RESUMO
This study examines funding from the National Institutes of Health (NIH) to US dental institutions between 2005 and 2014 based on publicly available data from the NIH Research Portfolio Online Reporting Tools. Over the 10-y span, 56 US dental institutions received approximately $2.2 billion from 20 Institutes, Centers, and Offices at the NIH. The National Institute of Dental and Craniofacial Research (NIDCR) is the largest NIH supporter of dental institutions, having invested 70% of the NIH total, about $1.5 billion. The NIDCR is also the primary supporter of research training and career development, as it has invested $177 million, which represents 92% of the total NIH investment of $192 million. Over the past 10 y, about half of the NIDCR's extramural award dollars have gone to dental schools, while the NIH has invested about 1%. There has been an approximately 10% net decrease in extramural dollars awarded to dental institutions over the past decade; however, given the year-to-year variability in support to dental institutions, it is unclear if this net decline reflects a long-term trend. In addition, there was an overall reduction in the extramural dollars awarded by the NIDCR and by the NIH. For example, from 2005 to 2014, the total NIDCR budget for extramural research decreased by roughly 4%, which represents a decrease of $20 million to dental institutions. After adjusting for inflation, the decline in funding to dental institutions from the NIDCR and NIH was approximately 30%. Although the NIDCR and NIH continue to invest in dental institutions, if the current decline were to continue, it could negatively affect the research conducted at dental institutions. Therefore, we discuss opportunities for dental institutions to increase NIDCR and NIH support and improve their capacity for research, research training, and career development.
Assuntos
Pesquisa em Odontologia/economia , National Institutes of Health (U.S.) , Apoio à Pesquisa como Assunto/estatística & dados numéricos , Pesquisa em Odontologia/educação , Pesquisa em Odontologia/organização & administração , Pesquisa em Odontologia/estatística & dados numéricos , Educação em Odontologia/economia , Educação em Odontologia/organização & administração , Humanos , National Institute of Dental and Craniofacial Research (U.S.)/economia , National Institute of Dental and Craniofacial Research (U.S.)/organização & administração , National Institutes of Health (U.S.)/economia , National Institutes of Health (U.S.)/organização & administração , Apoio à Pesquisa como Assunto/economia , Apoio à Pesquisa como Assunto/organização & administração , Estados UnidosRESUMO
G proteins and their cognate G protein-coupled receptors (GPCRs) function as critical signal transduction molecules that regulate cell survival, proliferation, motility and differentiation. The aberrant expression and/or function of these molecules have been linked to the growth, progression and metastasis of various cancers. As such, the analysis of mutations in the genes encoding GPCRs, G proteins and their downstream targets provides important clues regarding how these signaling cascades contribute to malignancy. Recent genome-wide sequencing efforts have unveiled the presence of frequent mutations in GNA13, the gene encoding the G protein Gα13, in Burkitt's lymphoma and diffuse large B-cell lymphoma (DLBCL). We found that mutations in the downstream target of Gα13, RhoA, are also present in Burkitt's lymphoma and DLBCL. By multiple complementary approaches, we now show that that these cancer-specific GNA13 and RHOA mutations are inhibitory in nature, and that the expression of wild-type Gα13 in B-cell lymphoma cells with mutant GNA13 has limited impact in vitro but results in a remarkable growth inhibition in vivo. Thus, although Gα13 and RhoA activity has previously been linked to cellular transformation and metastatic potential of epithelial cancers, our findings support a tumor suppressive role for Gα13 and RhoA in Burkitt's lymphoma and DLBCL.
Assuntos
Linfoma de Burkitt/genética , Subunidades alfa G12-G13 de Proteínas de Ligação ao GTP/genética , Linfoma Difuso de Grandes Células B/genética , Mutação , Proteína rhoA de Ligação ao GTP/genética , Animais , Linfócitos B/metabolismo , Linfócitos B/patologia , Western Blotting , Linfoma de Burkitt/patologia , Linhagem Celular Tumoral , Análise Mutacional de DNA , Cães , Subunidades alfa G12-G13 de Proteínas de Ligação ao GTP/metabolismo , Células HEK293 , Humanos , Linfoma Difuso de Grandes Células B/patologia , Células Madin Darby de Rim Canino , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Microscopia Confocal , Transdução de Sinais/genética , Transplante Heterólogo , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , Proteína rhoA de Ligação ao GTP/metabolismoAssuntos
Linfócitos B/metabolismo , Metilação de DNA , Leucemia Linfocítica Crônica de Células B/enzimologia , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Fosfoproteínas Fosfatases/genética , Fosfoproteínas Fosfatases/metabolismo , Linfócitos B/citologia , Western Blotting , Estudos de Casos e Controles , Humanos , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/patologia , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Fosforilação , Regiões Promotoras Genéticas/genética , Proteína Quinase C/genética , Proteína Quinase C/metabolismo , Proteína Quinase C beta , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Estabilidade de RNA , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Receptores CXCR4/genética , Receptores CXCR4/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Tumorais CultivadasRESUMO
Chemokines are small, secreted proteins that bind to the chemokine receptor subfamily of class A G protein-coupled receptors. Collectively, these receptor-ligand pairs are responsible for diverse physiological responses including immune cell trafficking, development and mitogenic signaling, both in the context of homeostasis and disease. However, chemokines and their receptors are not isolated entities, but instead function in complex networks involving homo- and heterodimer formation as well as crosstalk with other signaling complexes. Here the functional consequences of chemokine receptor activity, from the perspective of both direct physical associations with other receptors and indirect crosstalk with orthogonal signaling pathways, are reviewed. Modulation of chemokine receptor activity through these mechanisms has significant implications in physiological and pathological processes, as well as drug discovery and drug efficacy. The integration of signals downstream of chemokine and other receptors will be key to understanding how cells fine-tune their response to a variety of stimuli, including therapeutics.
