OMB No. 0925-0001 and 0925-0002 (Rev. 09/17 Approved Through 03/31/2020)

NAME: Terada, Lance

eRA COMMONS USER NAME (credential, e.g., agency login): LTERADA

POSITION TITLE:  Professor and Chief, Division of Pulmonary and Critical Care, Dept. Internal Medicine

EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, include postdoctoral training and residency training if applicable. Add/delete rows as necessary.)

A.        Personal Statement
I have had a sustained research focus on fundamental signaling pathways relevant to lung and vascular diseases, and an equally sustained focus on mentoring biomedical investigators, particularly physician scientists, and creating research opportunities for them. In 2008-13, my research productivity slowed significantly as a consequence of taking over the Pulmonary and Critical Care Division to lead deep reorganization and to expand the divisional faculty over four-fold. A major divisional focus of mine has been the building of clinical research infrastructure which has allowed us to establish specific research and research training programs. This infrastructure includes new clinical centers which now support robust disease-specific research in lung cancer, interstitial lung disease, cystic fibrosis, lung transplant immunology, interventional pulmonology device trials, and pulmonary hypertension. As an example, Dr. Newton’s current K23 application is a direct result of what is now a high-volume interstitial lung disease referral center. In addition, I have obtained and currently direct a T32 research training program which fosters and supports new lung scientists such as Dr. Newton. My own laboratory is now focused upon the epigenetic and molecular control of matrix mechanosensation and its direct implications for lung epithelial transformation in abnormal lung microenvironments. Given my strong emphasis on providing research opportunities and mentoring of young scientists, I am well suited to serve as a primary mentor for Dr. Chad Newton’s K23 Award.

Invited reviews which support my visibility in these fields include:

1. Terada LS. Specificity in reactive oxidant signaling: think globally, act locally. J Cell Biol. 2006 Aug 28; 174(5):615-23. PMID: 16923830; PMCID: PMC2064304.
2. Ma Z, Liu Z, Myers DP, Terada LS. Mechanotransduction and anoikis: death and the homeless cell. Cell Cycle. 2008 Aug 15; 7(16):2462-5. PMID: 18719379; PMCID: PMC2730734.
3. Wu RF, Terada LS.  Focal oxidant and Ras signaling on the ER surface activates autophagy. Autophagy.  2010; 6:828-9. DOI: 10.4161/auto.6.6.12857.
4. Terada LS, Liu Z. Aiolos and lymphocyte mimicry in lung cancer. Molecular & Cellular Oncology. 2014 July; 1(1):e29912.
5. Terada LS.  Shc and the mechanotransduction of cellular anchorage and metastasis.  Small GTPases.  2017 Feb 17:1-8 [Epub ahead of print].  PMID: 28632027; PMCID: In process. DOI: 10.1080/21541248.2016.1273172.

B.         Positions and Honors

Positions and Employment

Reviewer Experience (last 10 years)

Honors

C.        Contributions to Science

1. Signal transduction through Nox complexes and ER signaling to autophagic pathways.  My work in the area of ROS and cell signaling has led to pioneering studies in the understanding of redox biochemistry in signal transduction systems. We were the first to clone the bactericidal neutrophil NADPH oxidase regulatory subunit p47^phox from a non-phagocytic cell, and demonstrated its capacity to transduce specific signals through the JNK MAPK system. Through a series of yeast two-hybrid interaction screens, we deduced the signaling interactome of the Nox2 oxidase complex which led to the novel concept that the use of ROS as signaling intermediates requires focal macromolecular complexes that act to strictly confine ROS to oxidant-sensitive microdomains within the cell.  Our work has led to the identification of molecular complexes that control endothelial cell migration by Nox2 and endothelial ER stress response by Nox4.  The latter complex also interfaces with the initiation of Ras-dependent activation of autophagy, used as a protective process in both vascular and cancer cells.  Further work by our group has identified the ER resident signaling complex leading to autophagy and downstream events in normal vascular and transformed cancer cells.

Selected research papers:

1. 1. Nwariaku FE, Liu Z, Zhu X, Nahari D, Ingle C, Wu RF, Gu Y, Sarosi G, Terada LS. NADPH oxidase mediates vascular endothelial cadherin phosphorylation and endothelial dysfunction. Blood. 2004 Nov 15; 104(10):3214-20. PMID: 15271797.
   2. Wu RF, Gu Y, Xu YC, Nwariaku FE, Terada LS.  Vascular endothelial growth factor causes translocation of p47phox to membrane ruffles through WAVE1. J. Biol Chem. 2003; 278(38):36830-40.  PMID: 12855698.
   3. Wu RF, Xu YC, Ma Z, Nwariaku FE, Sarosi GA Jr, Terada LS. Subcellular targeting of oxidants during endothelial cell migration. J Cell Biol. 2005 Dec 5; 171(5):893-904.  PMID: 16330715; PMCID: PMC2171295.
   4. Wu RF, Ma Z, Myers DP, Terada LS. HIV-1 Tat activates dual Nox pathways leading to independent activation of ERK and JNK MAP kinases. J Biol Chem. 2007 Dec 28; 282(52):37412-9. PMID: 17940286.
   5. Wu RF, Ma Z, Liu Z, Terada LS. Nox4-derived H₂O₂ mediates endoplasmic reticulum signaling through local Ras activation. Mol Cell Biol. 2010 Jul; 30(14):3553-68. PMID: 20457808; PMCID: PMC2897542.
   6. Wu RF, Liao C, Hatoum H, Fu G, Ochoa CD, Terada LS.  RasGRF couples Nox4-dependent endoplasmic reticulum signaling to Ras.  Arterioscl. Thromb. Vascular Biol.  2017; 37(1):98-107.  PMID: 27856453; PMCID: PMC5222703.
   7. Mu, Y, Yan X, Li D, Zhao D, Wang , X. Wang L, Gao D, Yang J, Zhang H, Li Y, Sun Y, Wei Y, Zhang Z, Chang X, Yao Z, Tian S, Zhang K, Terada LS, Ma Z, Liu Z.  Nupr1 Maintains Autolysosomal Efflux by Activating SNAP-25 Transcription in Cancer Cells.  Autophagy. 2018; 14(4):654-670. [2017 Epub ahead of print]. PMID: 29130426; PMCID: In process. DOI: 10.1080/15548627.2017.1338556.
2. Anoikis and metastatic behavior.  The current focus of my lab is on mechanisms by which cancer cells metastasize. A key discovery we made was that the Shc isoform p66^Shc, a protein with no previously known adaptive function, is required for matrix sensing and thus anchorage sensitivity, and is highly expressed by normal epithelium but repressed by normal blood cells and metastatic cancer cells. We deduced that p66^Shc initiates a mechanosensory tension test of its physical environment, prompting cell death upon sensing mechanical load failure. This pathway controls a Ras/Rho rheostat through differential GEF activation, to link cellular adhesion states with cell cycle entry as well as death. In epithelial cells, the loss of p66^Shc uncouples Ras from its regulators, phenocopying oncogenic Ras and causing anchorage independence and metastatic behavior. More recently, we have worked through the epigenetic control of SHC1 and came to the surprising conclusion that metastatic lung cancers silence p66^Shc through aberrant expression of the lymphocyte chromatin regulator Aiolos. Parenthetically, this latter project was largely performed in my lab with a postdoctoral fellow, Zhe Liu, whom I placed as last author to assure her a permanent faculty position as she transitioned to her own lab in Tianjin Medical Center, documenting my commitment to my postdoctoral trainees.  My current focus is on identifying other upstream drivers of epigenetic reprogramming that capitalize on the lineage plasticity of premalignant and transformed cells.

Selected research papers:

1. 1. Ma Z, Myers DP, Wu RF, Nwariaku FE, Terada LS. p66^Shc mediates anoikis through RhoA. J Cell Biol. 2007 Oct 8; 179(1):23-31. PMID: 17908916; PMCID: PMC2064727. 
   2. Ma Z, Liu Z, Wu RF, Terada LS. p66^Shc restrains Ras hyperactivation and suppresses metastatic behavior. Oncogene. 2010 Oct 14; 29(41):5559-67. PMID: 20676142; PMCID: PMC3045677. 
   3. Terada LS, Nwariaku FE. Escaping Anoikis through ROS: ANGPTL4 controls integrin signaling through Nox1. Cancer Cell. 2011 Mar 8; 19(3):297-9. PMID: 21397852.
   4. Li X, Xu Z, Du W, Zhang Z, Wei Y, Wang H, Zhu Z, Qin L, Wang L, Niu Q, Zhao X, Girard L, Gong Y, Ma Z, Sun B, Yao Z, Minna JD, Terada LS*, Liu Z*. Aiolos promotes anchorage independence by silencing p66^Shc transcription in cancer cells.  Cancer Cell. 2014 May 12; 25(5):575-89. PMID: 24823637; PMCID: PMC4070880. *corresponding authors.
   5. Jiang L, Shestov AA, Swain P, Yang C, Parker SJ, Wang QA, Terada LS, Adams ND, McCabe MT, Pietrack B, Schmidt S, Metallo CM, Dranka BP, Schwartz B, DeBerardinis RJ. Reductive carboxylation supports redox homeostasis during anchorage-independent cell growth.  Nature. 2016; 532:255-258.  PMID: 27049945; PMCID: PMC4860952.
   6. Wu RF, Liao C, Fu G, Hayenga HN, Yang K, Ma Z, Liu Z, Terada LS.  p66Shc couples mechanical signals to RhoA through FAK-dependent recruitment of p115-RhoGEF and GEF-H1. Mol Cell Biol.  2016; 36:2824-2837.  PMID: 27573018; PMCID: PMC5086523.
   7. Li X, Lin Z, Wang H, Zhao D, Xu X, Wei Y, Li X, Li X, Xiang Y, Terada LS, Liu Z. Heritable, allele-specific chromosomal looping between tandem promoters specifies promoter usage of SHC1. Mol. Cell. Biol. 2018; [Epub ahead of print]. PMID: 29440311; PMCID: PMC5902595 [Available 2018-10-16].

Complete List of Published Work in My Bibliography:
http://www.ncbi.nlm.nih.gov/myncbi/lance.terada.2/bibliography/40173725/public/?sort=date&direction=ascending

D.        Research Support

Ongoing Research Support

R01CA208620                                                                                                Terada (PI)                                                                                    09/01/2016-08/31/2021

NIH/NCI                                                                      

Title: (PQ1) Epigenetic effects of the premalignant field

Goal: To study the epigenetic landscapes of emerging lung cancers.

T32 HL098040                                                                                                Terada/Shaul (Co-PDs)                                              09/01/2009-08/31/2019

NIH/NHLBI                                                                 

Title: Training Program in Lung Biology and Disease

Goal: This grant funds postdoctoral research fellows who will embark in careers in adult and pediatric lung-related research.

RP160307                                                                                                                   Terada (PI)                                                                  03/01/2016-02/28/2019

Cancer Prevention & Research Institute of Texas        

Title:  Targeting Metastatic Pathways

Goal:  To modify the upstream pathways leading to IKZF3 and SHC1 regulation.

Completed Research Support

14GRNT19010014-02                                                                         Terada (PI)                                                                  01/01/2014-12/31/2016

American Heart Association                          

Title: Endothelial cell anchorage signaling

Goal: To study the basis for mechanotransduction of the vascular endothelium through Shc protein signaling.  The aims are to study the mechanism by which the Ras and Rho GTPases are controlled by Shc and the means by which anchorage requirements are loosened during EndMT.

DOD Lung Cancer RFA                                                                      Spira (PI)                                                                                 01/01/2011-01/01/2016

Department of Defense                                             

Title: Detection of Lung Cancer among Military Personnel (DECAMP)

Goal: This is a multicenter, prospective, translational study of patients at high risk for lung cancer, to validate novel molecular biomarkers CT screening with clinical outcome.

Role: Site Co-Investigator

VA Cooperative, CCTA-002                                                   Banerjee (PI)                                                                          09/01/2009-08/31/2014

Veterans Affairs

Title: Plaque regression and progenitor cell mobilization with intensive lipid elimination trial (PREMIER).

Goal: Clinical Trial on plaque regression and progenitor cell mobilization.

Role: Collaborator

R01 HL067256-09                                                                                          Terada (PI)                                                                                     04/01/2001-03/31/2013

NIH/NHLBI

Title: p47 binding partners in endothelial cell function

Goal: To analyze several putative Nox-dependent subcellular microdomains and explore the signal pathways affected.

Role: PI