Pneumonia/genética , Pneumonia/patologia , Interferência de RNA , Receptores de LDL/genética , Fatores de Tempo , Transfecção , Proteínas Supressoras de Tumor/genética
6.
Nat Commun ; 12(1): 1927, 2021 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-33772019

RESUMO

Accumulating evidence suggests that chronic inflammation of metabolic tissues plays a causal role in obesity-induced insulin resistance. Yet, how specific endothelial factors impact metabolic tissues remains undefined. Bone morphogenetic protein (BMP)-binding endothelial regulator (BMPER) adapts endothelial cells to inflammatory stress in diverse organ microenvironments. Here, we demonstrate that BMPER is a driver of insulin sensitivity. Both global and endothelial cell-specific inducible knockout of BMPER cause hyperinsulinemia, glucose intolerance and insulin resistance without increasing inflammation in metabolic tissues in mice. BMPER can directly activate insulin signaling, which requires its internalization and interaction with Niemann-Pick C1 (NPC1), an integral membrane protein that transports intracellular cholesterol. These results suggest that the endocrine function of the vascular endothelium maintains glucose homeostasis. Of potential translational significance, the delivery of BMPER recombinant protein or its overexpression alleviates insulin resistance and hyperglycemia in high-fat diet-fed mice and Leprdb/db (db/db) diabetic mice. We conclude that BMPER exhibits therapeutic potential for the treatment of diabetes.


Assuntos
Proteínas de Transporte/genética , Endotélio Vascular/metabolismo , Resistência à Insulina/genética , Transdução de Sinais/genética , Animais , Glicemia/metabolismo , Proteínas de Transporte/metabolismo , Células Cultivadas , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Intolerância à Glucose/genética , Células HEK293 , Humanos , Hiperinsulinismo/genética , Hiperinsulinismo/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína C1 de Niemann-Pick/genética , Proteína C1 de Niemann-Pick/metabolismo , Receptores para Leptina/genética , Receptores para Leptina/metabolismo
7.
Nat Commun ; 12(1): 5296, 2021 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-34489478

RESUMO

The vascular endothelium is present within metabolic organs and actively regulates energy metabolism. Here we show osteocalcin, recognized as a bone-secreted metabolic hormone, is expressed in mouse primary endothelial cells isolated from heart, lung and liver. In human osteocalcin promoter-driven green fluorescent protein transgenic mice, green fluorescent protein signals are enriched in endothelial cells lining aorta, small vessels and capillaries and abundant in aorta, skeletal muscle and eye of adult mice. The depletion of lipoprotein receptor-related protein 1 induces osteocalcin through a Forkhead box O -dependent pathway in endothelial cells. Whereas depletion of osteocalcin abolishes the glucose-lowering effect of low-density lipoprotein receptor-related protein 1 depletion, osteocalcin treatment normalizes hyperglycemia in multiple mouse models. Mechanistically, osteocalcin receptor-G protein-coupled receptor family C group 6 member A and insulin-like-growth-factor-1 receptor are in the same complex with osteocalcin and required for osteocalcin-promoted insulin signaling pathway. Therefore, our results reveal an endocrine/paracrine role of endothelial cells in regulating insulin sensitivity, which may have therapeutic implications in treating diabetes and insulin resistance through manipulating vascular endothelium.


Assuntos
Células Endoteliais/metabolismo , Endotélio Vascular/metabolismo , Glucose/metabolismo , Hiperglicemia/genética , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Osteocalcina/genética , Animais , Células Endoteliais/patologia , Endotélio Vascular/patologia , Proteína Forkhead Box O1/genética , Proteína Forkhead Box O1/metabolismo , Regulação da Expressão Gênica , Genes Reporter , Teste de Tolerância a Glucose , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Células HEK293 , Humanos , Hiperglicemia/metabolismo , Hiperglicemia/patologia , Insulina/metabolismo , Proteínas Substratos do Receptor de Insulina/genética , Proteínas Substratos do Receptor de Insulina/metabolismo , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/deficiência , Masculino , Camundongos , Camundongos Knockout , Osteoblastos/metabolismo , Osteoblastos/patologia , Osteocalcina/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor IGF Tipo 1/genética , Receptor IGF Tipo 1/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Transdução de Sinais
8.
Dis Model Mech ; 9(3): 335-45, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26935106

RESUMO

HIRA is the histone chaperone responsible for replication-independent incorporation of histone variant H3.3 within gene bodies and regulatory regions of actively transcribed genes, and within the bivalent promoter regions of developmentally regulated genes. The HIRA gene lies within the 22q11.2 deletion syndrome critical region; individuals with this syndrome have multiple congenital heart defects. Because terminally differentiated cardiomyocytes have exited the cell cycle, histone variants should be utilized for the bulk of chromatin remodeling. Thus, HIRA is likely to play an important role in epigenetically defining the cardiac gene expression program. In this study, we determined the consequence of HIRA deficiency in cardiomyocytes in vivo by studying the phenotype of cardiomyocyte-specific Hira conditional-knockout mice. Loss of HIRA did not perturb heart development, but instead resulted in cardiomyocyte hypertrophy and susceptibility to sarcolemmal damage. Cardiomyocyte degeneration gave way to focal replacement fibrosis and impaired cardiac function. Gene expression was widely altered in Hira conditional-knockout hearts. Significantly affected pathways included responses to cellular stress, DNA repair and transcription. Consistent with heart failure, fetal cardiac genes were re-expressed in the Hira conditional knockout. Our results suggest that transcriptional regulation by HIRA is crucial for cardiomyocyte homeostasis.


Assuntos
Cardiomegalia/metabolismo , Cardiomegalia/patologia , Proteínas de Ciclo Celular/deficiência , Chaperonas de Histonas/deficiência , Miócitos Cardíacos/metabolismo , Sarcolema/metabolismo , Sarcolema/patologia , Fatores de Transcrição/deficiência , Animais , Apoptose/genética , Cardiomegalia/genética , Cardiomegalia/fisiopatologia , Proteínas de Ciclo Celular/metabolismo , Proliferação de Células , Dano ao DNA/genética , Reparo do DNA/genética , Feto/metabolismo , Regulação da Expressão Gênica , Testes de Função Cardíaca , Chaperonas de Histonas/metabolismo , Camundongos Knockout , Miócitos Cardíacos/patologia , Especificidade de Órgãos , Estresse Oxidativo/genética , Reprodutibilidade dos Testes , Estresse Fisiológico/genética , Fatores de Transcrição/metabolismo , Transcriptoma/genética
9.
Front Physiol ; 6: 242, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26379556

RESUMO

The physiological consequences of aberrant Ca(2+) binding and exchange with cardiac myofilaments are not clearly understood. In order to examine the effect of decreasing Ca(2+) sensitivity of cTnC on cardiac function, we generated knock-in mice carrying a D73N mutation (not known to be associated with heart disease in human patients) in cTnC. The D73N mutation was engineered into the regulatory N-domain of cTnC in order to reduce Ca(2+) sensitivity of reconstituted thin filaments by increasing the rate of Ca(2+) dissociation. In addition, the D73N mutation drastically blunted the extent of Ca(2+) desensitization of reconstituted thin filaments induced by cTnI pseudo-phosphorylation. Compared to wild-type mice, heterozygous knock-in mice carrying the D73N mutation exhibited a substantially decreased Ca(2+) sensitivity of force development in skinned ventricular trabeculae. Kaplan-Meier survival analysis revealed that median survival time for knock-in mice was 12 weeks. Echocardiographic analysis revealed that knock-in mice exhibited increased left ventricular dimensions with thinner walls. Echocardiographic analysis also revealed that measures of systolic function, such as ejection fraction (EF) and fractional shortening (FS), were dramatically reduced in knock-in mice. In addition, knock-in mice displayed electrophysiological abnormalities, namely prolonged QRS and QT intervals. Furthermore, ventricular myocytes isolated from knock-in mice did not respond to ß-adrenergic stimulation. Thus, knock-in mice developed pathological features similar to those observed in human patients with dilated cardiomyopathy (DCM). In conclusion, our results suggest that decreasing Ca(2+) sensitivity of the regulatory N-domain of cTnC is sufficient to trigger the development of DCM.

10.
J Mol Biol ; 425(18): 3277-88, 2013 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-23806656

RESUMO

Protein kinase A (PKA) substrate phosphorylation is facilitated through its co-localization with its signaling partner by A-kinase anchoring proteins (AKAPs). mAKAP (muscle-selective AKAP) localizes PKA and its substrates such as phosphodiesterase-4D3 (PDE4D3), ryanodine receptor, and protein phosphatase 2A (PP2A) to the sarcoplasmic reticulum and perinuclear space. The genetic role of mAKAP, in modulating PKA/PDE4D3 molecular signaling during cardiac diseases, remains unclear. The purpose of this study was to examine the effects of naturally occurring mutations in human mAKAP on PKA and PDE4D3 signaling. We have recently identified potentially important human mAKAP coding non-synonymous polymorphisms located within or near key protein binding sites critical to ß-adrenergic receptor signaling. Three mutations (P1400S, S2195F, and L717V) were cloned and transfected into a mammalian cell line for the purpose of comparing whether those substitutions disrupt mAKAP binding to PKA or PDE4D3. Immunoprecipitation study of mAKAP-P1400S, a mutation located in the mAKAP-PDE4D3 binding site, displayed a significant reduction in binding to PDE4D3, with no significant changes in PKA binding or PKA activity. Conversely, mAKAP-S2195F, a mutation located in mAKAP-PP2A binding site, showed significant increase in both binding propensity to PKA and PKA activity. Additionally, mAKAP-L717V, a mutation flanking the mAKAP-spectrin repeat domain, exhibited a significant increase in PKA binding compared to wild type, but there was no change in PKA activity. We also demonstrate specific binding of wild-type mAKAP to PDE4D3. Binding results were demonstrated using immunoprecipitation and confirmed with surface plasmon resonance (Biacore-2000); functional results were demonstrated using activity assays, Ca(2+) measurements, and Western blot. Comparative analysis of the binding responses of mutations to mAKAP could provide important information about how these mutations modulate signaling.


Assuntos
Proteínas de Ancoragem à Quinase A/genética , Proteínas de Ancoragem à Quinase A/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Miocárdio/enzimologia , Proteínas de Ancoragem à Quinase A/química , Substituição de Aminoácidos/fisiologia , Animais , Sítios de Ligação/genética , Células CHO , Cricetinae , Cricetulus , Células HEK293 , Humanos , Fosforilação/genética , Polimorfismo de Nucleotídeo Único/fisiologia , Ligação Proteica/genética , Domínios e Motivos de Interação entre Proteínas/genética , Domínios e Motivos de Interação entre Proteínas/fisiologia
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