A5087420789- Cell death mechanisms and regulation
- DNA Repair Mechanisms
- Hearing, Cochlea, Tinnitus, Genetics
- Zebrafish Biomedical Research Applications
- Developmental Biology and Gene Regulation
- Congenital heart defects research
- Microtubule and mitosis dynamics
- Signaling Pathways in Disease
- Ion Channels and Receptors
- Genetics and Neurodevelopmental Disorders
- Neuroblastoma Research and Treatments
- Ubiquitin and proteasome pathways
- Cancer-related Molecular Pathways
- Immune Response and Inflammation
- Epigenetics and DNA Methylation
- CRISPR and Genetic Engineering
- NF-κB Signaling Pathways
- Peptidase Inhibition and Analysis
- Mitochondrial Function and Pathology
- RNA modifications and cancer
- Immune cells in cancer
- Neurobiology and Insect Physiology Research
- Vestibular and auditory disorders
- PARP inhibition in cancer therapy
- Morphological variations and asymmetry
Icahn School of Medicine at Mount Sinai
2012-2024
The Graduate Center, CUNY
2015-2024
Tisch Cancer Institute
2017-2019
Tisch Hospital
2017
Harvard University
2005-2009
Dana-Farber Cancer Institute
2006-2009
Max Planck Institute for Developmental Biology
2003-2008
Harvard University Press
2005-2008
Vollum Institute
2005
University of Tübingen
2005
Hair cells detect sound and movement transmit this information via specialized ribbon synapses. Here we report that asteroid , a gene identified in an ethylnitrosourea mutagenesis screen of zebrafish larvae for auditory/vestibular mutants, encodes vesicular glutamate transporter 3 (Vglut3). A splice site mutation exon 2 vglut3 results severe truncation the predicted protein product morpholinos directed against ATG start or affected junction replicate phenotype. In situ hybridization shows is...
The senses of hearing and balance in vertebrates rely on the sensory hair cells (HCs) inner ear. central element HC's transduction apparatus is a mechanically gated ion channel unknown identity. Here we report that zebrafish ortholog Drosophila no mechanoreceptor potential C (nompC), which encodes transient receptor (TRP) channel, critical for HC mechanotransduction. In larvae, nompC selectively expressed HCs. Morpholino-mediated removal function eliminated transduction-dependent endocytosis...
Abstract Background DNA repair deficient tumor cells have been shown to accumulate high levels of damage. Consequently, these become hyper-dependent on damage response pathways, including the CHK1-kinase-mediated response. These observations suggest that tumors should exhibit increased sensitivity CHK1 inhibition. Here we offer experimental evidence in support this hypothesis. Results Using isogenic pairs cell lines differing only Fanconi Anemia (FA) pathway, showed FA were hypersensitive...
The PIDDosome (PIDD-RAIDD-caspase-2 complex) is considered to be the primary signaling platform for caspase-2 activation in response genotoxic stress. Yet studies of PIDD-deficient mice show that can proceed absence PIDD. Here we DNA damage induces assembly at least two distinct platforms caspase-2: a cytoplasmic RAIDD dependent but PIDD independent, and nucleolar requires both RAIDD. Furthermore, phosphoprotein nucleophosmin (NPM1) acts as scaffold essential nucleolus after damage....
L-type Ca2+ channels (LTCCs) drive the bulk of voltage-gated entry in vertebrate inner ear hair cells (HCs) and are essential for mammalian auditory processing. LTCC currents have been implicated neurotransmitter release at HC afferent active zone, ribbon synapse. It is likely that LTCCs play a direct role vesicle fusion; however, subcellular localization HCs has not fully resolved. Via positional cloning, we show mutations zebrafish encoding gene, cav1.3a, underlie auditory-vestibular...
In vertebrates, the senses of hearing and balance depend on hair cells, which transduce sounds with their bundles, containing actin-based stereocilia microtubule-based kinocilia. A longstanding question in auditory science is identity mechanically sensitive transduction channel thought to be localized at tips stereocilia. Experiments zebrafish implicated transient receptor potential (TRP) NOMPC (drTRPN1) this role; TRPN1 absent from genomes higher however, has not been cells. Another...
Acid-sensing ion channels (ASICs) are excitatory receptors for extracellular H+. Proposed functions include synaptic transmission, peripheral perception of pain, and mechanosensation. Despite the physiological importance these functions, precise role ASICs has not yet been established. In order to increase our understanding basic structure-function relationships ASICs, we report here cloning six new from zebrafish (zASICs). zASICs possess functional properties mammalian ASICs: activation by...
Large-scale mutagenesis screens in the zebrafish employing mutagen ENU have isolated several hundred mutant loci that represent putative developmental control genes. In order to realize potential of such screens, systematic genetic mapping mutations is necessary. Here we report on a large-scale effort map generated screening at Max Planck Institute for Developmental Biology by genome scanning with microsatellite markers.We selected set markers and developed methods scoring criteria suitable...
In vertebrate embryos, maternal determinants are thought to preestablish the dorsoventral axis by locally activating zygotic ventral- and dorsal-specifying genes, e.g., genes encoding bone morphogenetic proteins (BMPs) BMP inhibitors, respectively. Whereas canonical Wnt/β-catenin pathway fulfills this role dorsally, existence of a reciprocal ventralizing signal remains hypothetical. Maternal noncanonical Wnt/Ca 2+ signaling may promote ventral fates suppressing dorsalizing signals; however,...
Interleukin-1 receptor (IL-1R)–associated kinases (IRAKs) are core effectors of Toll-like receptors (TLRs) and IL-1R in innate immunity. Here, we found that IRAK4 IRAK1 together inhibited DNA damage–induced cell death independently TLR or signaling. In human cancer cells, was activated downstream ATR kinase response to double-strand breaks (DSBs) induced by ionizing radiation (IR). Activated then formed a complex with IRAK1. The formation this required the E3 ubiquitin ligase Pellino1,...
Antitumor immunity has emerged as a favorable byproduct of radiation therapy (RT), whereby tumor-associated antigens released from irradiated cells unleash innate and adaptive attacks on tumors located both within outside the field. RT-induced immune responses further provide actionable targets for overcoming tumor resistance to RT (R-RT); immunotherapy (IT) with checkpoint inhibitors or Toll-like receptor (TLR) agonists can markedly improve, if not synergize with, in preclinical models,...
Abstract The peptidyl-prolyl cis-trans isomerase, Pin1, acts as a unified signaling hub that is exploited in cancer to activate oncogenes and inactivate tumor suppressors, particular through up-regulation of c-Myc target genes. However, despite considerable efforts, Pin1 has remained an elusive drug target. Here, we screened electrophilic fragment library discover covalent inhibitors targeting Pin1’s active site nucleophile - Cys113, leading the development Sulfopin, double-digit nanomolar...
Interleukin-1 receptor (IL-1R)-associated kinases (IRAKs) are core effectors of Toll-like (TLR) and IL-1R signaling, with no reported roles outside innate immunity. We find that vertebrate cells exposed to ionizing radiation (IR) sequentially activate IRAK4 IRAK1 through a phosphorylation cascade mirroring induced by TLR/IL-1R, resulting in potent anti-apoptotic response. However, IR-induced activation does not require the receptors or IRAK4/1 adaptor protein MyD88, instead remaining...