I M Verma

University of California, San Diego, San Diego, California, United States

Are you I M Verma?

Claim your profile

Publications (423)4517.22 Total impact

  • Source
    Tatiana Hurtado de Mendoza · Fei Liu · Inder M Verma ·
    [Show abstract] [Hide abstract]
    ABSTRACT: Anti-apoptotic protein Lifeguard (LFG) is upregulated on T cells upon in vitro activation. To investigate its role in T cell immunity we infected wild type and LFG knockout bone marrow chimaeras mice with LCMV. We observed a decreased number of LFG KO activated CD8 and CD4 T cells throughout the infection and a marked decrease in LFG KO LCMV specific memory T cells. WT and KO T cells proliferated at the same rate, however, LFG KO CD44hi T cells showed increased cell death during the initial phase of the immune response. LFG KO and WT T cells were equally sensitive to the FAS antibody Jo-2 in ex vivo cultures, and blocking extrinsic pathways of cell death in vivo with Fas L or caspase 8 inhibitors did not rescue the increased apoptosis in LFG KO T cells. Our data suggest that LFG plays a role in T cell survival during the initial phase of anti-viral immune response by protecting pre-existing memory T cells and possibly newly activated T cells resulting in a diminished immune response and a decreased number of LCMV specific memory T cells.
    PLoS ONE 11/2015; 10(11):e0142161. DOI:10.1371/journal.pone.0142161 · 3.23 Impact Factor
  • Narayana Yeddula · Yifeng Xia · Eugene Ke · Joep Beumer · Inder M Verma ·
    [Show abstract] [Hide abstract]
    ABSTRACT: Lung adenocarcinoma, a major form of non-small cell lung cancer, is the leading cause of cancer deaths. The Cancer Genome Atlas analysis of lung adenocarcinoma has identified a large number of previously unknown copy number alterations and mutations, requiring experimental validation before use in therapeutics. Here, we describe an shRNA-mediated high-throughput approach to test a set of genes for their ability to function as tumor suppressors in the background of mutant KRas and WT Tp53. We identified several candidate genes from tumors originated from lentiviral delivery of shRNAs along with Cre recombinase into lungs of Loxp-stop-Loxp-KRas mice. Ephrin receptorA2 (EphA2) is among the top candidate genes and was reconfirmed by two distinct shRNAs. By generating knockdown, inducible knockdown and knockout cell lines for loss of EphA2, we showed that negating its expression activates a transcriptional program for cell proliferation. Loss of EPHA2 releases feedback inhibition of KRAS, resulting in activation of ERK1/2 MAP kinase signaling, leading to enhanced cell proliferation. Intriguingly, loss of EPHA2 induces activation of GLI1 transcription factor and hedgehog signaling that further contributes to cell proliferation. Small molecules targeting MEK1/2 and Smoothened hamper proliferation in EphA2-deficient cells. Additionally, in EphA2 WT cells, activation of EPHA2 by its ligand, EFNA1, affects KRAS-RAF interaction, leading to inhibition of the RAS-RAF-MEK-ERK pathway and cell proliferation. Together, our studies have identified that (i) EphA2 acts as a KRas cooperative tumor suppressor by in vivo screen and (ii) reactivation of the EphA2 signal may serve as a potential therapeutic for KRas-induced human lung cancers.
    Proceedings of the National Academy of Sciences 11/2015; DOI:10.1073/pnas.1520110112 · 9.67 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Lung disease is a major cause of death in the United States, with current therapeutic approaches serving only to manage symptoms. The most common chronic and life-threatening genetic disease of the lung is cystic fibrosis (CF) caused by mutations in the cystic fibrosis transmembrane regulator (CFTR). We have generated induced pluripotent stem cells (iPSCs) from CF patients carrying a homozygous deletion of F508 in the CFTR gene, which results in defective processing of CFTR to the cell membrane. This mutation was precisely corrected using CRISPR to target corrective sequences to the endogenous CFTR genomic locus, in combination with a completely excisable selection system, which significantly improved the efficiency of this correction. The corrected iPSCs were subsequently differentiated to mature airway epithelial cells where recovery of normal CFTR expression and function was demonstrated. This isogenic iPSC-based model system for CF could be adapted for the development of new therapeutic approaches. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 08/2015; 12(9). DOI:10.1016/j.celrep.2015.07.062 · 8.36 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Glioblastoma can originate from terminally differentiated astrocytes and neurons, which can dedifferentiate to a stem cell-like state upon transformation. In this study, we confirmed that transformed dedifferentiated astrocytes and neurons acquired a stem/progenitor cell state, although they still retained gene expression memory from their parental cell. Transcriptional network analysis on these cells identified upregulated genes in three main pathways: Wnt signaling, cell cycle and focal adhesion with the gene Spp1, also known as osteopontin (OPN) serving as a key common node connecting these three pathways. Inhibition of OPN blocked the formation of neurospheres, affected the proliferative capacity of transformed neurons and reduced the expression levels of neural stem cell markers. Specific inhibition of OPN in both murine and human glioma tumors prolonged mice survival. We conclude that OPN is an important player in dedifferentiation of cells during tumor formation, hence its inhibition can be a therapeutic target for glioblastoma.Oncogene advance online publication, 11 May 2015; doi:10.1038/onc.2015.119.
    Oncogene 05/2015; DOI:10.1038/onc.2015.119 · 8.46 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Lentiviral vectors pseudotyped with the rabies virus (RV) envelope glycoprotein efficiently infect via axon terminals to stably deliver transgenes to distant neurons projecting to an injection site, but the resulting expression levels are too low and variable for most neuroscientific applications. If used to deliver recombinases or transactivators, however, lentiviral vectors are excellent means of targeting projection neurons when used in reporter mice or in combination with a second virus to express "payload" transgenes at high levels. For retrograde infection of significant numbers of neurons, high virus titers are critical. Here we present reagents and a protocol for generating high-titer supernatants that can be concentrated 1000-fold for final titers in excess of 10(10) infectious units per milliliter. We demonstrate the usefulness of these vectors by selectively targeting corticothalamic and corticotectal neurons for high-level expression of a fluorophore in knock-in reporter mice. © 2015 Cold Spring Harbor Laboratory Press.
    Cold Spring Harbor Protocols 04/2015; 2015(4):pdb.prot075879. DOI:10.1101/pdb.prot075879 · 4.63 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: X-linked Severe Combined Immunodeficiency (SCID-X1) is a genetic disease that leaves newborns at high risk of serious infection and a predicted life span of less than 1 year in the absence of a matched bone marrow donor. The disease pathogenesis is due to mutations in the gene encoding the Interleukin-2 receptor gamma chain (IL-2Rγ), leading to a lack of functional lymphocytes. With the leukemogenic concerns of viral gene therapy there is a need to explore alternative therapeutic options. We have utilized induced pluripotent stem cell (iPSC) technology and genome editing mediated by TALENs to generate isogenic subject-specific mutant and gene-corrected iPSC lines. While the subject-derived mutant iPSCs have the capacity to generate hematopoietic precursors and myeloid cells, only wild-type and gene-corrected iPSCs can additionally generate mature NK cells and T cell precursors expressing the correctly spliced IL-2Rγ. This study highlights the potential for the development of autologous cell therapy for SCID-X1 subjects. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cell stem cell 03/2015; 16(4). DOI:10.1016/j.stem.2015.02.005 · 22.27 Impact Factor
  • Source
    Pao G · Zhu Q · Perez-Garcia CG · Chou SJ · Suh H · Gage F · O'Leary DDM · Verma I ·

  • [Show abstract] [Hide abstract]
    ABSTRACT: Lung cancer is the most common human malignancy and leads to about one-third of all cancer-related deaths. Lung adenocarcinomas harboring KRAS mutations, in contrast to those with EGFR and EML4-ALK mutations, have not been successfully targeted. We describe a combination therapy for treating these malignancies with two agents: a lipophilic bisphosphonate and rapamycin. This drug combination is much more effective than either agent acting alone in the KRAS G12D-induced mouse lung model. Lipophilic bisphosphonates inhibit both farnesyl and geranylgeranyldiphosphate synthases, effectively blocking prenylation of KRAS and other small G proteins (heterotrimeric GTP-binding protein, heterotrimeric guanine nucleotide-binding proteins) critical for tumor growth and cell survival. Bisphosphonate treatment of cells initiated autophagy but was ultimately unsuccessful and led to p62 accumulation and concomitant nuclear factor κB (NF-κB) activation, resulting in dampened efficacy in vivo. However, we found that rapamycin, in addition to inhibiting the mammalian target of rapamycin (mTOR) pathway, facilitated autophagy and prevented p62 accumulation-induced NF-κB activation and tumor cell proliferation. Overall, these results suggest that using lipophilic bisphosphonates in combination with rapamycin may provide an effective strategy for targeting lung adenocarcinomas harboring KRAS mutations. Copyright © 2014, American Association for the Advancement of Science.
    Science translational medicine 11/2014; 6(263):263ra161. DOI:10.1126/scitranslmed.3010382 · 15.84 Impact Factor

  • Cancer Research 10/2014; 74(19 Supplement):2973-2973. DOI:10.1158/1538-7445.AM2014-2973 · 9.33 Impact Factor

  • Cancer Research 10/2014; 74(19 Supplement):524-524. DOI:10.1158/1538-7445.AM2014-524 · 9.33 Impact Factor

  • Cancer Research 10/2014; 74(19 Supplement):1914-1914. DOI:10.1158/1538-7445.AM2014-1914 · 9.33 Impact Factor
  • Narayana Yeddula · Yifeng Xia · Inder Verma ·

    Cancer Research 10/2014; 74(19 Supplement):70-70. DOI:10.1158/1538-7445.AM2014-70 · 9.33 Impact Factor
  • Source
    Yifeng Xia · Shen Shen · Inder M Verma ·
    [Show abstract] [Hide abstract]
    ABSTRACT: NF-κB comprises a family of five transcription factors that form distinct protein complexes, which bind to consensus DNA sequences at promoter regions of responsive genes regulating cellular processes. The past three decades have witnessed remarkable progress in understanding the NF-κB signaling pathway in physiologic and pathologic conditions. The role of NF-κB in human cancer initiation, development, metastasis, and resistance to treatment has drawn particular attention. A significant number of human cancers have constitutive NF-κB activity due to the inflammatory microenvironment and various oncogenic mutations. NF-κB activity not only promotes tumor cells' proliferation, suppresses apoptosis, and attracts angiogenesis, but it also induces epithelial-mesenchymal transition, which facilitates distant metastasis. In certain circumstances, NF-κB activation may also remodel local metabolism and anergize the immune system to favor tumor growth. Suppression of NF-κB in myeloid cells or tumor cells usually leads to tumor regression, which makes the NF-κB pathway a promising therapeutic target. However, because of its vital role in various biologic activities, components of the NF-κB pathway need to be carefully selected and evaluated to design targeted therapies. Cancer Immunol Res; 2(9); 823-30. ©2014 AACR.
    09/2014; 2(9):823-830. DOI:10.1158/2326-6066.CIR-14-0112
  • Source

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Glial cells are an integral part of functional communication in the brain. Here we show that astrocytes contribute to the fast dynamics of neural circuits that underlie normal cognitive behaviors. In particular, we found that the selective expression of tetanus neurotoxin (TeNT) in astrocytes significantly reduced the duration of carbachol-induced gamma oscillations in hippocampal slices. These data prompted us to develop a novel transgenic mouse model, specifically with inducible tetanus toxin expression in astrocytes. In this in vivo model, we found evidence of a marked decrease in electroencephalographic (EEG) power in the gamma frequency range in awake-behaving mice, whereas neuronal synaptic activity remained intact. The reduction in cortical gamma oscillations was accompanied by impaired behavioral performance in the novel object recognition test, whereas other forms of memory, including working memory and fear conditioning, remained unchanged. These results support a key role for gamma oscillations in recognition memory. Both EEG alterations and behavioral deficits in novel object recognition were reversed by suppression of tetanus toxin expression. These data reveal an unexpected role for astrocytes as essential contributors to information processing and cognitive behavior.
    Proceedings of the National Academy of Sciences 07/2014; 111(32). DOI:10.1073/pnas.1410893111 · 9.67 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Alzheimer's Disease (AD) is characterized by widespread neurodegeneration throughout the association cortex and limbic system, deposition of Aβ in the neuropil and around the blood vessels, and formation of neurofibrillary tangles. The endopeptidase neprilysin has been successfully used to reduce the accumulation of Aβ following intra-cranial viral vector delivery or ex vivo manipulated intra-cranial delivery. These therapies have relied on direct injections into the brain, whereas a clinically desirable therapy would involve i.v infusion of a recombinant enzyme. We previously characterized a recombinant neprilysin that contained a 38 amino acid brain-targeting domain. Recombinant cell lines have been generated expressing this brain-targeted enzyme (ASN12). In this report, we characterize the ASN12 recombinant protein for pharmacology in a mouse as well as efficacy in two APPtg mouse models of AD. The recombinant ASN12 transited to the brain with a t1/2 of 24 hours and accumulated to 1.7% of injected dose at 24 hours following i.v. delivery. We examined pharmacodynamics in the tg2576 APPtg mouse with the prion promoter APP695 SWE mutation and in the Line41 mThy1 APP751 mutation mouse. Treatment of either APPtg mouse resulted in reduced Aβ, increased neuronal synapses and improved learning and memory. In addition, the Line41 APPtg mice showed increased levels of c-terminal NPY fragments and increased neurogenesis. These results suggest that the recombinant brain-targeted neprilysin, ASN12, may be an effective treatment for AD and warrant further investigation in clinical trials.
    Journal of Biological Chemistry 05/2014; 289(25). DOI:10.1074/jbc.M114.557439 · 4.57 Impact Factor
  • Source

  • Source

  • Source

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Despite therapeutic advancement, pulmonary disease still remains a major cause of morbidity and mortality around the world. Opportunities to study human lung disease either in vivo or in vitro are currently limited. Using induced pluripotent stem cells (iPSCs), we generated mature multiciliated cells in a functional airway epithelium. Robust multiciliogenesis occurred when notch signaling was inhibited and was confirmed by (i) the assembly of multiple pericentrin-stained centrioles at the apical surface, (ii) expression of transcription factor forkhead box protein J1, and (iii) presence of multiple acetylated tubulin-labeled cilia projections in individual cells. Clara, goblet, and basal cells were all present, confirming the generation of a complete polarized epithelial-cell layer. Additionally, cAMP-activated and cystic fibrosis transmembrane regulator inhibitor 172-sensitive cystic fibrosis transmembrane regulator currents were recorded in isolated epithelial cells. Our report demonstrating the generation of mature multiciliated cells in respiratory epithelium from iPSCs is a significant advance toward modeling a number of human respiratory diseases in vitro.
    Proceedings of the National Academy of Sciences 03/2014; 111(17). DOI:10.1073/pnas.1403470111 · 9.67 Impact Factor

Publication Stats

55k Citations
4,517.22 Total Impact Points


  • 1992-2014
    • University of California, San Diego
      • • Department of Neurosciences
      • • Division of Endocrinology & Metabolism
      • • Department of Chemistry and Biochemistry
      • • Department of Pediatrics
      San Diego, California, United States
  • 1976-2014
    • Salk Institute
      • • Laboratory of Genetics
      • • Molecular Biology and Virology Laboratory
      • • Clayton Foundation Laboratories for Peptide Biology
      لا هویا, California, United States
  • 2006
    • University of Freiburg
      • Institute of Molecular Medicine and Cell Research
      Freiburg, Baden-Württemberg, Germany
  • 2005
    • Università degli Studi di Sassari
      Sassari, Sardinia, Italy
  • 1999-2005
    • Torrey Pines Institute for Molecular Studies
      Port St. Lucie, Florida, United States
  • 1984
    • University of California, Los Angeles
      • Center for Culture and Health
      Los Ángeles, California, United States
  • 1980
    • ITH Nijmegen
      Nymegen, Gelderland, Netherlands
  • 1978
    • California Institute of Technology
      Pasadena, California, United States
  • 1972-1975
    • Massachusetts Institute of Technology
      • Department of Biology
      Cambridge, Massachusetts, United States
  • 1974
    • Yale University
      • School of Medicine
      New Haven, Connecticut, United States