Executive summary. I am an early career cardiovascular scientist with a strong vision to become a leader in medical research. I received my PhD in 2016 from the University of Sydney (USYD). I am currently a Chancellor’s Postdoctoral Research Fellow of the University of Technology Sydney (UTS). I have a proven track record in the fields of cancer and cardiovascular biology. I have published 14 peer-reviewed papers in international journals such as Nature (IF=43.1), Science Advances (IF=12.8), Journal of Experimental Medicine (IF=11.9) and Plos Biology (IF=8.4). I have first/senior authored ~60% of my publications with >180 total citations (last 5 years). I have received 20 international/national awards, research funding of >$800k and given 36 presentations (12 invited, 13 international, 11 national).
Research vision. Cerebral cavernous malformations (CCMs) (also known as cavernoma) are dilated blood vessels that form a non-malignant tumour and potentially fatal condition causing strokes. Commonly detected in the brain in as many as 1/200 individuals, around 20% are familial suggesting a strong genetic basis. CCM is a major cause of stroke in children and young adults who thereby lose disproportionately many years of productive life. Surgery is only effective in few cases and itself leads to complications. Hence discovery of new drugs to prevent and treat CCM is urgently needed. My research aims to understand CCM pathogenesis in order to find safe and effective therapeutic treatment options for CCM using novel mouse models.
Australian Vascular Biology Society (AVBS) (2019-Current)
NSW Cardiovascular Research Network (2019-Current)
Northern America Vascular Biology Organization (NAVBO) (2016-Current),
Angioma Alliance (2016-Current),
The Endocrine Society (ENDO) (2014-2015)
Endocrine Society of Australia (ESA) (2012-2015)
Sydney Catalyst-Translational Cancer Research (2012-2015)
Cancer Research Network-USYD (2011-2015)
Hong, CC, Tang, AT, Detter, MR, Choi, JP, Wang, R, Yang, X, Guerrero, AA, Wittig, CF, Hobson, N, Girard, R, Lightle, R, Moore, T, Shenkar, R, Polster, SP, Goddard, LM, Ren, AA, Leu, NA, Sterling, S, Yang, J, Li, L, Chen, M, Mericko-Ishizuka, P, Dow, LE, Watanabe, H, Schwaninger, M, Min, W, Marchuk, DA, Zheng, X, Awad, IA & Kahn, ML 2020, 'Cerebral cavernous malformations are driven by ADAMTS5 proteolysis of versican.', The Journal of experimental medicine, vol. 217, no. 10.View/Download from: Publisher's site
Cerebral cavernous malformations (CCMs) form following loss of the CCM protein complex in brain endothelial cells due to increased endothelial MEKK3 signaling and KLF2/4 transcription factor expression, but the downstream events that drive lesion formation remain undefined. Recent studies have revealed that CCM lesions expand by incorporating neighboring wild-type endothelial cells, indicative of a cell nonautonomous mechanism. Here we find that endothelial loss of ADAMTS5 reduced CCM formation in the neonatal mouse model. Conversely, endothelial gain of ADAMTS5 conferred early lesion genesis in the absence of increased KLF2/4 expression and synergized with KRIT1 loss of function to create large malformations. Lowering versican expression reduced CCM burden, indicating that versican is the relevant ADAMTS5 substrate and that lesion formation requires proteolysis but not loss of this extracellular matrix protein. These findings identify endothelial secretion of ADAMTS5 and cleavage of versican as downstream mechanisms of CCM pathogenesis and provide a basis for the participation of wild-type endothelial cells in lesion formation.
Li, J, Zhao, Y, Choi, J, Ting, KK, Coleman, P, Chen, J, Cogger, VC, Wan, L, Shi, Z, Moller, T, Zheng, X, Vadas, MA & Gamble, JR 2020, 'Targeting miR-27a/VE-cadherin interactions rescues cerebral cavernous malformations in mice.', PLoS biology, vol. 18, no. 6, p. e3000734.View/Download from: Publisher's site
Cerebral cavernous malformations (CCMs) are vascular lesions predominantly developing in the central nervous system (CNS), with no effective treatments other than surgery. Loss-of-function mutation in CCM1/krev interaction trapped 1 (KRIT1), CCM2, or CCM3/programmed cell death 10 (PDCD10) causes lesions that are characterized by abnormal vascular integrity. Vascular endothelial cadherin (VE-cadherin), a major regulator of endothelial cell (EC) junctional integrity is strongly disorganized in ECs lining the CCM lesions. We report here that microRNA-27a (miR-27a), a negative regulator of VE-cadherin, is elevated in ECs isolated from mouse brains developing early CCM lesions and in cultured ECs with CCM1 or CCM2 depletion. Furthermore, we show miR-27a acts downstream of kruppel-like factor (KLF)2 and KLF4, two known key transcription factors involved in CCM lesion development. Using CD5-2 (a target site blocker [TSB]) to prevent the miR-27a/VE-cadherin mRNA interaction, we present a potential therapy to increase VE-cadherin expression and thus rescue the abnormal vascular integrity. In CCM1- or CCM2-depleted ECs, CD5-2 reduces monolayer permeability, and in Ccm1 heterozygous mice, it restores dermal vessel barrier function. In a neonatal mouse model of CCM disease, CD5-2 normalizes vasculature and reduces vascular leakage in the lesions, inhibits the development of large lesions, and significantly reduces the size of established lesions in the hindbrain. Furthermore, CD5-2 limits the accumulation of inflammatory cells in the lesion area. Our work has established that VE-cadherin is a potential therapeutic target for normalization of the vasculature and highlights that targeting miR-27a/VE-cadherin interaction by CD5-2 is a potential novel therapy for the devastating disease, CCM.
Hansbro, P, Donovan, C, Liu, G, Shen, S, Marshall, J, Kim, R, Alamao, CA, Budden, KF, Choi, JP, Kohonen-Corish, M, El-Omar, EM & Yang, IA 2020, 'The role of microbiome and NLRP3 inflammasome in the gut and the lung', Journal of Leukocyte Biology, vol. accepted 4.7.20.
Li, J, Zhao, Y, Coleman, P, Chen, J, Ting, KK, Choi, JP, Zheng, X, Vadas, MA & Gamble, JR 2019, 'Low fluid shear stress conditions contribute to activation of cerebral cavernous malformation signalling pathways.', Biochimica et biophysica acta. Molecular basis of disease, vol. 1865, no. 11.View/Download from: Publisher's site
Cerebral cavernous malformations (CCMs) are vascular malformations that cause hemorrhagic stroke. CCMs can arise from loss-of-function mutations in any one of CCM1 (KRIT1), CCM2 or CCM3 (PDCD10). Despite the mutation being in all endothelial cells the CCM lesions develop primarily in the regions with low fluid shear stress (FSS). Here we investigated the role of FSS in the signalling pathways associated with loss of function of CCM genes. We performed transcriptomic analysis on CCM1 or CCM2-silenced endothelial cells subjected to various FSS. The results showed 1382 genes were deregulated under low FSS, whereas only 29 genes were deregulated under high FSS. Key CCM downstream signalling pathways, including increased KLF2/4 expression, actin cytoskeleton reorganization, TGF-β and toll-like receptor signalling pathways and also oxidative stress pathways, were all highly upregulated but only under low FSS. We also show that the key known phenotypes of CCM lesions such as disrupted endothelial cell junction, increased inflammatory response/oxidative stress and elevated RhoA-ROCK activity, are only exhibited in monolayers of CCM-silenced endothelial cells subjected to low FSS. Our data establishes that shear stress acts as a previously unappreciated but important regulator for CCM gene function and may determine the site of CCM lesion development.
Choi, JP, Wang, R, Yang, X, Wang, X, Wang, L, Ting, KK, Fo, M, Cogger, V, Yang, Z, Liu, F, Han, Z, Liu, R, Baell, J & Zheng, X 2018, 'Ponatinib (AP24534) inhibits MEKK3-KLF signaling and prevents formation and progression of cerebral cavernous malformations', SCIENCE ADVANCES, vol. 4, no. 11.View/Download from: Publisher's site
Choi, JP, Yang, X, Foley, M, Wang, X & Zheng, X 2017, 'Induction and Micro-CT Imaging of Cerebral Cavernous Malformations in Mouse Model', JOVE-JOURNAL OF VISUALIZED EXPERIMENTS, no. 127.View/Download from: Publisher's site
Tang, AT, Hoi, JPC, Kotzin, JJ, Yang, Y, Hong, CC, Hobson, N, Girard, R, Zeineddine, HA, Lightle, R, Moore, T, Cao, Y, Shenkar, R, Chen, M, Mericko, P, Yang, J, Li, L, Tanes, C, Kobuley, D, Vosa, U, Whitehead, KJ, Li, DY, Franke, L, Hart, B, Schwaninger, M, Henao-Mejia, J, Morrison, L, Kim, H, Awad, IA, Zheng, X & Kahn, ML 2017, 'Endothelial TLR4 and the microbiome drive cerebral cavernous malformations', NATURE, vol. 545, no. 7654, pp. 305-+.View/Download from: Publisher's site
Choi, JP, Foley, M, Zhou, Z, Wong, W-Y, Gokoolparsadh, N, Arthur, JSC, Li, DY & Zheng, X 2016, 'Micro-CT Imaging Reveals Mekk3 Heterozygosity Prevents Cerebral Cavernous Malformations in Ccm2-Deficient Mice', PLOS ONE, vol. 11, no. 8.View/Download from: Publisher's site
Choi, JP, Zheng, Y, Handelsman, DJ & Simanainen, U 2016, 'Glandular epithelial AR inactivation enhances PTEN deletion-induced uterine pathology', ENDOCRINE-RELATED CANCER, vol. 23, no. 5, pp. 377-390.View/Download from: Publisher's site
Choi, JP, Desai, R, Zheng, Y, Yao, M, Dong, Q, Watson, G, Handelsman, DJ & Simanainen, U 2015, 'Androgen actions via androgen receptor promote PTEN inactivation induced uterine cancer', ENDOCRINE-RELATED CANCER, vol. 22, no. 5, pp. 687-701.View/Download from: Publisher's site
Choi, JP, Zheng, Y, Skulte, KA, Handelsman, DJ & Simanainen, U 2015, 'Development and Characterization of Uterine Glandular Epithelium Specific Androgen Receptor Knockout Mouse Model', BIOLOGY OF REPRODUCTION, vol. 93, no. 5.View/Download from: Publisher's site
Choi, J, Psarommatis, B, Gao, YR, Zheng, Y, Handelsman, DJ & Simanainen, U 2014, 'The role of androgens in experimental rodent mammary carcinogenesis', BREAST CANCER RESEARCH, vol. 16, no. 6.View/Download from: Publisher's site
Zhao, B, Choi, JP, Jaehne, M, Gao, YRE, Desai, R, Tuckermann, J, Zhou, H, Handelsman, DJ & Simanainen, U 2014, 'Glucocorticoid Receptor in Prostate Epithelia is not Required for Corticosteroid-Induced Epithelial Hyperproliferation in the Mouse Prostate', PROSTATE, vol. 74, no. 10, pp. 1068-1078.View/Download from: Publisher's site