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1.
Circ Res ; 131(1): 109-126, 2022 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-35737757

RESUMO

Cardiovascular defects, injuries, and degenerative diseases often require surgical intervention and the use of implantable replacement material and conduits. Traditional vascular grafts made of synthetic polymers, animal and cadaveric tissues, or autologous vasculature have been utilized for almost a century with well-characterized outcomes, leaving areas of unmet need for the patients in terms of durability and long-term patency, susceptibility to infection, immunogenicity associated with the risk of rejection, and inflammation and mechanical failure. Research to address these limitations is exploring avenues as diverse as gene therapy, cell therapy, cell reprogramming, and bioengineering of human tissue and replacement organs. Tissue-engineered vascular conduits, either with viable autologous cells or decellularized, are the forefront of technology in cardiovascular reconstruction and offer many benefits over traditional graft materials, particularly in the potential for the implanted material to be adopted and remodeled into host tissue and thus offer safer, more durable performance. This review discusses the key advances and future directions in the field of surgical vascular repair, replacement, and reconstruction, with a focus on the challenges and expected benefits of bioengineering human tissues and blood vessels.


Assuntos
Sistema Cardiovascular , Engenharia Tecidual , Animais , Bioengenharia , Engenharia Biomédica , Prótese Vascular , Humanos
2.
Eur J Hum Genet ; 30(1): 7-12, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-33840813

RESUMO

Hearing loss (HL) is one of the most common sensory defects, of which X-linked nonsyndromic hearing loss (NSHL) accounts for only 1-2%. While a COL4A6 variant has been reported in a single Hungarian family with NSHL associated with inner ear malformation, causative role of COL4A6 variants and their phenotypic consequences in NSHL remain elusive. Here we report two families in which we identified a male member with X-linked HL. Each has inherited a rare hemizygous COL4A6 variant from their respective mothers, NM_001287758.1: c.3272 G > C (p.Gly1091Ala) and c.951 + 1 G > C. An in vitro minigene splicing assay revealed that c.951 + 1 G > T leads to skipping of exon 15, strongly suggesting a pathogenic role for this variant in the HL phenotype. The p.Gly1091Ala variant is classified as a variant of unknown significance based on the variant interpretation guidelines. This report provides evidence for variants in the COL4A6 gene resulting in X-linked NSHL. It highlights the importance of in-depth genetic studies in all family members in addition to the proband, especially in multiplex families, to determine the precise etiology of HL.


Assuntos
Colágeno Tipo IV/genética , Perda Auditiva Neurossensorial/genética , Feminino , Perda Auditiva Neurossensorial/patologia , Hemizigoto , Humanos , Masculino , Mutação de Sentido Incorreto , Linhagem
3.
J Med Chem ; 62(9): 4772-4778, 2019 05 09.
Artigo em Inglês | MEDLINE | ID: mdl-30973735

RESUMO

We describe the design of a set of inhibitors to investigate the relationship between cyclin G associated kinase (GAK) and epidermal growth factor receptor (EGFR) in chordoma bone cancers. These compounds were characterized both in vitro and using in cell target engagement assays. The most potent chordoma inhibitors were further characterized in a kinome-wide screen demonstrating narrow spectrum profiles. While we observed a direct correlation between EGFR and antiproliferative effects on chordoma, GAK inhibition appeared to have only a limited effect.


Assuntos
Antineoplásicos/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Aminoquinolinas/síntese química , Aminoquinolinas/metabolismo , Aminoquinolinas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cordoma/tratamento farmacológico , Desenho de Fármacos , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Células HEK293 , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Simulação de Acoplamento Molecular , Ligação Proteica , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Quinazolinas/síntese química , Quinazolinas/metabolismo , Quinazolinas/farmacologia
4.
Dev Cell ; 43(4): 403-417.e10, 2017 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-29161591

RESUMO

Invasive cells use small invadopodia to breach basement membrane (BM), a dense matrix that encases tissues. Following the breach, a large protrusion forms to clear a path for tissue entry by poorly understood mechanisms. Using RNAi screening for defects in Caenorhabditis elegans anchor cell (AC) invasion, we found that UNC-6(netrin)/UNC-40(DCC) signaling at the BM breach site directs exocytosis of lysosomes using the exocyst and SNARE SNAP-29 to form a large protrusion that invades vulval tissue. Live-cell imaging revealed that the protrusion is enriched in the matrix metalloprotease ZMP-1 and transiently expands AC volume by more than 20%, displacing surrounding BM and vulval epithelium. Photobleaching and genetic perturbations showed that the BM receptor dystroglycan forms a membrane diffusion barrier at the neck of the protrusion, which enables protrusion growth. Together these studies define a netrin-dependent pathway that builds an invasive protrusion, an isolated lysosome-derived membrane structure specialized to breach tissue barriers.


Assuntos
Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/metabolismo , Membrana Celular/metabolismo , Exocitose/fisiologia , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Lisossomos/metabolismo , Animais , Animais Geneticamente Modificados , Membrana Basal/metabolismo , Movimento Celular/fisiologia , Proteínas do Tecido Nervoso/metabolismo
5.
PLoS Genet ; 12(1): e1005786, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26765257

RESUMO

Invadopodia are specialized membrane protrusions composed of F-actin, actin regulators, signaling proteins, and a dynamically trafficked invadopodial membrane that drive cell invasion through basement membrane (BM) barriers in development and cancer. Due to the challenges of studying invasion in vivo, mechanisms controlling invadopodia formation in their native environments remain poorly understood. We performed a sensitized genome-wide RNAi screen and identified 13 potential regulators of invadopodia during anchor cell (AC) invasion into the vulval epithelium in C. elegans. Confirming the specificity of this screen, we identified the Rho GTPase cdc-42, which mediates invadopodia formation in many cancer cell lines. Using live-cell imaging, we show that CDC-42 localizes to the AC-BM interface and is activated by an unidentified vulval signal(s) that induces invasion. CDC-42 is required for the invasive membrane localization of WSP-1 (N-WASP), a CDC-42 effector that promotes polymerization of F-actin. Loss of CDC-42 or WSP-1 resulted in fewer invadopodia and delayed BM breaching. We also characterized a novel invadopodia regulator, gdi-1 (Rab GDP dissociation inhibitor), which mediates membrane trafficking. We show that GDI-1 functions in the AC to promote invadopodia formation. In the absence of GDI-1, the specialized invadopodial membrane was no longer trafficked normally to the invasive membrane, and instead was distributed to plasma membrane throughout the cell. Surprisingly, the pro-invasive signal(s) from the vulval cells also controls GDI-1 activity and invadopodial membrane trafficking. These studies represent the first in vivo screen for genes regulating invadopodia and demonstrate that invadopodia formation requires the integration of distinct cellular processes that are coordinated by an extracellular cue.


Assuntos
Proteínas de Caenorhabditis elegans/genética , Proteínas de Ciclo Celular/genética , Proteínas de Ligação ao GTP/genética , Inibidores de Dissociação do Nucleotídeo Guanina/genética , Neoplasias/genética , Podossomos/genética , Animais , Membrana Basal/crescimento & desenvolvimento , Caenorhabditis elegans/genética , Caenorhabditis elegans/crescimento & desenvolvimento , Proteínas de Caenorhabditis elegans/biossíntese , Proteínas de Ciclo Celular/biossíntese , Modelos Animais de Doenças , Matriz Extracelular/genética , Proteínas de Ligação ao GTP/biossíntese , Regulação da Expressão Gênica no Desenvolvimento , Inibidores de Dissociação do Nucleotídeo Guanina/biossíntese , Humanos , Neoplasias/patologia , Podossomos/patologia , Transdução de Sinais
6.
J Cell Biol ; 206(5): 619-33, 2014 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-25154398

RESUMO

The receptor deleted in colorectal cancer (DCC) directs dynamic polarizing activities in animals toward its extracellular ligand netrin. How DCC polarizes toward netrin is poorly understood. By performing live-cell imaging of the DCC orthologue UNC-40 during anchor cell invasion in Caenorhabditis elegans, we have found that UNC-40 clusters, recruits F-actin effectors, and generates F-actin in the absence of UNC-6 (netrin). Time-lapse analyses revealed that UNC-40 clusters assemble, disassemble, and reform at periodic intervals in different regions of the cell membrane. This oscillatory behavior indicates that UNC-40 clusters through a mechanism involving interlinked positive (formation) and negative (disassembly) feedback. We show that endogenous UNC-6 and ectopically provided UNC-6 orient and stabilize UNC-40 clustering. Furthermore, the UNC-40-binding protein MADD-2 (a TRIM family protein) promotes ligand-independent clustering and robust UNC-40 polarization toward UNC-6. Together, our data suggest that UNC-6 (netrin) directs polarized responses by stabilizing UNC-40 clustering. We propose that ligand-independent UNC-40 clustering provides a robust and adaptable mechanism to polarize toward netrin.


Assuntos
Proteínas de Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/fisiologia , Caenorhabditis elegans/citologia , Moléculas de Adesão Celular/metabolismo , Proteínas do Tecido Nervoso/fisiologia , Actinas/metabolismo , Animais , Caenorhabditis elegans/metabolismo , Polaridade Celular , Feminino , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Netrinas , Multimerização Proteica , Estabilidade Proteica , Transporte Proteico , Útero/citologia
7.
J Cell Biol ; 204(7): 1209-18, 2014 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-24662568

RESUMO

Invadopodia are protrusive, F-actin-driven membrane structures that are thought to mediate basement membrane transmigration during development and tumor dissemination. An understanding of the mechanisms regulating invadopodia has been hindered by the difficulty of examining these dynamic structures in native environments. Using an RNAi screen and live-cell imaging of anchor cell (AC) invasion in Caenorhabditis elegans, we have identified UNC-60A (ADF/cofilin) as an essential regulator of invadopodia. UNC-60A localizes to AC invadopodia, and its loss resulted in a dramatic slowing of F-actin dynamics and an inability to breach basement membrane. Optical highlighting indicated that UNC-60A disassembles actin filaments at invadopodia. Surprisingly, loss of unc-60a led to the accumulation of invadopodial membrane and associated components within the endolysosomal compartment. Photobleaching experiments revealed that during normal invasion the invadopodial membrane undergoes rapid recycling through the endolysosome. Together, these results identify the invadopodial membrane as a specialized compartment whose recycling to form dynamic, functional invadopodia is dependent on localized F-actin disassembly by ADF/cofilin.


Assuntos
Proteínas de Caenorhabditis elegans/fisiologia , Caenorhabditis elegans/citologia , Movimento Celular , Extensões da Superfície Celular/metabolismo , Proteínas dos Microfilamentos/fisiologia , Citoesqueleto de Actina/metabolismo , Actinas/metabolismo , Animais , Membrana Basal/metabolismo , Polaridade Celular , Endossomos/metabolismo , Lisossomos/metabolismo , Microscopia de Fluorescência , Multimerização Proteica , Transporte Proteico , Imagem com Lapso de Tempo
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