Dr Lin-Hua Jiang
- Position: Lecturer in Membrane Biology
- Areas of expertise: calcium channels; neurodegeneration; neuroinflammation; stem cell; cancer cell; drug discovery; neural tissue engineering
- Email: L.H.Jiang@leeds.ac.uk
- Phone: +44(0)113 343 4231
- Location: 6.44e Garstang Building
- Website: Googlescholar | ORCID
Dr Jiang studied BSc in Physics (1982-1987) and MSc in Biophysics (1987-1990) in the Department of Physics at East China Normal University in China, and PhD in Pharmacology (1995-1999) under the supervision of Prof D Wray in the School of Biomedical Sciences at University of Leeds. He received postdoctoral training (1999-2003) in the laboratory of Prof RA North FRS in the Department of Biomedical Science at University of Sheffield. He returned to Leeds in 2004 as a senior University Research Fellow and established his independent research group in the School of Biomedical Sciences at University of Leeds, supported by a five-year Wellcome Trust University Award. Since 2006, he is a lecturer in membrane biology and a research group leader. So far he has contributed 91 original research articles, reviews and book chapters, with h-index of 35 (Google Scholar) or 31 (Scopus).
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-related 2 (TRPM2) channel is gated by cytosolic ADP-ribose. Our studies contribute in better understanding 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., 2014, 2017, 2019). Currently, we are interested in studying the molecular and structural basis for ligand binding, channel gating and allosteric modulation, using molecular biology and electrophysiology in combination with cryo-EM and structural modelling.
The TRPM2 channel is strongly activated in cells exposed to elevated levels of reactive oxygen species (ROS) and acts as a molecular sensor or mediator of oxidative stress, which is a salient characteristic of normal ageing and diverse age-related pathophysiological processes, such as ischemic stroke, Alzheimer's and Parkinson's diseases (Jiang et al., 2010, 2018; Li et al., 2015; Syed Mortadza et al., 2015; Malko et al., 2019; Mai et al., 2019). The TRPM2 channel has been shown to be important in mediating ROS-associated neurodegeneration and neuroinflammation (Ye et al., 2014; Syed Mortadza et al., 2017, 2018; Li et al., 2017; Li and Jiang, 2018, 2019; An et al., 2019). We are currently investigating TRPM2-dependent signalling mechanisms underpinning normal ageing and age-related diseases that lead to a progressive decline or loss of cognitive function.
TRPM2-specific inhibitor or antagonist is still scarce. We are interested in developing TRPM2 channel inhibitors as research tools and therapeutics and understand the mechanisms of actions, by combining molecular biology, structural biology and electrophysiology,
P2X7 receptor in ATP-induced purinergic signalling
The P2X7 receptor, while belonging to the ATP-gated channel P2X receptor family, exhibits unique functional and pharmacological properties (Jiang et al., 2013). 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), using molecular biology and electrophysiology in combination with cryo-EM and structural modelling.
Activation of the P2X7 receptors requires high levels of extracellular ATP, which is associated with tissue damage and inflammation and also a feature of cancer microenvironments. The P2X7 receptor plays a critical role in normal immune response, but changes in the P2X7 receptor expression and/or function increase the susceptibility to various conditions such as cancers, age-dependent macular degeneration, anxiety and depression (Jelassi et al., 2013; Jiang et al., 2013; Caseley et al., 2014; Roger et al., 2015; Wei et al., 2018). We are interested in P2X7-dependent signalling mechanisms in the pathogenesis and progression of these conditions.
We were the first to report brilliant blue G as a P2X7 antagonist (Jiang et al., 2000), which has been widely used as pharmacological intervention 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 that it is effective in inhibiting P2X7-mediated cancer cell metastasis (Liu et al., 2010; Jelassi et al., 2013). With increasing availability of structural information, we are interested in using structure-guided approaches to develop novel P2X7 antagonists (Caseley et al., 2016), particularly brain-penetrable antagonits (Jiang et al., 2018).
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 several calcium signalling mechanisms play an important role in the regulaiton of MSC migration (Peng et al., 2016; Jiang et al., 2017; Mousawi et al., 2019, Wei et al., 2019). 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 Leeds.
Representative recent publications [*: senior author(s); IF: journal impact factor published by Clarivate Analytics in 2019]
- Peng, H.S., Hao, Y.J., Mousawi,F., Roger, S., Li, J., Sim, J. A., Ponnambalam, S., Yang, X.B. and Jiang, L.-H.* (2016) Purinergic and store-operated Ca2+ signalling mechanisms in mesenchymal stem cells and their roles in ATP-induced stimulation of cell migration. Stem Cells 34: 2102-2114 (IF5.614)
- Caseley, E.A., Muench, S.P., Fishwick, C.W. and Jiang, L.-H.* (2016) Structure-based identification and characterisation of structurally novel human P2X7 receptor antagonists. Biochemical Pharmacology 116: 130-139 (IF4.825)
- Zhao, H., Yu, Y., Wu, X., Liu, S., Liu, B., Du, J., Li, B., Jiang, L.-H.* and Feng, X.* (2017) A role of BK channel in regulation of Ca2+ channel in ventricular myocytes by substrate stiffness. Biophysical Journal 112: 1406-1416 (IF3.665)
- Li, X., Yang, W. and Jiang, L.-H.* (2017) Alteration in intracellular Zn2+ homeostasis as a result of TRPM2 channel activation contributes to ROS-induced hippocampal neuronal death. Frontiers in Molecular Neuroscience 10: 414 (IF3.725)
- Jiang, Q., Gao, Y., Wang, C., Liao, M., Wu, Y., Zhan, K., Lu, N., Tao, R., Lu, Y., Wilcox, C.S., Luo, J., Jiang, L.-H.*, Yang, W.* and Han, F.* (2017) Nitration of TRPM2 as a molecular switch induces autophagy during brain pericyte injury. Antioxidants and Redox Signaling 27: 1297-1316 (IF5.828)
- Jiang, L.-H.*, Mousawi, F., Yang, X.B. and Roger, S. (2017) ATP-induced Ca2+-signalling mechanisms in the regulation of mesenchymal stem cell migration. Cellular and Molecular Life Sciences 74: 3697-3710 (IF7.014)
- 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 (IF5.829)
- 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 (IF5.958)
- 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 (IF8.002)
- 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. Ageing Research Review 47: 67-79 (IF10.39)
- 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 (IF4.522)
- Malko, P., Syed Mortadza, S.A., McWilliam, J. and Jiang, L.-H.* (2019) TRPM2 channel in microglia as a new player in neuroinflammation associated with a spectrum of central nervous system pathologies. Frontiers in Pharmacology 10: 239 (IF3.845)
- Yu, P., Liu, Z., Yu, X., Ye, P., 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 (IF7.815)
- Mousawi, F., Peng, H.S., Li, J., Sreenivasan, P., Roger, S., Zhao, H., Yang, X.B. and Jiang, L.-H.* (2019) Chemical activation of the Piezo1 channel drives mesenchymal stem cell migration via inducing ATP release and activation of P2 receptor purinergic signalling. Stem Cells (doi: 10.1002/stem.3114) (IF5.614)
- Mai, C., Mankoo, H., Wei, L., An, X., Li, C., Li, D. and Jiang, L.-H.* (2019) TRPM2 channel: A novel target for alleviating ischaemia-reperfusion, chronic cerebral hypo-perfusion and neonatal hypoxic-ischaemic brain damage. Journal of Cellular and Molecular Medicine (doi: 10.1111/jcmm.14679) (IF4.568)
The following projects are currently available for PhD and MSc by Research studies. Please email to: email@example.com if you are interested in joining us for your postgraduate study.
- 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 neuronal tissue engineering
- 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 (2009-2013), PhD student
- Hongsen Peng (2010-2014), PhD student
- Yunjie Hao (2014-2015), MSc by Research student
- Emily A Caseley (2013-2016), PhD student
- Xin Li (2013-2017), PhD student
- Sharifah (Sherry) A Syed Mortadza (2013-2017), PhD student
- Fatema Mousawi (2015-2019), PhD student
- Harneet Mankoo (2017-2019), MSc by Research student
Current lab members
- John Brewster, PhD student
- Philippa Malko, PhD student
- Xiaoling Jia, Academic visitor
- Quanyou Zhang, Academic visitor
- PhD in Pharmacology, University of Leeds
- MSc in Biophysics, East China Normal University, China
- BSc in Physics, East China Normal University, China
FindaPhD Project details:
<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>