1 - Grey has made important contributions to our understanding of TNFAIP3’s function in inflammation (~22 publications & x3 PhD thesis focused on A20 biology), having being the first to identify A20/TNFAIP3 as an tissue [islet] expressed gene (Grey, JEM 1999) and more recently showing how A20 variants tune inflammation (Grey last author Nat. Immunol 2019). The latter study was highlighted in commentaries in both Nature Immunology and Nature Reviews Immunology. Further studies highlight how A20 contributes to Mendelian disease in patients treated at UNSW has been reviewed with positive comments and invited resubmission (J. Clinical Investigation Citescore: 17).

a. Nathan W. Zammit, Owen M. Siggs, Paul Gray, Keisuke Horikawa et., al Shane T. Grey. Denisovan, modern human, and mouse TNFAIP3 alleles tune A20 phosphorylation and immunity. Nature Immunology Sept 2019.

**Cover article and released with a commentary & Altmetric score 200+.

b. Zammit NW, Walters SN, Seeberger KL, O'Connell PJ, Korbutt GS, Grey ST. A20 as an immune tolerance factor can determine islet transplant outcomes.

JCI Insight. 2019 Nov 1;4(21):e131028.

c.   D Liuwantara, M Elliot, MW Smith, AO Yam, ... Grey, ST. Nuclear Factor κB Regulates β Cell Death A Critical Role for A20 in β Cell Protection. Diabetes 2006, 55 (9), 249173;2501. PMID: 16936197

d.   Daniel S, Arvelo MB, Patel VI, Longo CR, Shrikhande G, Shukri T, Mahiou J, Sun DW, Mottley C, Grey ST, Ferran C. A20 protects endothelial cells from TNF-, Fas-, and NK-mediated cell death by inhibiting caspase 8 activation. Blood. 2004 Oct 15;104(8):2376-84. PMID:15251990

e.   Grey ST*, Longo C, Shukri T, Patel VI, Csizmadia E, Daniel S, Arvelo MB, Tchipashvili V, Ferran C*.

Genetic engineering of a suboptimal islet graft with A20 preserves beta cell mass and function. J Immunol. 2003 Jun 15;170(12):6250-6. PMID:12794157. *Grey is equal senior & co-corresponding author.

f. Shane T. Grey*, Maria B. Arvelo, Wendy Hasenkamp, Fritz H. Bach, Christiane Ferran*. A20 Inhibits Cytokine-Induced Apoptosis and NF-kB Dependent Gene Activation in Islets. J. Exp. Med., 1999, 190 (8), 1135-1145. PMID:10523611. *Grey is equal senior & co-corresponding author.

2 - Further, A20 regulates the NF-kB system and Grey has identified key functional components of the NF-kB system in pancreatic islets including BIRC 2&3, TRAF2&3, NIK; as well as A20.

a.   Zammit NW, Grey ST. Equipping the islet graft for self defence: targeting nuclear factor κB and implications for tolerance. Curr Opin Organ Transplant. 2018 Feb;23(1):97-105. PMID:29120883

b.   Malle EK, Zammit NW, Walters SN, Koay YC, Wu J, Tan BM, Villanueva JE, Brink R, Loudovaris T, Cantley J, McAlpine SR, Hesselson D, Grey ST. Nuclear factor κB-inducing kinase activation as a mechanism of pancreatic β cell failure in obesity. J Exp Med. 2015 Jun 29. PMID:26122662.

*Released with commentary.

c.   B. M. Tan, N. W. Zammit, A. O. Yam, R. Slattery, S. N. Walters, E. Malle and S. T. Grey. BIRC proteins fine-tune TNF-induced NF-kB and JNK signalling in pancreatic beta cells. Diabetologia. 2013 Mar;56(3):520-32. PMID: 23250032

d.   Zammit NW, Tan BM, Walters SN, Liuwantara D, Villanueva JE, Malle EK, Grey ST. Low-dose rapamycin unmasks the protective potential of targeting intragraft NF-κB for islet transplants. Cell Transplant. 2013;22(12):2355-66. PMID:23127588

e. Zammit NW, Wong YY, Walters SN, Warren J, Barry SC, Grey ST. RELA governs a network of islet-specific metabolic genes necessary for beta cell function. Diabetologia. 2023 Aug;66(8):1516-1531. PMID: 37311878

3 - Grey has made important contributions to clinical translation of islet transplantation, through the development of novel islet trophic factors with translational potential, and significantly, as a lead co-PI on Australia’s first clinical islet transplant trial. This trial changed Australian medical practice with the Federal adoption (reimbursed through NFC scheme) of islet transplantation as a treatment for some T1D patients and resulted in a number of clinical/translational research papers highlighted below. In further translation, this application seeks support to develop A20 as an anti-inflammatory agent for use in islet transplantation. Excitingly, this work is advancing with the RAH being the intended performance site for this first in human study – in collaboration with Professor Toby Coates. Grey’s experience in clinical translation and understanding in speaking the languages of basic and clinical science strongly supports his translational capabilities.

a.   Loh K, Shi YC, Walters S, Bensellam M, Lee K, Dezaki K, Nakata M, Ip CK, Chan JY, Gurzov EN, Thomas HE, Waibel M, Cantley J, Kay TW, Yada T, Laybutt DR, Grey ST*, Herzog H*. Inhibition of Y1 receptor signaling improves islet transplant outcome. Nat Commun. 2017 Sep 8;8(1):490. PMID:2888756. *Grey is equal senior & co-corresponding author.

b.   O'Connell PJ, Holmes-Walker DJ, Goodman D, Hawthorne WJ, Loudovaris T, Gunton JE, Thomas HE, Grey ST, Drogemuller CJ, Ward GM, Torpy DJ, Coates PT, Kay TW; Australian Islet Transplant Consortium. Multicenter Australian trial of islet transplantation: improving accessibility and outcomes. Am J Transplant. 2013 Jul;13(7):1850-8. PMID:23668890

c.   Cowley MJ, Weinberg A, Zammit N, Walters SN, Hawthorne WJ, Loudovaris T, Thomas H, Kay T, Gunton JE, Alexander SI, Kaplan W, Chapman J, O'Connell PJ, Grey ST. Human islets express a marked pro-inflammatory molecular signature prior to transplantation. Cell Transplant. 2012 Mar 8. PMID:22404979

d.   James Cantley, Stacey N Walters, Min-Ho Jung, Anita Weinberg, Mark J Cowley, Warren Kaplan, Wayne J Hawthorne, Philip J O’Connell, Gordon Weir, Shane T Grey. A pre-existent hypoxic gene signature predicts impaired islet graft function and glucose homeostasis. Cell Transplant. 2012 Oct 31. PMID:23127310.

4 – Grey has a developing expertise in cancer research and is building skills, knowhow and collaborative networks within this space. This capacity will support the feasibility and success of his new oncology program; supported by his newly minted NHMRC (~$1 million) Ideas grant. Preliminary data for the oncology program was generated by 2 sequential PanKind peer reviewed research grants.

a. Vennin C, Mélénec P, Rouet R, Nobis M, Cazet AS, Murphy KJ, Herrmann D, Reed DA, Lucas MC, Warren SC, Elgundi Z, Pinese M, Kalna G, Roden D, Samuel M, Zaratzian A, Grey ST, et al., Timpson P. CAF hierarchy driven by pancreatic cancer cell p53-status creates a pro-metastatic and chemoresistant environment via perlecan. Nat Commun. 2019 Aug 12;10(1):3637.

b. Chou A, Froio D, Nagrial AM, Parkin A, Murphy KJ, Chin VT, Wohl D, Steinmann A, Stark R, Drury A, Walters SN, Vennin C, Burgess A, Pinese M, Chantrill LA, Cowley MJ, Molloy TJ; Australian Pancreatic Cancer Genome Initiative (APGI), Waddell N, Johns A, Grimmond SM, Chang DK, Biankin AV, Sansom OJ, Morton JP, Grey ST, et al.,  Pajic M. Tailored first-line and second-line CDK4-targeting treatment combinations in mouse models of pancreatic cancer. Gut. 2018 Dec;67(12):2142-215

c. Nobis M, Herrmann D, Warren SC, Kadir S, Leung W, Killen M, Magenau A, Stevenson D, Lucas MC, Reischmann N, Vennin C, Conway JRW, Boulghourjian A, Zaratzian A, Law AM, Gallego-Ortega D, Ormandy CJ, Walters SN, Grey ST, et al.,  Timpson, P. A RhoA-FRET Biosensor Mouse for Intravital Imaging in Normal Tissue Homeostasis and Disease Contexts. Cell Rep. 2017 Oct 3;21(1):274-288.

d. Vennin C, Chin VT, Warren SC, Lucas MC, Herrmann D, Magenau A, Melenec P, Walters SN, Del Monte-Nieto G, Conway JR, Nobis M, Allam AH, McCloy RA, Currey N, Pinese M, Boulghourjian A, Zaratzian A, Adam AA, Heu C, Nagrial AM, Chou A, Steinmann A, Drury A, Froio D, Giry-Laterriere M, Harris NL, Phan T, Jain R, Weninger W, McGhee EJ, Whan R, Johns AL, Samra JS, Chantrill L, Gill AJ, Kohonen-Corish M, Harvey RP, Biankin AV; Australian Pancreatic Cancer Genome Initiative (APGI), Evans TR, Anderson KI, Grey ST, et al., Timpson P. Transient tissue priming via ROCK inhibition uncouples pancreatic cancer progression, sensitivity to chemotherapy, and metastasis. Sci Transl Med. 2017 Apr 5;9(384):

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e. Erami Z, Herrmann D, Warren SC, Nobis M, McGhee EJ, Lucas MC, Leung W, Reischmann N, Mrowinska A, Schwarz JP, Kadir S, Conway JRW, Vennin C, Karim SA, Campbell AD, Gallego-Ortega D, Magenau A, Murphy KJ, Ridgway RA, Law AM, Walters SN, Grey ST, et al., Timpson P. Intravital FRAP Imaging using an E-cadherin-GFP Mouse Reveals Disease- and Drug-Dependent Dynamic Regulation of Cell-Cell Junctions in Live Tissue. Cell Rep. 2016 Jan 5;14(1):152-167.