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1.
Sci Adv ; 9(31): eadg8694, 2023 08 04.
Artículo en Inglés | MEDLINE | ID: mdl-37540748

RESUMEN

The magnitude of CAR T cell expansion has been associated with clinical efficacy. Although cytokines can augment CAR T cell proliferation, systemically administered cytokines can result in toxicities. To gain the benefits of cytokine signaling while mitigating toxicities, we designed constitutively active synthetic cytokine receptor chimeras (constitutive Turbodomains) that signal in a CAR T cell-specific manner. The modular design of Turbodomains enables diverse cytokine signaling outputs from a single homodimeric receptor chimera and allows multiplexing of different cytokine signals. Turbodomains containing an IL-2/15Rß-derived signaling domain closely mimicked IL-15 signaling and enhanced CAR T cell potency. Allogeneic TurboCAR T cells targeting BCMA showed no evidence of aberrant proliferation yet displayed enhanced expansion and antitumor activity, prolonging survival and preventing extramedullary relapses in mouse models. These results illustrate the potential of constitutive Turbodomains to achieve selective potentiation of CAR T cells and demonstrate the safety and efficacy of allogeneic BCMA TurboCAR T cells, supporting clinical evaluation in multiple myeloma.


Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Receptores Quiméricos de Antígenos , Animales , Ratones , Receptores Quiméricos de Antígenos/genética , Inmunoterapia Adoptiva/métodos , Antígeno de Maduración de Linfocitos B , Recurrencia Local de Neoplasia , Linfocitos T , Citocinas
2.
Cancer Immunol Immunother ; 70(12): 3525-3540, 2021 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-33903974

RESUMEN

Immune checkpoint inhibitors (ICIs) have emerged as promising therapies for the treatment of cancer. However, existing ICIs, namely PD-(L)1 and CTLA-4 inhibitors, generate durable responses only in a subset of patients. TIGIT is a co-inhibitory receptor and member of the DNAM-1 family of immune modulating proteins. We evaluated the prevalence of TIGIT and its cognate ligand, PVR (CD155), in human cancers by assessing their expression in a large set of solid tumors. TIGIT is expressed on CD4+ and CD8+ TILs and is upregulated in tumors compared to normal tissues. PVR is expressed on tumor cells and tumor-associated macrophages from multiple solid tumors. We explored the therapeutic potential of targeting TIGIT by generating COM902, a fully human anti-TIGIT hinge-stabilized IgG4 monoclonal antibody that binds specifically to human, cynomolgus monkey, and mouse TIGIT, and disrupts the binding of TIGIT with PVR. COM902, either alone or in combination with a PVRIG (COM701) or PD-1 inhibitor, enhances antigen-specific human T cell responses in-vitro. In-vivo, a mouse chimeric version of COM902 in combination with an anti-PVRIG or anti-PD-L1 antibody inhibited tumor growth and increased survival in two syngeneic mouse tumor models. In summary, COM902 enhances anti-tumor immune responses and is a promising candidate for the treatment of advanced malignancies.


Asunto(s)
Anticuerpos Monoclonales/inmunología , Antígeno B7-H1/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Receptores de Superficie Celular/inmunología , Receptores Inmunológicos/inmunología , Transducción de Señal/inmunología , Animales , Línea Celular Tumoral , Proliferación Celular/fisiología , Femenino , Humanos , Inmunoglobulina G/inmunología , Inmunoterapia/métodos , Células Jurkat , Macaca fascicularis , Ratones , Ratones Endogámicos BALB C
3.
Mol Ther ; 28(10): 2237-2251, 2020 10 07.
Artículo en Inglés | MEDLINE | ID: mdl-32592688

RESUMEN

Patients with relapsed or refractory acute myeloid leukemia (AML) have a dismal prognosis and limited treatment options. Chimeric antigen receptor (CAR) T cells have achieved unprecedented clinical responses in patients with B cell leukemias and lymphomas and could prove highly efficacious in AML. However, a significant number of patients with AML may not receive treatment with an autologous product due to manufacturing failures associated with low lymphocyte counts or rapid disease progression while the therapeutic is being produced. We report the preclinical evaluation of an off-the-shelf CAR T cell therapy targeting Fms-related tyrosine kinase 3 (FLT3) for the treatment of AML. Single-chain variable fragments (scFvs) targeting various epitopes in the extracellular region of FLT3 were inserted into CAR constructs and tested for their ability to redirect T cell specificity and effector function to FLT3+ AML cells. A lead CAR, exhibiting minimal tonic signaling and robust activity in vitro and in vivo, was selected and then modified to incorporate a rituximab-responsive off-switch in cis. We found that allogeneic FLT3 CAR T cells, generated from healthy-donor T cells, eliminate primary AML blasts but are also active against mouse and human hematopoietic stem and progenitor cells, indicating risk of myelotoxicity. By employing a surrogate CAR with affinity to murine FLT3, we show that rituximab-mediated depletion of FLT3 CAR T cells after AML eradication enables bone marrow recovery without compromising leukemia remission. These results support clinical investigation of allogeneic FLT3 CAR T cells in AML and other FLT3+ hematologic malignancies.


Asunto(s)
Inmunoterapia Adoptiva , Leucemia Mieloide Aguda/inmunología , Leucemia Mieloide Aguda/terapia , Receptores Quiméricos de Antígenos/inmunología , Linfocitos T/inmunología , Tirosina Quinasa 3 Similar a fms/inmunología , Animales , Médula Ósea/inmunología , Médula Ósea/metabolismo , Modelos Animales de Enfermedad , Humanos , Inmunoterapia Adoptiva/efectos adversos , Inmunoterapia Adoptiva/métodos , Leucemia Mieloide Aguda/diagnóstico , Ratones , Receptores Quiméricos de Antígenos/genética , Especificidad del Receptor de Antígeno de Linfocitos T , Linfocitos T/metabolismo , Resultado del Tratamiento , Ensayos Antitumor por Modelo de Xenoinjerto , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidores
4.
J Clin Invest ; 126(9): 3236-46, 2016 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-27482882

RESUMEN

ATP-binding cassette transporter G1 (ABCG1) promotes cholesterol accumulation and alters T cell homeostasis, which may contribute to progression of atherosclerosis. Here, we investigated how the selective loss of ABCG1 in T cells impacts atherosclerosis in LDL receptor-deficient (LDLR-deficient) mice, a model of the disease. In LDLR-deficient mice fed a high-cholesterol diet, T cell-specific ABCG1 deficiency protected against atherosclerotic lesions. Furthermore, T cell-specific ABCG1 deficiency led to a 30% increase in Treg percentages in aorta and aorta-draining lymph nodes (LNs) of these mice compared with animals with only LDLR deficiency. When Abcg1 was selectively deleted in Tregs of LDLR-deficient mice, we observed a 30% increase in Treg percentages in aorta and aorta-draining LNs and reduced atherosclerosis. In the absence of ABCG1, intracellular cholesterol accumulation led to downregulation of the mTOR pathway, which increased the differentiation of naive CD4 T cells into Tregs. The increase in Tregs resulted in reduced T cell activation and increased IL-10 production by T cells. Last, we found that higher ABCG1 expression in Tregs was associated with a higher frequency of these cells in human blood samples. Our study indicates that ABCG1 regulates T cell differentiation into Tregs, highlighting a pathway by which cholesterol accumulation can influence T cell homeostasis in atherosclerosis.


Asunto(s)
Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 1/metabolismo , Aterosclerosis/metabolismo , Linfocitos T CD4-Positivos/citología , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 1/genética , Adulto , Anciano , Anciano de 80 o más Años , Animales , Aorta/metabolismo , Diferenciación Celular , Proliferación Celular , Colesterol/metabolismo , Progresión de la Enfermedad , Femenino , Factores de Transcripción Forkhead/metabolismo , Humanos , Interleucina-10/metabolismo , Selectina L/metabolismo , Lipoproteínas/sangre , Ganglios Linfáticos/patología , Masculino , Microdominios de Membrana , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Persona de Mediana Edad , Fenotipo , Receptores de LDL/genética , Transducción de Señal , Linfocitos T Reguladores/citología
5.
Atherosclerosis ; 234(2): 265-9, 2014 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-24704628

RESUMEN

OBJECTIVE: Gammadelta (γδ) T cells are a subset of pro-inflammatory innate-like T lymphocytes that serve as a bridge between innate and adaptive immunity. γδ T cells are highly enriched in cholesterol compared to αß T cells. In this study, we aimed to identify the role of γδ T cells in atherosclerosis, a cholesterol and inflammation-driven disease. METHODS: We found that the percentages of γδ T cells are increased in ApoE(-/-) mice fed a Western diet. We generated TCRδ(-/-)ApoE(-/-) mice and fed them either rodent chow or a Western diet for ten weeks for the assessment of atherosclerosis. RESULTS: The atherosclerotic lesion size in diet-fed TCRδ(-/-)ApoE(-/-) mice was similar to that of diet-fed ApoE(-/-) mice. There were no differences in cytokine production or numbers of αß T cells in aorta of TCRδ(-/-)ApoE(-/-) mice. Plasma lipoprotein profiles were unchanged by the absence of γδ T cells. CONCLUSION: Our data suggest that γδ T cells do not contribute to early atherosclerotic plaque development.


Asunto(s)
Aorta/inmunología , Enfermedades de la Aorta/inmunología , Aterosclerosis/inmunología , Receptores de Antígenos de Linfocitos T gamma-delta/metabolismo , Subgrupos de Linfocitos T/inmunología , Animales , Aorta/metabolismo , Aorta/patología , Enfermedades de la Aorta/genética , Enfermedades de la Aorta/metabolismo , Enfermedades de la Aorta/patología , Apolipoproteínas E/deficiencia , Apolipoproteínas E/genética , Aterosclerosis/genética , Aterosclerosis/metabolismo , Aterosclerosis/patología , Citocinas/sangre , Dieta Occidental , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Lípidos/sangre , Masculino , Ratones Noqueados , Placa Aterosclerótica , Receptores de Antígenos de Linfocitos T gamma-delta/deficiencia , Receptores de Antígenos de Linfocitos T gamma-delta/genética , Factores de Riesgo , Subgrupos de Linfocitos T/metabolismo , Factores de Tiempo
6.
PLoS One ; 8(5): e63746, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23704936

RESUMEN

Gammadelta (γδ) T lymphocytes respond quickly upon antigen encounter to produce a cytokine response. In this study, we sought to understand how functions of γδ T cells are differentially regulated compared to αß T cells. We found that cholesterol, an integral component of the plasma membrane and a regulator of TCR signaling, is increased in γδ T cells compared to αß T cells, and modulates their function. Higher levels of activation markers, and increased lipid raft content in γδ cells suggest that γδ T cells are more activated. Cholesterol depletion effectively decreased lipid raft formation and activation of γδ T cells, indicating that increased cholesterol content contributes to the hyper-activated phenotype of γδ T cells, possibly through enhanced clustering of TCR signals in lipid rafts. TCR stimulation assays and western blotting revealed that instead of a lower TCR threshold, enhanced TCR signaling through ERK1/2 activation is likely the cause for high cholesterol-induced rapid activation and proliferation in γδ T cells. Our data indicate that cholesterol metabolism is differentially regulated in γδ T cells. The high intracellular cholesterol content leads to enhanced TCR signaling and increases activation and proliferation of γδ T cells.


Asunto(s)
Colesterol/metabolismo , Activación de Linfocitos/inmunología , Receptores de Antígenos de Linfocitos T gamma-delta/metabolismo , Linfocitos T/metabolismo , Animales , Proliferación Celular , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Espacio Intracelular/metabolismo , Activación de Linfocitos/genética , Microdominios de Membrana/metabolismo , Ratones , Ratones Endogámicos C57BL , Fenotipo , Fosforilación , Receptores de Antígenos de Linfocitos T alfa-beta/metabolismo , Linfocitos T/citología , Linfocitos T/enzimología
7.
Arterioscler Thromb Vasc Biol ; 32(1): 24-32, 2012 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-22015657

RESUMEN

OBJECTIVE: Lysophosphatidic acid (LPA) is a bioactive lipid molecule produced by the plasma lysophospholipase D enzyme autotaxin that is present at ≥100 nmol/L in plasma. Local administration of LPA promotes systemic arterial remodeling in rodents. To determine whether LPA contributes to remodeling of the pulmonary vasculature, we examined responses in mice with alterations in LPA signaling and metabolism. METHODS AND RESULTS: Enpp2(+/-) mice, which are heterozygous for the autotaxin-encoding gene and which have reduced expression of autotaxin/lysophospholipase D and approximately half normal plasma LPA, were hyperresponsive to hypoxia-induced vasoconstriction and remodeling, as evidenced by the development of higher right ventricular (RV) systolic pressure, greater decline in peak flow velocity across the pulmonary valve, and a higher percentage of muscularized arterioles. Mice lacking LPA(1) and LPA(2), 2 LPA receptors abundantly expressed in the vasculature, also had enhanced hypoxia-induced pulmonary remodeling. With age, Lpar1(-/-)2(-/-) mice spontaneously developed elevated RV systolic pressure and RV hypertrophy that was not observed in Lpar1(-/-) mice or Lpar2(-/-) mice. Expression of endothelin-1, a potent vasoconstrictor, was elevated in lungs of Lpar1(-/-)2(-/-) mice, and expression of endothelin(B) receptor, which promotes vasodilation and clears endothelin, was reduced in Enpp2(+/-) and Lpar1(-/-)2(-/-) mice. CONCLUSIONS: Our findings indicate that LPA may negatively regulate pulmonary vascular pressure through LPA(1) and LPA(2) receptors and that in the absence of LPA signaling, upregulation in the endothelin system favors remodeling.


Asunto(s)
Hipoxia/patología , Hipoxia/fisiopatología , Lisofosfolípidos/fisiología , Arteria Pulmonar/patología , Arteria Pulmonar/fisiopatología , Animales , Presión Sanguínea/fisiología , Endotelina-1/fisiología , Hipertensión Pulmonar/etiología , Hipertensión Pulmonar/patología , Hipertensión Pulmonar/fisiopatología , Hipertrofia Ventricular Derecha/etiología , Hipertrofia Ventricular Derecha/patología , Hipertrofia Ventricular Derecha/fisiopatología , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Hidrolasas Diéster Fosfóricas/deficiencia , Hidrolasas Diéster Fosfóricas/genética , Hidrolasas Diéster Fosfóricas/fisiología , Receptores del Ácido Lisofosfatídico/deficiencia , Receptores del Ácido Lisofosfatídico/genética , Receptores del Ácido Lisofosfatídico/fisiología , Transducción de Señal
8.
Biochim Biophys Acta ; 1781(9): 563-70, 2008 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-18586114

RESUMEN

The bioactive lipid mediator lysophosphatidic acid (LPA) exerts a range of effects on the cardiovasculature that suggest a role in a variety of critical cardiovascular functions and clinically important cardiovascular diseases. LPA is an activator of platelets from a majority of human donors identifying a possible role as a regulator of acute thrombosis and platelet function in atherogenesis and vascular injury responses. Of particular interest in this context, LPA is an effective phenotypic modulator of vascular smooth muscle cells promoting the de-differentiation, proliferation and migration of these cells that are required for the development of intimal hyperplasia. Exogenous administration of LPA results in acute and systemic changes in blood pressure in different animal species, suggesting a role for LPA in both normal blood pressure regulation and hypertension. Advances in our understanding of the molecular machinery responsible for the synthesis, actions and inactivation of LPA now promise to provide the tools required to define the role of LPA in cardiovascular physiology and disease. In this review we discuss aspects of LPA signaling in the cardiovasculature focusing on recent advances and attempting to highlight presently unresolved issues and promising avenues for further investigation.


Asunto(s)
Enfermedades Cardiovasculares/metabolismo , Fenómenos Fisiológicos Cardiovasculares , Lisofosfolípidos/metabolismo , Animales , Plaquetas/metabolismo , Enfermedades Cardiovasculares/inmunología , Enzimas/metabolismo , Humanos , Leucocitos/inmunología
9.
Arterioscler Thromb Vasc Biol ; 28(3): 555-61, 2008 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-18202325

RESUMEN

OBJECTIVE: The bioactive lipid lysophosphatidic acid (LPA) stimulates platelet actin reorganization, adhesion, shape change, and aggregation. LPA is present in blood and exposure or release of LPA after atherosclerotic plaque rupture has been proposed to trigger platelet thrombus formation. METHODS AND RESULTS: In this report, we characterize heterogeneity in LPA responses among individuals. Platelets isolated from approximately 20% of healthy donors consistently failed to aggregate in response to LPA. Our studies indicate that, rather than lacking stimulatory pathways, platelets from "nonresponsive" donors respond to LPA by triggering inhibitory pathway(s) to block platelet aggregation. Consistent with this observation, LPA-induced aggregation could be partially restored to "nonresponsive" platelets by pharmacological inhibition of cAMP generation. LPA "nonresponsiveness" may be related to heightened platelet expression of LPA receptor 4 and PPARgamma. Among 70 patients with stable coronary artery disease (CAD), only 1 (1.4%) was identified as an LPA nonresponder. Moreover, in 33 patients presenting for diagnostic catheterization, CAD was identified as having a bivariate association with platelet LPA responder/nonresponder status. CONCLUSIONS: Platelet LPA signaling may involve stimulatory and inhibitory pathways, with the inhibitory pathway predominating in approximately 20% of individuals. Diseases such as CAD that affect platelet reactivity may attenuate this inhibitory pathway in platelets.


Asunto(s)
Plaquetas/efectos de los fármacos , Enfermedad Coronaria/sangre , Lisofosfolípidos/farmacología , Activación Plaquetaria/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Factores de Edad , Anciano , Anciano de 80 o más Años , Plaquetas/citología , Enfermedad Coronaria/genética , Enfermedad Coronaria/fisiopatología , Humanos , Persona de Mediana Edad , Activación Plaquetaria/fisiología , Agregación Plaquetaria/efectos de los fármacos , Agregación Plaquetaria/fisiología , Reacción en Cadena de la Polimerasa , Receptores del Ácido Lisofosfatídico/metabolismo , Valores de Referencia , Factores de Riesgo , Sensibilidad y Especificidad , Factores Sexuales , Transducción de Señal/fisiología
10.
J Am Soc Nephrol ; 16(6): 1612-22, 2005 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-15814834

RESUMEN

GP135 is an apical membrane protein expressed in polarized MDCK epithelial cells. When cultured in three-dimensional collagen gel, MDCK cells form branching tubules in response to hepatocyte growth factor stimulation in a manner that simulates the embryonic renal development. During this process, GP135 displays transient loss of membranous localization but reappears at the cell surface when nascent lumen emerges from the developing tubules. Despite being used for decades as the canonical hallmark of apical surface, the molecular identity and the significance of the dynamic expression of GP135 during the tubulogenic process remain elusive. For exploring the function of GP135, the full-length cDNA encoding GP135 was obtained. Sequence alignments and features analysis confirm GP135 as a canine homolog of podocalyxin, confirming the finding of an earlier independent study. Immunohistochemical assays on canine kidney sections identified both glomerular and tubular distribution of GP135 along the nephron. Mutant MDCK cells expressing siRNA targeted at two regions of GP135 show defects in hepatocyte growth factor-induced tubulogenesis. Re-expression of full-length and an O-linked glycosylation abbreviated construct of GP135 could recapitulate the tubulogenesis process lacking in siRNA knockdown cells; however, a deletion construct devoid of the cytoplasmic domain failed to rescue the phenotype. In summary, the data identify the MDCK apical domain marker GP135 as a tubular form of podocalyxin and provide evidence for its importance in renal tubulogenesis.


Asunto(s)
Túbulos Renales/fisiología , Sialoglicoproteínas/fisiología , Animales , Línea Celular , Clonación Molecular , ADN Complementario , Perros , Células Epiteliales , Glicoproteínas de Membrana/fisiología , Ratones
11.
J Gene Med ; 6(12): 1403-13, 2004 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-15523716

RESUMEN

BACKGROUND: The tetracycline-regulated transcriptional silencer (tTS) has been demonstrated to mitigate leaky expression of the tetracycline-inducible promoter under uninduced condition, and, when conjugated with reverse-type tetracycline-controlled transactivator (rtTA), shows great promise for gene therapy. This effect was attributed to the effectiveness of tTS as a repressor of transcription at the tetracycline-regulated promoter. However, we observed an unexpected increase in transactivational activity by rtTA in the presence of tTS under inducible condition. METHODS: To explore the nature of this co-activational effect of tTS on rtTA, we examined the expression patterns of rtTA by Western blotting analysis of total cellular lysates or an enriched ubiquitinated pool of proteins under various conditions, including the one when proteasomal degradation is inhibited. RESULTS: We demonstrate tTS, in addition to its established role as a transcriptional silencer, can enhance rtTA expression level by salvaging rtTA from the ubiquitin-dependent proteasomal degradation pathway. Along with this finding, we also demonstrate that doxycycline, a commonly used tetracycline analogue, inhibits the susceptibility of rtTA to ubiquitin/proteasome-mediated degradation and enhances the expression level of rtTA. CONCLUSIONS: Taken together, our data establish an unappreciated role of doxycycline and tTS in tetracycline-regulated gene expression and the functionality of rtTA, and should shed light on the design of gene therapy vectors based on tetracycline-controlled transcriptional regulation systems.


Asunto(s)
Antibacterianos/farmacología , Doxiciclina/farmacología , Perfilación de la Expresión Génica , Regulación de la Expresión Génica/efectos de los fármacos , Silenciador del Gen , Terapia Genética/métodos , Elementos Silenciadores Transcripcionales , Tetraciclina/farmacología , Animales , Western Blotting , Perros , Vectores Genéticos , Immunoblotting , Riñón/citología , Luciferasas/análisis , Luciferasas/biosíntesis , Plásmidos , Regiones Promotoras Genéticas , Complejo de la Endopetidasa Proteasomal , Transactivadores , Ubiquitina/farmacología
12.
Am J Physiol Cell Physiol ; 285(3): C711-9, 2003 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-12736135

RESUMEN

Regulated expression systems are invaluable for studying gene function, offer advantages of dosage-dependent and temporally defined gene expression, and limit possible clonal variation when toxic or pleiotropic genes are overexpressed. Previously, establishment of inducible expression systems, such as tetracycline- and ecdysone-inducible systems, required assessment of the inducible characteristics of individual clones by tedious luciferase assays. Taking advantage of a green fluorescent protein (GFP) reporter controlled by tetracycline- or ecdysone-responsive element and fluorescence-activated cell sorting, we propose a simple and efficient strategy to select highly inducible cell lines according to their fluorescence profiles after transiently transfecting the candidate cell pools with a surrogate GFP reporter. We have demonstrated that tetracycline- and ecdysone-inducible systems could be set up in Madin-Darby canine kidney and HEK-293 cells by employing this selection scheme. Importantly, this dual regulatory expression system is applied in studying the complex interplay between two Ras-related small GTPases, Cdc42 and Rac1, on detachment-induced apoptosis. Furthermore, establishment of two tightly regulated expression systems in one target cell line could be of great advantage for dissecting small GTPase Rac1-transduced signaling pathways by using global gene expression approaches such as proteomic assays.


Asunto(s)
Ecdisona/farmacología , Biología Molecular/métodos , Tetraciclinas/farmacología , Proteína de Unión al GTP rac1/genética , Animales , Citometría de Flujo , Regulación de la Expresión Génica/efectos de los fármacos , Genes Reporteros , Proteínas Fluorescentes Verdes , Humanos , Indicadores y Reactivos/metabolismo , Riñón/citología , Proteínas Luminiscentes/genética , Proteómica , Transducción de Señal/genética , Proteína de Unión al GTP rac1/metabolismo
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