Dr Lin-Hua Jiang

Profile

Dr Jiang studied BSc in Physics and MSc in Biophysics in the Department of Physics at East China Normal University in China, and PhD in Pharmacology in the School of Biomedical Sciences at University of Leeds. He received postdoctoral training in the Department of Biomedical Science at University of Sheffield. He returned to Leeds in 2004 as a University Research Fellow and established his independent research group in the School of Biomedical Sciences at University of Leeds, supported by a prestigious five-year Wellcome Trust University Award. He became a lecturer in Membrane Biology in 2006. He has contributed >110 original research and review articles, with h-index of 38 (Scopus) (https://www.scopus.com/authid/detail.uri?authorId=35200765000). He has been invited to review manuscripts for >100 SCI journals. Currently, he is Associate Editor or Member of Editorial Board of Antioxidants, Cells, Current Research in Pharmacology and Drug Discovery, Frontiers in Bioscience-Landmark, Frontiers in Pharmacology, and Scientific Reports.

Research interests

Molecular and structural mechanisms of calcium-permeable ion channels in health and disease

The research in my laboratory aims to understand the molecular and structural mechanisms of calcium-permeable channels in health and disease and to develop novel inhibitors as research tools and therapeutics, focusing on the following areas.

TRPM2 channel in oxidative stress signalling

The transient receptor potential melastatin 2 (TRPM2) channel is a calcium-permeable cation channel gated by cytosolic ADP-ribose. Our studies contribute to the understanding of the molecular basis determining the channel assembly, ion permeation, ligand binding and functional regulation (Mei et al., 2006; Xia et al., 2008; Yang et al., 2010, 2011; Zou et al., 2011; Yu et al., 2017, 2019; Yu et al., 2021). We are interested in the molecular and structural basis for ligand binding, channel gating, and allosteric modulation by combining molecular biology and electrophysiology with structural biology and computational modelling.

The TRPM2 channel is activated by reactive oxygen species (ROS) and acts as a key molecular sensor or mediator of oxidative stress, which is an important factor in normal ageing and age-related pathological conditions (Jiang et al., 2010, 2018; Li et al., 2015; Syed Mortadza et al., 2015; Malko et al., 2019; Mai et al., 2020; Malko and Jiang, 2020; Ding et al., 2021). Our work contributes to the understanding of the TRPM2 channel mechanisms in ischemic stroke, Alzheimer's and Parkinson's diseases, ischemic stroke and other oxidative stress-related pathologies (Ye et al., 2014; Syed Mortadza et al., 2017, 2018; Li et al., 2017; Jiang et al. 2017; Li and Jiang, 2018, 2019; Wang et al., 2020; Hu et al., 2021).  We are interested in TRPM2-dependent signalling mechanisms that underpin ageing and age-related diseases in the central nervous system that lead to a progressive decline of cognitive function. We are also interested in developing TRPM2 channel inhibitors or allosteric modulators as research tools and therapeutics, and understand the molecular mechanisms of their actions. 

P2X7 receptor in ATP-induced purinergic signalling

The P2X7 receptor, while belonging to the P2X receptor family of ATP-gated calcium-permeable cation channels, exhibits unique functional and pharmacological properties (Jiang et al., 2013; Di Virgilio et al., 2019; Jiang et al., 2021). We are interested in the structural basis that governs ligand binding, channel gating, and ion permeation (Bradley et al., 2010, 2011; Caseley et al., 2015, 2017, 2020, 2021), using molecular biology and electrophysiology in combination with cryo-EM and structural modelling.

Activation of the P2X7 receptor requires high levels of extracellular ATP, which is associated with tissue damage and inflammation and also a salient feature of tumour microenvironments. The P2X7 receptor plays a critical role in normal immune responses, but changes its expression or function increase the susceptibility to various conditions such as cancer development, anxiety and depression (Caseley et al., 2014; Roger et al., 2015; Wei et al., 2018; Jiang  and Roger, 2020). We are interested in P2X7-dependent signalling mechanisms in the pathogenesis and progression of these conditions (Jelassi et al., 2013; Brisson et al., 2020).

We were the first to report brilliant blue G as a P2X7 antagonist (Jiang et al., 2000), which has been widely used as the pharmacological intervention in both in vitro and in vivo studies to unravel previously unknown physiological and pathological roles of the P2X7 receptor. Our collaborative research has identified emodin, a natural compound with anti-inflamamtory properties, as a P2X7 antagonist and shows its effectiveness in inhibiting P2X7-mediated cancer cell metastasis (Liu et al., 2010; Jelassi et al., 2013). With the increasing availability of structural information, we are interested in using structure-guided approaches to develop novel P2X7 antagonists (Caseley et al., 2016).

Ionic signalling mechanisms in mesenchymal stem cell functions

Mesenchymal stem cells (MSCs) hold great promise in cell-based therapies and tissue regeneration. The extrinsic and intrinsic signals and associated signalling mechanisms that control or regulate MSC proliferation, migration and differentiation are still poorly understood.  We are interested in identifying the extrinsic signalling molecules and related intrinsic mechanisms in MSCs. Our recent studise have revealed calcium-permeable channels (P2X recptor, calcium release-activated calcium channels and Piezo1 channel)  and calcium-activated potassium channel play an important role in the regulaiton of MSC function (Peng et al., 2016; Jiang et al., 2017; Wei et al., 2019; Jia et al., 2020; Mousawi et al., 2020). We are also interested in exploring the translational potential of manipulating such signalling mechanisms in tissue engineering.

Our researches have been supported by (1) grants from Wellcome Trust, BBSRC, Royal Society, and Alzheimer Research Trust; (2) scholarships to talented postgraduate students from BBSRC, EPSRC, Wellcome Trust, University of Leeds, Chinese Scholar Council and other governmental agencies; and (3) productive collaborations with scientists in diverse disciplines in and outside of Leeds.

Representative recent publications (since 2018) [*: senior author(s); IF: the latest journal impact factor]

• Li, X. and Jiang, L.-H.* (2018) Multiple molecular mechanisms form a positive feedback loop driving amyloid β42 peptide-induced neurotoxicity via activation of the TRPM2 channel in hippocampal neurons. Cell Death & Disease 9:195 (IF9.685)
• Syed Mortadza, S.A., Sim, J.A., Neubrand, V.E. and Jiang, L.-H.* (2018) A critical role of TRPM2 channel in Aβ₄₂-induced microglial activation and generation of tumour necrosis factor-α. Glia 66:562-575 (IF8.073)
• Wei, L., Syed Mortadza, S.A., Yan, J., Zhang, L., Wang, L., Yin, Y., Li, C., Chalon, S., Emond, P., Belzung, C., Li, D., Lu, C., Roger, R. and Jiang, L.-H.* (2018) ATP-activated P2X7 receptor in the pathophysiology of mood disorders and as an emerging target for the development of novel antidepressant therapeutics. Neuroscience & Biobehavioral Reviews 87:192-205 (IF9.995)
• Jiang, L.-H.*, Li, X., Syed Mortadza, S.A., Lovatt, M. and Yang, W. (2018) The TRPM2 channel nexus from oxidative damage to Alzheimer’s pathologies: an emerging novel intervention target for age-related dementia. Aging Research Reviews 47:67-79 (IF11.788)
• Li, X. and Jiang, L.-H.* (2019) A critical role of the TRPM2 channel in a positive feedback mechanism for ROS-induced delayed cell death. Journal of Cellular Physiology 234:3647-3660 (IF6.513)
• Yu, P., Liu, Z., Yu, X., Ye, P., Liu, H., Xue, X., Yang, L., Li, Z., Wu, Y., Fang, C., Zhao, Y.J., Yang, F., Luo, J.H., Jiang, L.-H., Zhang, L., Zhang, L. and Yang, W. (2019) Direct gating of the TRPM2 channel by cADPR via specific interactions with the ADPR binding pocket. Cell Reports 27:3684-3695 (IF9.995)
• Mousawi, F., Peng, H., Li, J., Sreenivasan, P., Roger, S., Zhao, H., Yang, X.B. and Jiang, L.-H.* (2020) Chemical activation of the Piezo1 channel drives mesenchymal stem cell migration via inducing ATP release and activation of P2 receptor purinergic signalling. Stem Cells 38:410-421 (IF5.845)
• Brisson, L., Chadet, S., Lopez-Charcas, O., Jelassi, B., Ternant, D., Chamouton, J., Lerondel, S., Le Pape, A., Couillin, I., Gombault, A., Trovero, F., Chevalier, S., Besson, P., Jiang, L.-H. and Roger, S. (2020) P2X7 receptor promotes mouse mammary cancer cell invasiveness and tumour progression, and is a target for anticancer treatment. Cancers 12: E2342 (IF6.575)
• Wang, M., Li, J., Dong, S., Cai, X., Simaiti, A., Yang, X., Zhu, X., Luo, J., Jiang, L.-H., Du, B., Yu, P. and Yang, W. (2020) Silica nanoparticles induce lung inflammation in mice via ROS/PARP/TRPM2 signaling-mediated lysosome impairment and autophagy dysfunction. Particle & Fibre Toxicology 17:23 (IF9.112)
• Malko, P. and Jiang, L.-H.* (2020) TRPM2 channel-mediated cell death: an important mechanism linking oxidative stress-inducing pathological factors to associated pathological conditions. Redox Biology 37:101755 (IF10.787)
• Yu, X., Xie, Y., Zhang, X., Ma, C., Liu, L., Zhen, W., Xu, L., Zhang, J., Zhao, L., Gao, X., Yu, P., Luo, J., Jiang, L.-H., Nie, Y., Yang, F., Guo, J. and Yang, W. (2021)  Structural and functional basis of the selectivity filter as a gate in human TRPM2 channel. Cell Reports 37:110025 (IF9.995)
• Chadet, S., Allard, J., Brisson, L., Lopez-Charcas, O., Lemoine, R., Heraud, A., Lerondel, S., Guibon, R., Fromont, G., Le Pape, A., Angoulvant, D., Jiang, L.-H., Murrell-Lagnado, R, and Roger, S. (2022) P2X4 receptor promotes mammary cancer progression by sustaining 3 autophagy and associated mesenchymal transition. Oncogene 41: 2920-2931 (8.756)
• Yin, Y.-L., Wang, H.-H., Gui, Z.-C., Mi, S., Guo, S., Wang, Y., Wang, Q.-Q., Yue, R.-Z., Lin, L.-B., Fan, J.-X., Zhang, X., Mao, B.-Y., Liu, T.-H., Wan, G.-R., Zhan, H.-Q., Zhu, M.-L., Jiang, L.-H.* and Li, P.* (2022) Citronellal attenuates oxidative stress–induced mitochondrial damage through TRPM2/NHE1 pathway and effectively inhibits endothelial dysfunction in type 2 diabetes mellitus. Antioxidants 11: 2241-2241 (IF7.675)
• Malko, P., Jia, X.L., Wood, I. and Jiang, L.H.* (2022) Piezo1 channel-mediated Ca2+ signalling inhibits LPS-induced activation of the NF-κB inflammatory signalling pathway and generation of TNF-α and IL-6 in microglial cells. Glia (in press) (IF8.073)

The following projects are currently available for PhD and MSc by Research studies. Individuals who are interested in our research are warmly welcome to join us. The lab can supports suitable candidates to apply for China Scholar Council/University of Leeds joint scholarship, and other governmental PhD scholarships. Please email to: l.h.jiang@leeds.ac.uk before application.

• TRPM2 channel signalling in neurodegeneration related to ageing, ischemic stroke and neurodegenerative diseases
• TRPM2 channel signalling in neuroinflammation contributing to ageing, age-related neurodegenerative and psychiatric diseases
• Regulation of TRPM2 channel expression and trafficking by interacting proteins
• Structural basis of TRPM2 channel gating and interactions with ligands
• Structure-guided design of TRPM2 channel antagonists and negative allosteric modulators

• P2X7 receptor signalling in neuroinflammation contributing to ageing, age-related neurodegenerative and psychiatric diseases
• Structural basis of P2X7 receptor gating and interactions with ligands
• Structure-guided design of P2X7 receptor antagonists and negative allosteric modulators

• ATP-induced purinergic signalling in regulating stem cell functions
• ATP-induced purinergic signalling in regulating cancer cell functions

• Mechanical signalling in regulating stem cell functions
• Mechanical signalling in regulating cancer cell functions

• Ionic signalling mechanisms underlying brain cell-substrate interactions

• Development of novel 2D and 3D cell-supporting substrates/scaffolds for neural tissue engineering

Current lab members

• Philippa Malko, PhD student
• Najoud Alsayegh, PhD student

Lab alumni

• Zhuzhong Mei (2004-2007), Research fellow
• Rong Xia (2005-2009), PhD student
• Hongju Mao (2005-2006), Research fellow
• Xing Liu (2006-2009), Research fellow
• Helen J Bradley (2006-2010), PhD student
• Wei Yang (2009-2011), Research fellow
• Jie Zou (2009-2014), PhD student
• Hongsen Peng (2010-2015), PhD student
• Emily A Caseley (2013-2016), PhD student
• Xin Li (2013-2017), PhD student
• Sharifah A Syed Mortadza (2013-2017), PhD student
• Yunjie Hao (2014-2015), MSc by Research student
• Fatema Mousawi (2015-2019), PhD student
• Harneet Mankoo (2017-2019), MSc by Research student
• John Brewster (2016-2021), PhD student
• Zijian Han (2021-2022), Master by Research in Neuroscience student

Qualifications

• PhD in Pharmacology, University of Leeds
• MSc in Biophysics, East China Normal University, China
• BSc in Physics, East China Normal University, China

Projects

<li><a href="//phd.leeds.ac.uk/project/419-structure-guided-development-of-p2x7-receptor-inhibitory-ligands">Structure-guided development of P2X7 receptor inhibitory ligands</a></li> <li><a href="//phd.leeds.ac.uk/project/418-trpm2-channel-mechanism-of-neuroinflammation-and-neurodegeneration">TRPM2 channel mechanism of neuroinflammation and neurodegeneration</a></li>