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1.
Nature ; 545(7653): 224-228, 2017 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-28467822

RESUMO

Blood and lymphatic vasculatures are intimately involved in tissue oxygenation and fluid homeostasis maintenance. Assembly of these vascular networks involves sprouting, migration and proliferation of endothelial cells. Recent studies have suggested that changes in cellular metabolism are important to these processes. Although much is known about vascular endothelial growth factor (VEGF)-dependent regulation of vascular development and metabolism, little is understood about the role of fibroblast growth factors (FGFs) in this context. Here we identify FGF receptor (FGFR) signalling as a critical regulator of vascular development. This is achieved by FGF-dependent control of c-MYC (MYC) expression that, in turn, regulates expression of the glycolytic enzyme hexokinase 2 (HK2). A decrease in HK2 levels in the absence of FGF signalling inputs results in decreased glycolysis, leading to impaired endothelial cell proliferation and migration. Pan-endothelial- and lymphatic-specific Hk2 knockouts phenocopy blood and/or lymphatic vascular defects seen in Fgfr1/Fgfr3 double mutant mice, while HK2 overexpression partly rescues the defects caused by suppression of FGF signalling. Thus, FGF-dependent regulation of endothelial glycolysis is a pivotal process in developmental and adult vascular growth and development.


Assuntos
Células Endoteliais/citologia , Células Endoteliais/metabolismo , Fatores de Crescimento de Fibroblastos/metabolismo , Glicólise , Neovascularização Fisiológica , Transdução de Sinais , Animais , Movimento Celular , Proliferação de Células , Feminino , Hexoquinase/metabolismo , Linfangiogênese , Vasos Linfáticos/citologia , Vasos Linfáticos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Proto-Oncogênicas c-myc/metabolismo , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/deficiência , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/deficiência , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/metabolismo
2.
J Chem Inf Model ; 59(2): 673-688, 2019 02 25.
Artigo em Inglês | MEDLINE | ID: mdl-30642173

RESUMO

Chemical synthesis planning is a key aspect in many fields of chemistry, especially drug discovery. Recent implementations of machine learning and artificial intelligence techniques for retrosynthetic analysis have shown great potential to improve computational methods for synthesis planning. Herein, we present a multiscale, data-driven approach for retrosynthetic analysis with deep highway networks (DHN). We automatically extracted reaction rules (i.e., ways in which a molecule is produced) from a data set consisting of chemical reactions derived from U.S. patents. We performed the retrosynthetic reaction prediction task in two steps: first, we built a DHN model to predict which group of reactions (consisting of chemically similar reaction rules) was employed to produce a molecule. Once a reaction group was identified, a DHN trained on the subset of reactions within the identified reaction group, was employed to predict the transformation rule used to produce a molecule. To validate our approach, we predicted the first retrosynthetic reaction step for 40 approved drugs using our multiscale model and compared its predictive performance with a conventional model trained on all machine-extracted reaction rules employed as a control. Our multiscale approach showed a success rate of 82.9% at generating valid reactants from retrosynthetic reaction predictions. Comparatively, the control model trained on all machine-extracted reaction rules yielded a success rate of 58.5% on the validation set of 40 pharmaceutical molecules, indicating a significant statistical improvement with our approach to match known first synthetic reaction of the tested drugs in this study. While our multiscale approach was unable to outperform state-of-the-art rule-based systems curated by expert chemists, multiscale classification represents a marked enhancement in retrosynthetic analysis and can be easily adapted for use in a range of artificial intelligence strategies.


Assuntos
Quimioinformática/métodos , Aprendizado Profundo , Técnicas de Química Sintética , Bases de Dados de Produtos Farmacêuticos , Descoberta de Drogas , Patentes como Assunto , Estados Unidos
3.
J Proteome Res ; 14(2): 953-66, 2015 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-25476789

RESUMO

HERC2 is a large E3 ubiquitin ligase with multiple structural domains that has been implicated in an array of cellular processes. Mutations in HERC2 are linked to developmental delays and impairment caused by nervous system dysfunction, such as Angelman Syndrome and autism-spectrum disorders. However, HERC2 cellular activity and regulation remain poorly understood. We used a broad proteomic approach to survey the landscape of cellular proteins that interact with HERC2. We identified nearly 300 potential interactors, a subset of which we validated binding to HERC2. The potential HERC2 interactors included the eukaryotic translation initiation factor 3 complex, the intracellular transport COPI coatomer complex, the glycogen regulator phosphorylase kinase, beta-catenin, PI3 kinase, and proteins involved in fatty acid transport and iron homeostasis. Through a complex bioinformatic analysis of potential interactors, we linked HERC2 to cellular processes including intracellular protein trafficking and transport, metabolism of cellular energy, and protein translation. Given its size, multidomain structure, and association with various cellular activities, HERC2 may function as a scaffold to integrate protein complexes and bridge critical cellular pathways. This work provides a significant resource with which to interrogate HERC2 function more deeply and evaluate its contributions to mechanisms governing cellular homeostasis and disease.


Assuntos
Fatores de Troca do Nucleotídeo Guanina/metabolismo , Mapeamento de Interação de Proteínas/métodos , Proteoma/análise , Proteoma/metabolismo , Fatores de Troca do Nucleotídeo Guanina/análise , Humanos , Proteínas/análise , Proteínas/metabolismo , Proteínas/fisiologia , Proteômica , Ubiquitina-Proteína Ligases
4.
Cell Rep ; 43(1): 113622, 2024 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-38159274

RESUMO

While ATM loss of function has long been identified as the genetic cause of ataxia-telangiectasia (A-T), how it leads to selective and progressive degeneration of cerebellar Purkinje and granule neurons remains unclear. ATM expression is enriched in microglia throughout cerebellar development and adulthood. Here, we find evidence of microglial inflammation in the cerebellum of patients with A-T using single-nucleus RNA sequencing. Pseudotime analysis revealed that activation of A-T microglia preceded upregulation of apoptosis-related genes in granule and Purkinje neurons and that microglia exhibited increased neurotoxic cytokine signaling to granule and Purkinje neurons in A-T. To confirm these findings experimentally, we performed transcriptomic profiling of A-T induced pluripotent stem cell (iPSC)-derived microglia, which revealed cell-intrinsic microglial activation of cytokine production and innate immune response pathways compared to controls. Furthermore, A-T microglia co-culture with either control or A-T iPSC-derived neurons was sufficient to induce cytotoxicity. Taken together, these studies reveal that cell-intrinsic microglial activation may promote neurodegeneration in A-T.


Assuntos
Ataxia Telangiectasia , Humanos , Ataxia Telangiectasia/genética , Microglia/metabolismo , Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Neurônios/metabolismo , Citocinas/metabolismo
5.
Bioinformatics ; 28(5): 726-8, 2012 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-22247278

RESUMO

UNLABELLED: High-throughput technologies can identify genes whose expression profiles correlate with specific phenotypes; however, placing these genes into a biological context remains challenging. To help address this issue, we developed nested Expression Analysis Systematic Explorer (nEASE). nEASE complements traditional gene ontology enrichment approaches by determining statistically enriched gene ontology subterms within a list of genes based on co-annotation. Here, we overview an open-source software version of the nEASE algorithm. nEASE can be used either stand-alone or as part of a pathway discovery pipeline. AVAILABILITY: nEASE is implemented within the Multiple Experiment Viewer software package available at http://www.tm4.org/mev. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.


Assuntos
Algoritmos , Perfilação da Expressão Gênica/métodos , Software , Humanos , Neoplasias/genética , Análise de Sequência com Séries de Oligonucleotídeos , Vocabulário Controlado
7.
Dev Cell ; 10(6): 783-95, 2006 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-16740480

RESUMO

Branching morphogenesis is a key process in the formation of vascular networks. To date, little is known regarding the molecular events regulating this process. We investigated the involvement of synectin in this process. In zebrafish embryos, synectin knockdown resulted in a hypoplastic dorsal aorta and hypobranched, stunted, and thin intersomitic vessels due to impaired migration and proliferation of angioblasts and arterial endothelial cells while not affecting venous development. Synectin(-/-) mice demonstrated decreased body and organ size, reduced numbers of arteries, and an altered pattern of arterial branching in multiple vascular beds while the venous system remained normal. Murine synectin(-/-) primary arterial, but not venous, endothelial cells showed decreased in vitro tube formation, migration, and proliferation and impaired polarization due to abnormal localization of activated Rac1. We conclude that synectin is involved in selective regulation of arterial, but not venous, growth and branching morphogenesis and that Rac1 plays an important role in this process.


Assuntos
Artérias/embriologia , Artérias/crescimento & desenvolvimento , Morfogênese , Neuropeptídeos/deficiência , Proteínas de Peixe-Zebra/metabolismo , Peixe-Zebra/embriologia , Proteínas Adaptadoras de Transdução de Sinal , Animais , Artérias/anormalidades , Artérias/citologia , Proteínas de Transporte/química , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Movimento Celular , Proliferação de Células , Células Cultivadas , Embrião não Mamífero , Células Endoteliais/citologia , Células Endoteliais/fisiologia , Endotélio Vascular/citologia , Feminino , Artéria Femoral/citologia , Regulação da Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento , Camundongos , Camundongos Knockout , Miocárdio/citologia , Neuropeptídeos/genética , Gravidez , Veias Cavas/citologia , Proteínas de Peixe-Zebra/genética
8.
Patterns (N Y) ; 2(6): 100246, 2021 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-34179840

RESUMO

Recent advances in high-throughput genomic technologies coupled with exponential increases in computer processing and memory have allowed us to interrogate the complex molecular underpinnings of human disease from a genome-wide perspective. While the deluge of genomic information is expected to increase, a bottleneck in conventional high-performance computing is rapidly approaching. Inspired by recent advances in physical quantum processors, we evaluated several unconventional machine-learning (ML) strategies on actual human tumor data, namely "Ising-type" methods, whose objective function is formulated identical to simulated annealing and quantum annealing. We show the efficacy of multiple Ising-type ML algorithms for classification of multi-omics human cancer data from The Cancer Genome Atlas, comparing these classifiers to a variety of standard ML methods. Our results indicate that Ising-type ML offers superior classification performance with smaller training datasets, thus providing compelling empirical evidence for the potential future application of unconventional computing approaches in the biomedical sciences.

9.
J Clin Invest ; 130(3): 1233-1251, 2020 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-32039915

RESUMO

Smooth muscle cell (SMC) proliferation has been thought to limit the progression of thoracic aortic aneurysm and dissection (TAAD) because loss of medial cells associates with advanced disease. We investigated effects of SMC proliferation in the aortic media by conditional disruption of Tsc1, which hyperactivates mTOR complex 1. Consequent SMC hyperplasia led to progressive medial degeneration and TAAD. In addition to diminished contractile and synthetic functions, fate-mapped SMCs displayed increased proteolysis, endocytosis, phagocytosis, and lysosomal clearance of extracellular matrix and apoptotic cells. SMCs acquired a limited repertoire of macrophage markers and functions via biogenesis of degradative organelles through an mTOR/ß-catenin/MITF-dependent pathway, but were distinguishable from conventional macrophages by an absence of hematopoietic lineage markers and certain immune effectors even in the context of hyperlipidemia. Similar mTOR activation and induction of a degradative SMC phenotype in a model of mild TAAD due to Fbn1 mutation greatly worsened disease with near-uniform lethality. The finding of increased lysosomal markers in medial SMCs from clinical TAAD specimens with hyperplasia and matrix degradation further supports the concept that proliferation of degradative SMCs within the media causes aortic disease, thus identifying mTOR-dependent phenotypic modulation as a therapeutic target for combating TAAD.


Assuntos
Aorta/enzimologia , Aneurisma da Aorta Torácica/enzimologia , Dissecção Aórtica/enzimologia , Miócitos de Músculo Liso/enzimologia , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Dissecção Aórtica/genética , Dissecção Aórtica/patologia , Animais , Aorta/patologia , Aneurisma da Aorta Torácica/genética , Aneurisma da Aorta Torácica/patologia , Modelos Animais de Doenças , Lisossomos/enzimologia , Lisossomos/genética , Lisossomos/patologia , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Camundongos , Camundongos Knockout para ApoE , Fator de Transcrição Associado à Microftalmia/genética , Fator de Transcrição Associado à Microftalmia/metabolismo , Miócitos de Músculo Liso/patologia , Serina-Treonina Quinases TOR/genética , Proteína 1 do Complexo Esclerose Tuberosa/genética , Proteína 1 do Complexo Esclerose Tuberosa/metabolismo , beta Catenina/genética , beta Catenina/metabolismo
10.
Cell Stem Cell ; 26(4): 542-557.e11, 2020 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-32243809

RESUMO

The etiology of aortic aneurysms is poorly understood, but it is associated with atherosclerosis, hypercholesterolemia, and abnormal transforming growth factor ß (TGF-ß) signaling in smooth muscle. Here, we investigated the interactions between these different factors in aortic aneurysm development and identified a key role for smooth muscle cell (SMC) reprogramming into a mesenchymal stem cell (MSC)-like state. SMC-specific ablation of TGF-ß signaling in Apoe-/- mice on a hypercholesterolemic diet led to development of aortic aneurysms exhibiting all the features of human disease, which was associated with transdifferentiation of a subset of contractile SMCs into an MSC-like intermediate state that generated osteoblasts, chondrocytes, adipocytes, and macrophages. This combination of medial SMC loss with marked increases in non-SMC aortic cell mass induced exuberant growth and dilation of the aorta, calcification and ossification of the aortic wall, and inflammation, resulting in aneurysm development.


Assuntos
Aneurisma Aórtico , Músculo Liso Vascular , Animais , Aorta , Reprogramação Celular , Camundongos , Miócitos de Músculo Liso , Fator de Crescimento Transformador beta
11.
Genomics ; 91(6): 508-11, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18434084

RESUMO

A recent study published by Sjoblom and colleagues [T. Sjoblom, S. Jones, L.D. Wood, D.W. Parsons, J. Lin, T.D. Barber, D. Mandelker, R.J. Leary, J. Ptak, N. Silliman, S. Szabo, P. Buckhaults, C. Farrell, P. Meeh, S.D. Markowitz, J. Willis, D. Dawson, J.K. Willson, A.F. Gazdar, J. Hartigan, L. Wu, C. Liu, G. Parmigiani, B.H. Park, K.E. Bachman, N. Papadopoulos, B. Vogelstein, K.W. Kinzler, V.E. Velculescu, The consensus coding sequences of human breast and colorectal cancers. Science 314 (2006) 268-274.] performed comprehensive sequencing of 13,023 human genes and identified mutations in genes specific to breast and colorectal tumors, providing insight into organ-specific tumor biology. Here we present a systematic analysis of the functional classifications of Sjoblom's "CAN" genes, a subset of these validated mutant genes, that identifies novel organ-specific biological themes and molecular pathways associated with disease-specific etiology. This analysis links four somatically mutated genes associated with diverse oncological types to colorectal and breast cancers through established TGF-beta1-regulated interactions, revealing mechanistic differences in these cancers and providing potential diagnostic and therapeutic targets.


Assuntos
Neoplasias da Mama/genética , Neoplasias Colorretais/genética , Biologia Computacional , Genes Neoplásicos , Mutação , Neoplasias da Mama/metabolismo , Neoplasias Colorretais/metabolismo , Análise Mutacional de DNA , Regulação Neoplásica da Expressão Gênica , Humanos , Software , Fator de Crescimento Transformador beta1/metabolismo
12.
J Exp Med ; 216(8): 1874-1890, 2019 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-31196980

RESUMO

To define the role of ERK1/2 signaling in the quiescent endothelium, we induced endothelial Erk2 knockout in adult Erk1-/- mice. This resulted in a rapid onset of hypertension, a decrease in eNOS expression, and an increase in endothelin-1 plasma levels, with all mice dying within 5 wk. Immunostaining and endothelial fate mapping showed a robust increase in TGFß signaling leading to widespread endothelial-to-mesenchymal transition (EndMT). Fibrosis affecting the cardiac conduction system was responsible for the universal lethality in these mice. Other findings included renal endotheliosis, loss of fenestrated endothelia in endocrine organs, and hemorrhages. An ensemble computational intelligence strategy, comprising deep learning and probabilistic programing of RNA-seq data, causally linked the loss of ERK1/2 in HUVECs in vitro to activation of TGFß signaling, EndMT, suppression of eNOS, and induction of endothelin-1 expression. All in silico predictions were verified in vitro and in vivo. In summary, these data establish the key role played by ERK1/2 signaling in the maintenance of vascular normalcy.


Assuntos
Endotélio/metabolismo , Hipertensão/metabolismo , Sistema de Sinalização das MAP Quinases/genética , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Animais , Aprendizado Profundo , Modelos Animais de Doenças , Endotelina-1/metabolismo , Transição Epitelial-Mesenquimal/genética , Células Endoteliais da Veia Umbilical Humana , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/genética , Óxido Nítrico Sintase Tipo III/metabolismo , RNA-Seq , Transfecção , Fator de Crescimento Transformador beta/metabolismo
13.
Nat Metab ; 1(9): 912-926, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31572976

RESUMO

Atherosclerosis is a progressive vascular disease triggered by interplay between abnormal shear stress and endothelial lipid retention. A combination of these and, potentially, other factors leads to a chronic inflammatory response in the vessel wall, which is thought to be responsible for disease progression characterized by a buildup of atherosclerotic plaques. Yet molecular events responsible for maintenance of plaque inflammation and plaque growth have not been fully defined. Here we show that endothelial TGFß signaling is one of the primary drivers of atherosclerosis-associated vascular inflammation. Inhibition of endothelial TGFß signaling in hyperlipidemic mice reduces vessel wall inflammation and vascular permeability and leads to arrest of disease progression and regression of established lesions. These pro-inflammatory effects of endothelial TGFß signaling are in stark contrast with its effects in other cell types and identify it as an important driver of atherosclerotic plaque growth and show the potential of cell-type specific therapeutic intervention aimed at control of this disease.


Assuntos
Aterosclerose/metabolismo , Endotélio Vascular/metabolismo , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismo , Vasculite/metabolismo , Animais , Permeabilidade Capilar , Linhagem Celular , Progressão da Doença , Endotélio Vascular/patologia , Humanos , Camundongos , Camundongos Knockout , Fator de Crescimento Transformador beta/genética
14.
Science ; 359(6375): 555-559, 2018 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-29217584

RESUMO

It has long been hypothesized that aging and neurodegeneration are associated with somatic mutation in neurons; however, methodological hurdles have prevented testing this hypothesis directly. We used single-cell whole-genome sequencing to perform genome-wide somatic single-nucleotide variant (sSNV) identification on DNA from 161 single neurons from the prefrontal cortex and hippocampus of 15 normal individuals (aged 4 months to 82 years), as well as 9 individuals affected by early-onset neurodegeneration due to genetic disorders of DNA repair (Cockayne syndrome and xeroderma pigmentosum). sSNVs increased approximately linearly with age in both areas (with a higher rate in hippocampus) and were more abundant in neurodegenerative disease. The accumulation of somatic mutations with age-which we term genosenium-shows age-related, region-related, and disease-related molecular signatures and may be important in other human age-associated conditions.


Assuntos
Envelhecimento/genética , Reparo do DNA/genética , Taxa de Mutação , Doenças Neurodegenerativas/genética , Neurogênese/genética , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Síndrome de Cockayne/genética , Análise Mutacional de DNA , Feminino , Hipocampo/citologia , Hipocampo/embriologia , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Neurônios , Córtex Pré-Frontal/citologia , Córtex Pré-Frontal/embriologia , Análise de Célula Única , Sequenciamento Completo do Genoma , Xeroderma Pigmentoso/genética , Adulto Jovem
15.
J Clin Endocrinol Metab ; 103(7): 2601-2612, 2018 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-29726959

RESUMO

Context: The hypothalamic melanocortin 4 receptor (MC4R) pathway serves a critical role in regulating body weight. Loss of function (LoF) mutations in the MC4R pathway, including mutations in the pro-opiomelanocortin (POMC), prohormone convertase 1 (PCSK1), leptin receptor (LEPR), or MC4R genes, have been shown to cause early-onset severe obesity. Methods: Through a comprehensive epidemiological analysis of known and predicted LoF variants in the POMC, PCSK1, and LEPR genes, we sought to estimate the number of US individuals with biallelic MC4R pathway LoF variants. Results: We predict ~650 α-melanocyte-stimulating hormone (MSH)/POMC, 8500 PCSK1, and 3600 LEPR homozygous and compound heterozygous individuals in the United States, cumulatively enumerating >12,800 MC4R pathway-deficient obese patients. Few of these variants have been genetically diagnosed to date. These estimates increase when we include a small subset of less rare variants: ß-MSH/POMC,PCSK1 N221D, and a PCSK1 LoF variant (T640A). To further define the MC4R pathway and its potential impact on obesity, we tested associations between body mass index (BMI) and LoF mutation burden in the POMC, PCSK1, and LEPR genes in various populations. We show that the cumulative allele burden in individuals with two or more LoF alleles in one or more genes in the MC4R pathway are predisposed to a higher BMI than noncarriers or heterozygous LoF carriers with a defect in only one gene. Conclusions: Our analysis represents a genetically rationalized study of the hypothalamic MC4R pathway aimed at genetic patient stratification to determine which obese subpopulations should be studied to elucidate MC4R agonist (e.g., setmelanotide) treatment responsiveness.


Assuntos
Mutação com Perda de Função/genética , Obesidade/epidemiologia , Obesidade/genética , Receptor Tipo 4 de Melanocortina/genética , Transdução de Sinais/genética , Alelos , Fármacos Antiobesidade/farmacologia , Índice de Massa Corporal , Feminino , Heterozigoto , Homozigoto , Humanos , Masculino , Obesidade/tratamento farmacológico , Pró-Opiomelanocortina/genética , Pró-Proteína Convertase 1/genética , Receptor Tipo 4 de Melanocortina/agonistas , Receptores para Leptina/genética , Estados Unidos/epidemiologia , alfa-MSH/análogos & derivados , alfa-MSH/farmacologia
16.
Circulation ; 114(17): 1811-20, 2006 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-17043168

RESUMO

BACKGROUND: The development of collateral circulation plays an important role in protecting tissues from ischemic damage, and its stimulation has emerged as one of principal approaches to therapeutic angiogenesis. Clinical observations have documented substantial differences in the extent of collateralization among patients with coronary artery disease (CAD), with some individuals demonstrating marked abundance and others showing nearly complete absence of these vessels. Recent studies have suggested that circulating monocytes play a major role in collateral growth. The present study was undertaken to determine transcriptional profiles of circulating monocytes in CAD patients with different extents of collateral growth. METHODS AND RESULTS: Monocyte transcriptomes from CAD patients with and without collateral vessels were obtained by use of high-throughput expression profiling. Using a newly developed redundancy-based data mining method, we have identified a set of molecular markers characteristic of a "noncollateralgenic" phenotype. Moreover, we show that these transcriptional abnormalities are independent of the severity of CAD or any other known clinical parameter thought to affect collateral development and correlated with protein expression levels in monocytes and plasma. CONCLUSIONS: Monocyte transcription profiling identifies sets of patients with extensive versus poorly developed collateral circulation. Thus, genetic factors may heavily influence coronary collateral vessel growth in CAD and affect prognosis and response to therapeutic interventions.


Assuntos
Circulação Colateral/genética , Doença das Coronárias/fisiopatologia , Perfilação da Expressão Gênica , Monócitos/metabolismo , Idoso , Biomarcadores , Western Blotting , Comorbidade , Angiografia Coronária , Doença das Coronárias/diagnóstico por imagem , Doença das Coronárias/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Família Multigênica , Análise de Componente Principal , RNA Complementar/genética , Fatores de Risco , Transcrição Gênica
17.
Sleep Med ; 8(2): 160-8, 2007 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17275399

RESUMO

BACKGROUND: Obstructive sleep apnea (OSA) is characterized by repetitive nighttime obstructions of the upper airway that induce hypoxemia, hypercapnia, sympathetic activation, and arousals. This disorder induces cardiovascular autonomic imbalance and contributes to the development of hypertension. While the diagnostic and prognostic utility of exercise testing is well established in cardiology, the clinical utility of the exercise test in screening for OSA has not been carefully explored. To explore this potential application, we contrasted cardiopulmonary responses to exercise testing in patients recently diagnosed with OSA with apparently healthy counterparts of similar physical inactivity history, age, and body habitus. METHODS: Twenty-three normotensive overweight adults with OSA [apnea-hypopnea index (AHI)=24.7+/-13.5 events h(-1); body mass index (BMI)=33.1+/-5.5 kg m(-2); age=45.6+/-10.7 years] and nine apparently healthy controls of similar age and morphology (BMI=29.5+/-5.5 kg m(-2); age=40.2+/-8.1 years; AHI=4.9+/-0.1) completed a maximal ramping cardiopulmonary exercise tolerance test on a cycle ergometer. Measures included oxygen consumption (VO(2)pk), ventilation (V(E)), heart rate (HR), blood pressure (BP), cardiac output (Qc), and stroke volume (SV). RESULTS: Age, BMI, rest HR, rest BP, rest and exercise cardiac index (QI), rest and exercise stroke volume index (SVI), and V O(2)pk were not different between OSA patients and controls (p>0.05). Exercise heart rate was significantly lower and diastolic BP higher in the OSA group (p<0.05). In the physically active recovery (low-load pedaling), systolic BP recovery was delayed (p<0.05) in the OSA group while diastolic BP tended to remain higher (p=0.056). CONCLUSION: Patients with OSA have a distinctive response to graded exercise, characterized by a blunted HR response, markedly delayed systolic BP response in early recovery, and elevated diastolic BP in both exercise and early recovery. Clinical trials are justified to determine the clinical utility of graded exercise testing to independently inform clinical decision-making for triaging patients to diagnostic polysomnography.


Assuntos
Teste de Esforço , Sobrepeso/fisiologia , Apneia Obstrutiva do Sono/diagnóstico , Adulto , Sistema Nervoso Autônomo/fisiopatologia , Pressão Sanguínea/fisiologia , Índice de Massa Corporal , Débito Cardíaco/fisiologia , Feminino , Frequência Cardíaca/fisiologia , Humanos , Hipertensão/diagnóstico , Hipertensão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Oxigênio/sangue , Ventilação Pulmonar/fisiologia , Fatores de Risco , Apneia Obstrutiva do Sono/fisiopatologia , Volume Sistólico/fisiologia
18.
Nat Commun ; 8(1): 2149, 2017 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-29247167

RESUMO

Establishment of a functional vascular network is rate-limiting in embryonic development, tissue repair and engineering. During blood vessel formation, newly generated endothelial cells rapidly expand into primitive plexi that undergo vascular remodeling into circulatory networks, requiring coordinated growth inhibition and arterial-venous specification. Whether the mechanisms controlling endothelial cell cycle arrest and acquisition of specialized phenotypes are interdependent is unknown. Here we demonstrate that fluid shear stress, at arterial flow magnitudes, maximally activates NOTCH signaling, which upregulates GJA4 (commonly, Cx37) and downstream cell cycle inhibitor CDKN1B (p27). Blockade of any of these steps causes hyperproliferation and loss of arterial specification. Re-expression of GJA4 or CDKN1B, or chemical cell cycle inhibition, restores endothelial growth control and arterial gene expression. Thus, we elucidate a mechanochemical pathway in which arterial shear activates a NOTCH-GJA4-CDKN1B axis that promotes endothelial cell cycle arrest to enable arterial gene expression. These insights will guide vascular regeneration and engineering.


Assuntos
Pontos de Checagem do Ciclo Celular/genética , Conexinas/genética , Inibidor de Quinase Dependente de Ciclina p27/genética , Células Endoteliais da Veia Umbilical Humana/metabolismo , Receptor Notch1/genética , Animais , Artérias/metabolismo , Artérias/fisiologia , Células Cultivadas , Conexinas/metabolismo , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Feminino , Regulação da Expressão Gênica , Células Endoteliais da Veia Umbilical Humana/citologia , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neovascularização Fisiológica/genética , Receptor Notch1/metabolismo , Estresse Mecânico , Proteína alfa-4 de Junções Comunicantes
19.
Physiol Genomics ; 27(3): 380-90, 2006 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-16940428

RESUMO

Synectin (GIPC1), a receptor scaffold protein, has been isolated by our laboratory as a syndecan-4 cytoplasmic domain binding partner that regulates important aspects of cell motility (Gao Y, Li M, Chen W, Simons M. J Cell Physiol 184: 373-379, 2000; Tkachenko E, Elfenbein A, Tirziu D, Simons M. Circ Res 98: 1398-1404, 2006). Moreover, synectin plays a major role in arterial morphogenesis and in growth factor signaling in arterial endothelial cells by regulating Rac1 activity (Chittenden TW, Claes F, Lanahan AA, Autiero M, Palac RT, Tkachenko EV, Elfenbein A, Ruiz de Almodovar C, Dedkov E, Tomanek R, Li W, Westmore M, Singh J, Horowitz A, Mulligan-Kehoe MJ, Moodie KL, Zhuang ZW, Carmeliet P, Simons M. Dev Cell 10: 783-795, 2006). The present study was carried out to characterize changes in synectin-dependent gene expression induced by homozygous disruption of the gene in endothelial cells. Using a combination of suppression subtraction hybridization and high throughput microarray technology, we have identified aberrant biological processes of transcriptional regulation in synectin(-/-) primary endothelial cells including abnormal basal regulation of genes associated with development, cell organization and biogenesis, intracellular tracking, and cell adhesion. Analysis of gene expression following FGF2 treatment demonstrated significant abnormalities in transcription, cytoskeletal organization and biogenesis, and protein modification and transport in synectin(-/-) compared with synectin(+/+) endothelial cells. These results confirm synectin involvement in FGF2-dependent signal transduction and provide insights into synectin-dependent gene expression in the endothelium.


Assuntos
Proteínas de Transporte/genética , Proteínas de Transporte/fisiologia , Células Endoteliais/fisiologia , Regulação da Expressão Gênica , Neuropeptídeos/genética , Neuropeptídeos/fisiologia , Proteínas Adaptadoras de Transdução de Sinal , Animais , Adesão Celular , Separação Celular , Células Endoteliais/citologia , Regulação da Expressão Gênica/efeitos dos fármacos , Coração , Pulmão/citologia , Camundongos , Camundongos Knockout , Hibridização de Ácido Nucleico/métodos , Análise de Sequência com Séries de Oligonucleotídeos , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/farmacologia
20.
Sci Rep ; 6: 32249, 2016 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-27577089

RESUMO

Balance in the transcriptome is regulated by coordinated synthesis and degradation of RNA molecules. Here we investigated whether mammalian cell types intrinsically differ in global coordination of gene splicing and expression levels. We analyzed RNA-seq transcriptome profiles of 8 different purified mouse cell types. We found that different cell types vary in proportion of highly expressed genes and the number of alternatively spliced transcripts expressed per gene, and that the cell types that express more variants of alternatively spliced transcripts per gene are those that have higher proportion of highly expressed genes. Cell types segregated into two clusters based on high or low proportion of highly expressed genes. Biological functions involved in negative regulation of gene expression were enriched in the group of cell types with low proportion of highly expressed genes, and biological functions involved in regulation of transcription and RNA splicing were enriched in the group of cell types with high proportion of highly expressed genes. Our findings show that cell types differ in proportion of highly expressed genes and the number of alternatively spliced transcripts expressed per gene, which represent distinct properties of the transcriptome and may reflect intrinsic differences in global coordination of synthesis, splicing, and degradation of RNA molecules.


Assuntos
Processamento Alternativo , Transcriptoma , Animais , Células Cultivadas , Células Endoteliais/fisiologia , Regulação da Expressão Gênica , Camundongos Transgênicos , Neuroglia/fisiologia , Neurônios/fisiologia , Análise de Sequência de RNA
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