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1 NAME: Andrea Todisco OMB No and (Rev. 09/17 Approved Through 03/31/2020) 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. era COMMONS USER NAME (credential, e.g., agency login): atodisco POSITION TITLE: Professor of 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.) INSTITUTION AND LOCATION DEGREE (if applicable) Completion Date MM/YYYY FIELD OF STUDY Univ. of Rome, Italy, La Sapienza Med School M.D Medicine Henry Ford Hospital, Detroit, Michigan Intern Medicine Henry Ford Hospital, Detroit, Michigan Resident Medicine University of MI Med. School, Ann Arbor, MI Fellow Gastroenterology A. Personal Statement I will be the Principal Investigator of this project. I am an established investigator with a long-standing interest in the elucidation of the mechanisms that regulate epithelial cell growth and differentiation in the luminal gastrointestinal tract. In particular, my investigations have been focused on the intracellular signal transduction pathways that mediate the multiple, complex actions of growth factors and morphogens such as gastrin, epidermal growth factor (EGF), Sonic Hedgehog (Shh) and the BMPs in the stomach. My most recent investigations, centered on the role of BMP signaling in gastric inflammation and carcinogenesis, have involved the use of both primary cultures of gastric epithelial cells and transgenic mice. These studies have unraveled novel and important mechanisms that appear to play a significant role in the pathophysiology of gastric dysplasia and neoplasia. I am a member of the University of Michigan Center for Gastrointestinal Research (UMCGR) and of the Cancer Center, where I have established long lasting collaborations with several other Center Investigators such as Drs. Juanita Merchant, Linda Samuelson, Deb Gumucio and Kathryn Eaton who are conducting complementary studies focused on the mechanisms that regulate gastric epithelial cell homeostasis and gastric carcinogenesis. a. Shinohara M, Mao M, Keeley TM, El-Zaatari M, Lee HJ, Eaton KA, Samuelson LC, Merchant JL, Goldenring JR, Todisco A. Bone Morphogenetic Protein signaling Regulates Gastric Epithelial Cell Development and Proliferation in Mice. Gastroenterology 139(6): e PMCID:PMC b. Takabayashi H, Shinohara M, Mao M, Phaosawasdi P, El-Zaatari M, Zhang M, Ji T, Eaton KA, Dang D, Kao J, Todisco A. Anti-inflammatory Activity of Bone Morphogenetic Protein Signaling Pathways in Stomachs of Mice. Gastroenterology 147(2): e2, PMCID: PMC c. Todisco A, Mao M, Keeley TM, Ye W, Samuelson LC, Eaton KA. Regulation of gastric epithelial cell homeostasis by gastrin and bone morphogenetic protein signaling. Physiol Rep. 3(8), PMCID: PMC

2 d. Ye W, Takabayashi H, Yang Y, Mao M, Hibdon ES, Samuelson LC, Eaton KA, Todisco A. Regulation of gastric Lgr5+ve cell homeostasis by Bone Morphogenetic Protein (BMP) signaling and inflammatory stimuli. Cell Mol Gastroenterol Hepatol. 2018, in press. B. Positions and Honors Positions and Employment Instructor, Gastroenterology Division, Department of Internal Medicine University of Michigan Medical School, Ann Arbor, Michigan Assistant Professor, Gastroenterology Division, Department of Internal Medicine University of Michigan Medical School, Ann Arbor, Michigan Associate Professor with tenure, Gastroenterology Division, Department of Internal Professor with tenure, Gastroenterology Division, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan Staff Physician, University of Michigan Health Systems, Ann Arbor, Michigan Staff Physician, Ann Arbor VA Health Systems, Ann Arbor, Michigan Other Experience and Professional Memberships Regular Member, Clinical Integrative Molecular Gastroenterology (CIMG) Study Section Editorial Board, Am J Physiology: Gastrointestinal and Liver Physiology Editorial Board, Therapeutic Advances in Gastroenterology Editorial Board, Gastroenterology Honors 1983 Morton I. Grossman Fellowship in Gastroenterology 1984 American Gastroenterological Association Summer Student Fellowship 1984, 1985 Runner- up, AGA Student Research Prize 1991 AGA Senior Fellow Research Award 1992 AGA Advanced Research Training Award 1992 Glaxo Fellow Award th International Symposium on Gastrointestinal Hormones Travel Scholarship 1995 AGA Industry Scholar Award 1996 Henry Christian Award for Excellence in Clinical Research (AFCR Foundation) 2005 Membership, American Society of Clinical Investigations 2006 Fellow of the American Gastroenterological Association 2011 AGA/R. Robert and Sally D. Funderburg Research Scholar Award in Gastric Biology Related to Cancer 2011, 2014 Becker s ASC Review list of 125 Leading Gastroenterologists in America C. Contribution to Science 1. My first investigations were focused on understanding the intracellular mechanisms that mediate the antiproliferative and anti-secretory actions of the gastrointestinal hormone somatostatin. In a series of published studies I reported that somatostatin inhibits the activation and regulatory actions of the early response genes c-fos and c-jun through the induction of multiple protein phosphatases. These studies led to the definition of novel signal transduction pathways linked to the activation of somatostatin receptors in both primary gastric epithelial cells and GH3 endocrine adenomas cells.this work was recognized by the 1995 AGA Industry Scholar Award. a. Todisco A, Campbell V, Dickinson CJ, Del Valle J, Yamada T. Molecular basis for somatostatin action: inhibition of c-fos expression and AP-1 binding. Am J Physiol. 267:G245-G 253, b. Todisco A, Seva C, Takeuchi Y, Dickinson CJ, Yamada T. Somatostatin inhibits AP-1 function via multiple protein phosphatases. Am J Physiol. 269:G160-G166, c. Todisco A, Takeuchi Y, Yamada J, Sadoshima JI, Yamada T. Molecular mechanisms for somatostatin inhibition of c-fos gene expression. Am J Physiol. 272:G721-G726, 1997.

3 2. An additional focus of my laboratory has been to define the signal transduction pathways that mediate the growth promoting and anti-apoptotic actions of the gastrointestinal hormone gastrin. In these investigations I made the novel observation that gastrin induces early gene expression and that it inhibits pancreatic cancer cell apoptosis through the induction of protein kinase B/Akt. In additional investigations I examined the signaling mechanisms activated by glycine-extended intermediates of progastrin post-translational processing (G-Gly), the substrate for formation of carboxyl-terminally amidated gastrins, which were found to exert growth-promoting effects of their own via interaction with distinct receptors. These studies demonstrated that gastrin stimulates cell proliferation by inducing early gene expression, while G-Gly acts by regulating post-translationally early gene transcriptional activation. These findings represented a novel model in which both the precursor and the product of a key processing reaction, peptide -amidation, act cooperatively to stimulate cell proliferation via distinct receptors linked to different signal transduction pathways. Part of this work was recognized by the 1996 Henry Christian Award for Excellence in Clinical Research from the AFCR Foundation. a. Todisco A, Takeuchi Y, Seva C, Dickinson CJ, Yamada T. Gastrin and Glycine-extended progastrin processing intermediates induce different programs of early gene activation. J Biol Chem. 270: , b. Stepan VM, Tatewaki M, Matsushima M, Dickinson CJ, Del Valle J, Todisco A. Gastrin induces c- fos gene transcription via multiple signaling pathways. Am J Physiol. 276:G415-G424, c. Todisco A, Ramamoorthy S, Witham T, Pausawasdi N, Srinivasan S, Dickinson CJ, Askari FK, Krametter D. Molecular mechanisms for the anti-apoptotic action of gastrin. Am J Physiol. 280:G , d. Stepan V, Ramamoorthy S, Pausawasdi N, Logsdon CD, Askari FK, Todisco A. Role of small GTP- binding proteins in the growth promoting and anti-apoptotic actions of gastrin. Am J Physiol. 287:G , My laboratory has had a long-standing interest in the molecular mechanisms that regulate the biological functions of the gastric parietal cells, highly specialized gastric epithelial cells that appear to play an important role in the complex process of differentiation and development of multiple cell lineages in the stomach. My studies have identified a series of novel signaling mechanisms that regulate parietal cell homeostasis and gastric acid production. In particular, I reported that protein kinase B/Akt regulates H/K- ATPase expression and gastric acid secretion and that prolonged exposure of the parietal cells to growth factors, such as EGF, leads to their morphological and functional modification through MAPK-dependent mechanisms. I also made the novel observation that protein kinase B/Akt links EGF signaling to Sonic Hedgehog expression and release by the parietal cells. These studies have underscored the importance of MAPK, Shh and EGF signaling in gastric epithelial cell proliferation and differentiation. a. Todisco A, Pausawasdi N, Ramamoorthy S, Del Valle J, Van Dyke RW, Askari FK. Functional role of protein kinase B/Akt in gastric acid secretion. J Biol Chem. 276: , b. Stepan V, Pausawasdi N, Ramamoorthy S, Todisco A. The Akt and MAPK signal transduction pathways regulate growth factors actions in isolated gastric parietal cells. Gastroenterology 127: , c. Stepan V, Ramamoorthy S, Nitsche H, Zavros Y, Merchant JL, Todisco A. Regulation and function of the Sonic Hedgehog (Shh) signal transduction pathway in isolated gastric parietal cells. J Biol Chem. 280: , d. Waghray M, Zavros Y, Saqui-Salces M, Todisco A, Eaton KA, Merchant JL. Interleukin1β promotes gastric atrophy through suppression of sonic hedgehog. Gastroenterology 138: , PMCID: PMC My most recent work has been focused on understanding the mechanisms involved in the pathogenesis of dysplasia in the context of chronic inflammation of the gastric mucosa. In a series of published studies I examined the role of BMP signaling in the regulation of gastric epithelial cell growth and differentiation by generating transgenic mice that express the BMP inhibitor noggin in the stomach. These investigations have demonstrated that loss of BMP signaling leads to the development of a reduced number of parietal cell, to induction of epithelial cell proliferation, to increased level of expression of growth factors, and to

4 enhanced activation of MAPK/ERK2 signaling. Moreover, I reported that expression of noggin causes the occurrence of SPEM, a type of metaplasia that has been associated with the development of gastric neoplasias. In additional studies I observed that inhibition of BMP signaling in the stomach enhances Helicobacter-induced inflammation, accelerates the development of dysplasia, and it increases the expression and activation of the pro-oncogenic molecule STAT3. The significance of these investigations was underscored by an editorial article published in Gastroenterology in conjunction with our paper (Gastroenterology 139(6): , 2010) and by the listing of our manuscript on the anti-inflammatory actions of BMP signaling in the July 24, 2014, issue of AGA e-digest, an electronic notification system from the AGA that reports the latest and most significant news affecting the science and practice of Gastroenterology. This work was also recognized by the 2010 AGA/R. Robert and Sally D. Funderburg Research Scholar Award in Gastric Biology Related to Cancer. a. Shinohara M, Mao M, Keeley TM, El-Zaatari M, Lee HJ, Eaton KA, Samuelson LC, Merchant JL, Goldenring JR, Todisco A. Bone Morphogenetic Protein signaling Regulates Gastric Epithelial Cell Development and Proliferation in Mice. Gastroenterology 139(6): e PMCID: PMC b. Takabayashi H, Shinohara M, Mao M, Phaosawasdi P, El-Zaatari M, Zhang M, Ji T, Eaton KA, Dang D, Kao J, Todisco A. Anti-inflammatory Activity of Bone Morphogenetic Protein Signaling Pathways in Stomachs of Mice. Gastroenterology 147(2): e2, PMCID: PMC c. Ji T, Takabayashi H, Mao M, Han X, Xue X, Brazil JC, Eaton KA, Shah YM, Todisco A. Regulation and function of Bone Morphogenetic Protein Signaling in colonic injury and inflammation. Am J Physiol Gastrointest Liver Physiol. 1;312(1):G24-G33, PMCID: PMC d. Ye W, Takabayashi H, Yang Y, Mao M, Hibdon ES, Samuelson LC, Eaton KA, Todisco A. Regulation of gastric Lgr5+ve cell homeostasis by Bone Morphogenetic Protein (BMP) signaling and inflammatory stimuli. Cell Mol Gastroenterol Hepatol. 2018, in press. Complete List of Published Work in MyBibliography: ascending. D. Additional Information: Research Support and/or Scholastic Performance Ongoing Research Support University of Michigan Comprehensive Cancer Center John S. and Suzanne C. Munn Cancer Fund "Regulation of gastric metaplasia, dysplasia and neoplasia by Bone Morphogenetic Protein signaling"; Specific Aims of project: 1) To test the hypothesis that BMP signaling regulates Lgr5 cell homeostasis during gastric inflammation in vivo. 2) To test the hypothesis that inflammatory stimuli regulate Lgr5 cells and that BMP signaling modulates this event in vitro. 06/01/ /31/2018 (total: $75,000) National Institute of Health (1-R56-DK ) "Regulation of gastric metaplasia, dysplasia and neoplasia by Bone Morphogenetic Protein signaling"; Specific Aims of project: 1) To test the hypothesis that BMP signaling regulates Lgr5 cell homeostasis during gastric inflammation in vivo. 2) To test the hypothesis that inflammatory stimuli regulate Lgr5 cells and that BMP signaling modulates this event, in vitro. 3) To test the hypothesis that gastric cancer, gastritis and intestinal metaplasia exhibit abnormal BMP expression and signaling. 09/30/ /29/2018 (total: $375,677)

5 Completed Research Support UMOR-FGA Todisco (PI) 04/01/16 03/31/17 OVPRE Bridge Funding Bone Morphogenic Protein Signaling regulates gastric progenitor cell homeostasis during gastric inflammation. Specific Aims of Project: 1) To test the hypothesis that BMP signaling regulates Lgr5 cell homeostasis during gastric inflammation in vivo. 2) To test the hypothesis that inflammatory stimuli regulate Lgr5 cell fate and function and that BMP signaling modulate these events, in vitro. 3) To test the hypothesis that gastric cancer, gastritis and intestinal metaplasia exhibit abnormal expression of BMPs and of BMP signaling molecules. BMRC Todisco (PI) 04/01/16 03/31/17 Bridge Funding Bone Morphogenic Protein Signaling regulates gastric progenitor cell homeostasis during gastric inflammation Specific Aims of Project: 1) To test the hypothesis that BMP signaling regulates Lgr5 cell homeostasis during gastric inflammation in vivo 2) To test the hypothesis that inflammatory stimuli regulate Lgr5 cell fate and function and that BMP signaling modulate these events, in vitro. 3) To test the hypothesis that gastric cancer, gastritis and intestinal metaplasia exhibit abnormal expression of BMPs and of BMP signaling molecules. R01 DK A2 Todisco (PI) 04/01/11-03/31/16 National Institute of Health Anti-inflammatory Actions of Bone Morphogenetic Proteins (BMPs) in the Stomach Specific Aims of Project: 1) To test the hypothesis that inflammatory stimuli regulate BMP expression. 2) To test the hypothesis that the BMPs exert anti-inflammatory actions in vivo. 3) To test the hypothesis that BMP-4 inhibits the expression of pro-inflammatory molecules in gastric epithelial cells. FDHN Todisco (PI) 01/01/11-12/31/12 Foundation for Digestive Health and Nutrition AGA/R. Robert and Sally D. Funderburg Research Scholar Award in Gastric Biology Related to Cancer Physiological Significance of Bone Morphogenic Signaling in Gastric Epithelial Homeostasis Specific Aims of Project: The overall goal of this application is to investigate the function of BMP signaling in the regulation of inflammatory mechanisms in the gastric mucosa by using in vivo approaches. R56 DK A2 Todisco (PI) 07/15/08-06/30/11 Regulation and Function of Sonic Hedgehog Signaling in the Stomach Specific Aims of Project: 1) To test the hypothesis that Shh promotes the expression of markers of parietal cell differentiation. 2) To test the hypothesis that Shh and BMP-4 inhibit gastric epithelial cell proliferation. 3) To test the hypothesis that Shh and BMP-4 regulate the process of parietal cell differentiation and maturation in vivo, by analyzing transgenic mice expressing inhibitors of both Shh and BMP-4 signaling.