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BIOGRAPHICAL SKETCH Provide the following information for the Senior/key personnel and other significant contributors. Follow this format for each person. DO NOT EXCEED FIVE PAGES. NAME: Pineda, Gabriel eRA COMMONS USER NAME (agency login): GPINEDA POSITION TITLE: Assistant Project Scientist EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, include postdoctoral training and residency training if applicable.) INSTITUTION AND LOCATION DEGREE (if applicable) University of Texas at Austin, Austin, TX BS University of Texas at El Paso, El Paso, TX MS University of Texas Southwestern Medical Center at PHD Dallas, Dallas, TX St. Elizabeth School of Medical Technology, Other training Beaumont, TX Marine Biological Laboratory, Woods Hole, MA, Other training Woods Hole, MA University of California, San Diego, San Diego, CA Other training University of California, San Diego, Moores Cancer Postdoctoral Center, San Diego, CA Fellow University of California, San Diego, Sanford Postdoctoral Consortium for Regenerative Medicine, San Diego, CA Fellow Completion Date MM/YYYY 08/1998 12/2001 05/2008 FIELD OF STUDY 08/1999 Microbiology Molecular Biology Biochemistry-Ubiquitination, Innate Immunity Medical Technology 08/2002 Physiology Course 03/2011 09/2011 Clinical Research Certificate Cancer Biology 09/2014 Cancer Stem Cell Biology A. Personal Statement Proposal Goal - The ultimate goal of the proposed research is to understand how WNT mediated signaling regulates survival and self-renewal in acute myeloid leukemia (AML) stem cells. The knowledge gained from these studies will elucidate molecular mechanisms that will be exploited to identify new therapeutic targets to treat AML. Relevant Experiences - My research background and experience in molecular biology, biochemistry, cancer biology, clinical research, and cancer stem cell biology have prepared me for a career in the translational cancer research field. From my Ph.D. training in biochemistry under the mentorship of HHMI investigator Dr. Zhijian J. Chen, my postdoctoral training in the distinguished laboratory of cancer biologist Dr. Jean Wang, and renowned cancer stem cell biologist Dr. Catriona Jamieson I believe I have mastered the foundation to be an independent scientist who can perform hypothesis-driven translational research. My doctoral work at UT Southwestern Medical Center at Dallas biochemically elucidated how the post-translational modification by ubiquitin leads to activation or inhibition of NF-κB signaling in human cancer cells. I was trained to decipher cell-signaling events in cancer cells by utilizing in vitro cell free systems to recapitulate and define molecular mechanisms. From my postdoctoral training in cancer biology in the distinguished lab of Dr. Jean Wang at the University of California, San Diego, we discovered, developed, and validated a proteomic approach to study the interactome of RNA polymerase II C-terminal repeated domain. To compete these studies I successfully collaborated with other preeminent researchers in the fields of phospho and functional proteomics. During 2009-2011 my career was disrupted due to obligations required to cope with a family illness. However, during this time I generated a substantial amount of data that has resulted in one first author manuscript that was recently revised and submitted to the peer-reviewed journal BMC Research Notes entitled “Proteomics Studies of the Interactome of RNA Polymerase II C-Terminal Repeated Domain” concluding my collaborative studies on the CTD code and how the CTD phosphorylation code can be regulated by DNA damage. Results from these studies provided the basis for successful application to obtain Recovery Act funds (NOT-OD-09-058). I also successfully completed all classwork to obtain a CREST certificate in clinical research. In my postdoctoral training in cancer stem cell biology in the laboratory of Dr. Catriona Jamieson at the University of California, San Diego, I have gained training in methods used to study leukemia stem cell (LSC) biology. My current studies involve understanding which pathways promote dormant human leukemia stem cell generation. My contribution and collaboration on the studies of the deregulation of hedgehog (Hh) signaling were published in the Journal of Translational Medicine. This publication is evidence that I have successfully managed to translate preclinical discoveries to establish new therapeutic options for patients with cancer. I recently have submitted a manuscript to Nature Methods entitled “Real-time Live Single Normal and Malignant Progenitor Cell Cycle Transit Time Tracking in a Defined Niche” describing my studies of cell cycle kinetics and gene expression profiles of leukemic progenitors on a defined niche using a lentiviral bicistronic Fucci2BL reporter I developed. Leadership Qualifications - From these experiences it is clear I have a pension to establish innovative methods to generate high impact discoveries. I am now poised to make translational discoveries that will make a direct contribution to human health. In summary, my mentor and I have a demonstrated record of accomplished and productive research projects in areas of high relevance for our proposed research. My expertise and experience have prepared me to lead the proposed project. 1. Sadarangani A, Pineda G, Lennon KM, et. al. (2015) GLI2 inhibition abrogates human leukemia stem cell dormancy. J Transl Med, 13(98). (PMID:25889765) B. Positions and Honors Positions and Employment 1998 - 1999 1998 - 1999 1999 - 2000 2000 - 2001 2000 - 2001 2001 - 2008 2008 - 2011 2010 - 2011 2011 - 2012 2012 - 2014 2012 - 2014 2014 - Medical Technology Student, St. Elizabeth Hospital, Beaumont, TX Phlebotomist/Assistant Diener/Lab Technician , St. Elizabeth Hospital, Beaumont, TX Medical Technologist, Providence Memorial Hospital, El Paso, TX Master's Graduate Student, University of Texas at El Paso, El Paso, TX Graduate Teaching Assistant, University of Texas at El Paso, El Paso, TX Doctoral Graduate Student, UT Southwestern, Zhijian J. Chen Lab, Dallas, TX Postdoctoral fellow-Jean Wang Lab, University of California, San Diego, San Diego, CA Lecturer, San Diego State University, San Diego, CA Scientist, GenWay Biotech Inc., San Diego, CA Lecturer, San Diego State University, San Diego, CA Postdoctoral fellow, University of California, San Diego, Jamieson Lab, San Diego, CA Assistant Project Scientist, University of California, San Diego, Jamieson Lab, San Diego, CA Other Experience and Professional Memberships 2014 2014 - Associate Member, American Association for Cancer Research Member, American Society for Cell Biology Honors 1994 2000 2000 2000 2000 2001 2002 2002 2002 2002 SUCCESS Scholarship, University of Texas at Austin Graduate Professional Funding, University of Texas as El Paso Travel Award for Genetic Education for Native Americans Workshop, SACNAS Travel Award for 40th Annual ASCB Meeting, American Society for Cell Biology, MAC Travel Award for SACNAS Annual Conference, SACNAS First Place Poster at ASM Regional Conference, American Society of Microbiology Rio Grande Branch William Townsend Porter Scholarship to attend Physiology course at Marine Biological Laboratory, William Townsend Porter Foundation Scholarship from Division of Cellular and Molecular Biology to attend Physiology course at Marine Biological Laboratory, UT Southwestern Invited Seminar Speaker, University of Texas at El Paso Scholarship to attend Physiology course at Marine Biological Laboratory, American Society for 2008 2010 2012 2012 2013 2014 Cell Biology, MAC CREST Scholar , Clinical Research Enhancement through Supplemental Training, University of California, San Diego Carl Storm URM Fellowship, Gordon Research Conference Mountain West Summer Institute Fellow, HHMI / National Academy of Sciences Invited Seminar Speaker , California State University Northridge Mountain West Summer Institute Alumni Fellow, HHMI / National Academy of Sciences AACR Minority Scholar in Cancer Research Award, AACR C. Contribution to Science 1. For years the emphasis of studying the function of ubiquitination focused on how this post-translational modification regulated protein turnover through proteosomal dependent degradation. The tagging of proteins with lysine-48 linked ubiquitin chains is responsible for proteasomal degradation. In the following studies I made significant contributions by establishing an in vitro cell free system to analyze how lysine-63 linked ubiquitination regulated NF-KappaB activation. In particular I established an assay using highly purified recombinant proteins to study the isopeptidase activity of CYLD a lysine-63 specific deubiquitinase. This enzyme is a very useful tool used to help confirm free lysine-63 linked ubiquitin chains can activate IKK. I also contributed to generating mutants and stable cells lines used to study how NEMO ubiquitin binding leads to the activation IKK. a. Ea CK, Deng L, Xia ZP, Pineda G, Chen ZJ. Activation of IKK by TNFalpha requires site-specific ubiquitination of RIP1 and polyubiquitin binding by NEMO. Mol Cell. 2006 Apr 21;22(2):245-57. PubMed PMID: 16603398. b. Pineda G, Ea CK, Chen ZJ. Ubiquitination and TRAF signaling. Adv Exp Med Biol. 2007;597:80-92. PubMed PMID: 17633019. c. Xia ZP, Sun L, Chen X, Pineda G, Jiang X, Adhikari A, Zeng W, Chen ZJ. Direct activation of protein kinases by unanchored polyubiquitin chains. Nature. 2009 Sep 3;461(7260):114-9. PubMed PMID: 19675569; PubMed Central PMCID: PMC2747300. 2. It had been shown that the hepatitis C protease NS3/4A could negatively regulate interferon in infected mammalian cells. The mechanism of this inhibition had not been known until our work identified the protein MAVS as the substrate and target of the NS3/4A proteases. MAVS is a key activator of interferon signaling in the cell. Specifically my contribution to the work was to determine levels of interferon activated target genes by QPCR in cells overexpressing NS3/4A and to generate a panel of MAVS mutants used to identify key domains required for inhibition by MAVS. a. Li XD, Sun L, Seth RB, Pineda G, Chen ZJ. Hepatitis C virus protease NS3/4A cleaves mitochondrial antiviral signaling protein off the mitochondria to evade innate immunity. Proc Natl Acad Sci U S A. 2005 Dec 6;102(49):17717-22. PubMed PMID: 16301520; PubMed Central PMCID: PMC1308909. D. Research Support Completed Research Support 2012/07/01-2014/06/01 K12GM068524, NIH/NIGMS IRACDA JoAnn Trejo (PI) Wnt Mediated Regulation of ROR1 Signaling in Acute Myeloid Leukemia Role: Post-Doctoral Scholar 2011/08/01-2012/09/30 K12GM068524, NIH/NIGMS IRACDA Laurence Brunton (PI) Proteomics Studies of the Interactome of RNA Polymerase II C-Terminal Repeated Domain Role: Post-Doctoral Scholar 2009/09/01-2011/09/01 CA043054, National Cancer Institute Jean Y.J. Wang (PI) Nuclear Function of Abl in DNA Damage Response Role: KP 2008/07/01-2011/07/01 T32CA121938, National Cancer Institute Pineda, Gabriel (PI) Proteomics Studies of the Interactome of RNA Polymerase II C-Terminal Repeated Domain Role: Post-Doctoral Scholar 2003/08/01-2007/08/20 F31GM068979, NIH/NIGMS Pineda, Gabriel (PI) NF-Kappa B Signaling Pathway & Ubiquitin Proteasome Degradation Pathway Role: GR