Faculty Bibliography
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119
Sonic Hedgehog Signaling Regulates Alveolarization During Postnatal Lung Development [Meeting Abstract]
ISI:000400372504570
ISSN: 1535-4970
CID: 2591162
American journal of respiratory cell & molecular biology. 2017:57(3):280-293.DOI: 10.1165/rcmb.2016-0268OC
Sonic Hedgehog Signaling Regulates Myofibroblast Function During Alveolar Septum Formation in Murine Postnatal Lung
Sonic Hedgehog (Shh) signaling regulates mesenchymal proliferation and differentiation during embryonic lung development. In the adult lung, Shh signaling maintains mesenchymal quiescence and is dysregulated in diseases such as IPF and COPD. Our previous data implicated a role for Shh in postnatal lung development. Here we report a detailed analysis of Shh signaling during murine postnatal lung development. We show that Shh pathway expression and activity during alveolarization (P0-P14) are distinct from those during maturation (P14-P24). This biphasic pattern is paralleled by the transient presence of Gli1+;alpha-smooth muscle actin (aSMA)+ myofibroblasts in the growing alveolar septal tips. Carefully-timed inhibition of Hedgehog (Hh) signaling during alveolarization defined mechanisms by which Shh influences the mesenchymal compartment. First, interruption of Hh signaling at earlier time points results in increased lung compliance and wall structure defects of increasing severity, ranging from moderately enlarged alveolar airspaces to markedly enlarged airspaces and fewer secondary septa. Second, Shh signaling is required for myofibroblast differentiation: Hh inhibition during early alveolarization almost completely eliminates Gli1+;aSMA+ cells at the septal tips, and Gli1-lineage tracing revealed that Gli1+ cells do not undergo apoptosis after Hh inhibition, but remain in the alveolar septa and are unable to express aSMA. Third, Shh signaling is vital to mesenchymal proliferation during alveolarization, as Hh inhibition decreased proliferation of Gli1+ cells and their progeny. Our study establishes Shh as a new alveolarization promoting factor that might be affected in perinatal lung diseases that are associated with impaired alveolarization.
PMCID:5625221
PMID: 28379718
ISSN: 1535-4989
CID: 2521512
Sonic Hedgehog (shh) Signaling Regulates Myofibroblast Function During Alveolar Septum Formation In Postnatal Lung [Meeting Abstract]
ISI:000390749601588
ISSN: 1535-4970
CID: 2414542
Implementation of tissue clearing, fluorescence labeling, and imaging via lightsheet as a cross-core collaborative service [Meeting Abstract]
Recent developments in tissue clearing methods have provided investigators with an invaluable tool for visualizing and mapping three dimensional macromolecular structures and processes. By implementing a routine protocol, based on the passive clarity technique (PACT) method, for tissue clearing, the Research Histopathology Core at NYU Langone Medical Center seeks to provide investigators with a reliable, customizable service in conjunction with the immunohistochemistry (IHC) and Microscopy Cores in order to produce results in the most efficient way possible for both the investigators and the cores. The PACT method of clearing allows visualization of endogenous fluorescence and immunofluorescence labeling performed by the Core, or both. Stabilization through transparent hydrogel cross-linking, followed by delipidation in an sodium dodecyl sulfate buffer, results in a clear tissue sample that remains structurally sound with proteins, nucleic acids, and any associated labels in place. The clearing buffer can also be modified to allow simultaneous decalcification of bone specimens. Final clearing is achieved in a refractive index matching solution (RIMS buffer) which also serves as the microscopy medium. Cleared and labeled tissue can then be imaged on the Microscopy Core's Zeiss lightsheet microscope, allowing multichannel fluorescence from a range of angles and Z-stacking. The lightsheet microscope excites and detects only one thin optical section of the specimen at a time, making three dimensional imaging exceptionally light efficient. By honing proficiency in tissue clearing via the PACT method and working in close collaboration with neighboring core labs, the Histopathology Core can increase its breadth of expertise while relieving investigators of the time and cost intensive burden of protocol development and training.
EMBASE:613792615
ISSN: 0147-8885
CID: 2396962
Methylation profiling of locally advanced rectal cancer (LARC): Exploration of potential predictive markers for neoadjuvant chemoradiation (NACR). [Meeting Abstract]
ISI:000378109600591
ISSN: 1527-7755
CID: 2169652
Netrin-1 is highly expressed and required in inflammatory infiltrates in wear particle-induced osteolysis
OBJECTIVE: Netrin-1 is a chemorepulsant and matrix protein expressed during and required for osteoclast differentiation, which also plays a role in inflammation by preventing macrophage egress. Because wear particle-induced osteolysis requires osteoclast-mediated destruction of bone, we hypothesised that blockade of Netrin-1 or Unc5b, a receptor for Netrin-1, may diminish this pathological condition. METHODS: C57BL/6 mice, 6-8 weeks old, had 3 mg of ultrahigh-molecular-weight polyethylene particles implanted over the calvaria and then received 10 microg of monoclonal antibodies for Netrin-1 or its receptors, Unc5b and deleted in colon cancer (DCC), injected intraperitoneally on a weekly basis. After 2 weeks, micro-computed tomography and histology analysis were performed. Netrin-1 expression was analysed in human tissue obtained following primary prosthesis implantation or after prosthesis revision for peri-implant osteolysis and aseptic implant loosening. RESULTS: Weekly injection of anti-Netrin-1 or anti-Unc5b-antibodies significantly reduced particle-induced bone pitting in calvaria exposed to wear particles (46+/-4% and 49+/-3% of control bone pitting, respectively, p<0.001) but anti-DCC antibody did not affect inflammatory osteolysis (80+/-7% of control bone pitting, p=ns). Anti-Netrin-1 or anti-Unc5b, but not anti-DCC, antibody treatment markedly reduced the inflammatory infiltrate and the number of tartrate resistance acid phosphatase (TRAP)-positive osteoclasts (7+/-1, 4+/-1 and 14+/-1 cells/high power field (hpf), respectively, vs 12+/-1 cells/hpf for control, p<0.001), with no significant changes in alkaline phosphatase-positive osteoblasts on bone-forming surfaces in any antibody-treated group. Netrin-1 immunostaining colocalised with CD68 staining for macrophages. The peri-implant tissues of patients undergoing prosthesis revision surgery showed an increase in Netrin-1 expression, whereas there was little Netrin-1 expression in soft tissues removed at the time of primary joint replacement. CONCLUSIONS: These results demonstrate a unique role for Netrin-1 in osteoclast biology and inflammation and may be a novel target for prevention/treatment of inflammatory osteolysis.
PMCID:5349296
PMID: 26452536
ISSN: 1468-2060
CID: 1794812
Expression Of Sonic Hedgehog Pathway Genes Is Different During Alveolarization And Maturation Phase In Postnatal Lung Development [Meeting Abstract]
ISI:000377582807337
ISSN: 1535-4970
CID: 2162152
Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture
The extent to which low-frequency (minor allele frequency (MAF) between 1-5%) and rare (MAF
PMCID:4755714
PMID: 26367794
ISSN: 1476-4687
CID: 1779142
American journal of respiratory cell & molecular biology. 2015:52(1):1-13.DOI: 10.1165/rcmb.2014-0132TR
Sonic Hedgehog Signaling in the Lung - from Development to Disease
Over the past two decades, the secreted protein sonic hedgehog (SHH) has emerged as a critical morphogen during embryonic lung development, regulating the interaction between epithelial and mesenchymal cell populations in both the airway and alveolar compartments. There is increasing evidence that the SHH pathway is active in adult lung diseases such as pulmonary fibrosis, asthma, chronic obstructive pulmonary disease (COPD) and lung cancer, which raises two questions: (1) what role does SHH signaling play in these diseases? (2) Is it a primary driver of the disease, or a response (perhaps beneficial) to the primary disturbance? In this review we aim to fill the gap between the well-studied period of embryonic lung development and the adult diseased lung by reviewing the HH pathway during the postnatal period, and in adult uninjured and injured lungs. We elucidate the similarities and differences in the epithelial-mesenchymal interplay during the fibrosis response to injury in lung compared to other organs, and present a critical appraisal of tools and agents available to evaluate HH signaling.
PMCID:4370254
PMID: 25068457
ISSN: 1044-1549
CID: 1089832
Genetic Suppression of Inflammation Blocks the Tumor-Promoting Effects of TGF-beta in Gastric Tissue
The contributions of TGF-beta signaling to cancer are complex but involve the inflammatory microenvironment as well as cancer cells themselves. In mice encoding a TGF-beta mutant that precludes its binding to the latent TGF-beta binding protein (Tgfb1-/C33S), we observed multiorgan inflammation and an elevated incidence of various types of gastrointestinal solid tumors due to impaired conversion of latent to active TGF-beta1. By genetically eliminating activators of latent TGF-beta, we further lowered the amount of TGF-beta, which enhanced tumor frequency and multiorgan inflammation. This model system was used to further investigate the relative contribution of TGF-beta1 to lymphocyte-mediated inflammation in gastrointestinal tumorigenesis. Toward this end, we generated Tgfb1-/C33S;Rag2-/- mice that lacked adaptive immune function, which eliminated tumor production. Analysis of tissue from Tgfb1-/C33S mice indicated decreased levels of P-Smad3 compared to wild type animals, whereas tissue from Tgfb1-/C33S;Rag2-/- mice had normal P-Smad3 levels. Inhibiting the inflammatory response normalized levels of IL-1beta and IL-6 and reduced tumor cell proliferation. Additionally, Tgfb1-/C33S;Rag2-/- mice exhibited reduced paracrine signaling in the epithelia, mediated by hepatocyte growth factor produced by gastric stroma. Together, our results indicate that many of the responses of the gastric tissue associated with decreased TGF-beta1 may be directly or indirectly affected by inflammatory processes, which accompany loss of TGF-beta1, rather than a direct effect of loss of the cytokine.
PMCID:4158836
PMID: 24590056
ISSN: 0008-5472
CID: 831432
