Dr. Xu Zhang is a neurobiologist working as a senior principal investigator at the Institute of Neuroscience, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS). He was conferred the Bachelor degree of Medicine from the Fourth Military Medical University (FMMU) in 1985. He received the Ph.D. in the Department of Neuroscience, Karolinska Institute, in 1994 in Sweden. He was appointed as associate professor and professor successively at the Institute of Neuroscience, FMMU. He was recruited as a Principal Investigator in 1999 by the Institute of Neuroscience, SIBS, CAS. He served as the vice president of SIBS, CAS in 2008. Now he is the Vice-President of Shanghai Branch, CAS.
Dr. Zhang’s research is mainly focused on the molecular and cellular mechanisms of neural diseases, such as chronic pain and X-linked intellectual disability. He has found the changes in gene expression patterns of somatosensory ganglia and the spinal cord after nerve injury and inflammation, and several important mechanisms for regulating the functions of neuropeptides, opioid receptors and Na+/K+ pump in the nociceptive sensory neurons. His study also shows that during the brain development, X-linked FGF13 regulates cortical neuron development and loss function of FGF13 causes the defect of learning and memory. Dr. Zhang has published more than one hundred research articles and invited reviews, and contributed to the Wall and Melzack’s Textbook of Pain. Dr. Zhang is an outstanding neuroscientist with international reputation. He has given many lectures at the international conferences, including a plenary lecture at 9th World Congress of International Brain Research Organization in 2015. He was honored several awards including the Prize for Science and Technology from Ho Leung Ho Lee Foundation.
In October 2015, Dr. Zhang answered APBN’s questions on pain modulation and biomedical research in China.
- What are the frontiers of Biomedical Research in China?
Stem cell and developmental biology could be the most advanced biomedical research area in China. In addition to the basic study of cell biology and the novel methods to produce animal models, the development of cell therapies will make significant contributions to medical care in future. Protein science, particularly research protein structural biology, is a rapidly expanding growing research area, and it will facilitate the developments in drug discovery development and disease studies.
- Please discuss on the research growth and the investments into academic research of your field over the last five years.
Neuroscience has always been a major research focus in China, and it has been viewed as one of the scientific disciplines which carries a good weightage of impact factor, and its growth has never ceased. Most investments into neuroscience research are from the Natural Science Foundation, Ministry of Science and Technology, and Chinese Academy of Sciences (CAS). In 2012, CAS started a Strategic Priority Research Program (B), Mapping Brain Functional Connections. This brain research program will last for 10 years. It supports neuroscientists from several CAS institutes and universities, focusing on several functional connections; such as sensory perception, learning and memory, emotion and decision making.
- Chronic and ongoing pain can affect the quality of life of a patient. Are there any target treatments that are available to relieve or to diminish pain?
Peripheral nerve injury may cause chronic pain, also called neuropathic pain, which is less sensitive to agonists of μ-opioid receptor, including morphine. However, there are drug targets appearing in primary sensory neurons and spinal cord neurons after nerve injury, such as the increase of α2/δ1 subunit of Ca2+ channel. It serves as a target for gabapentin, an analgesic use for the treatment of neuropathic pain in clinics. However, we need to develop more effective and selective analgesics with less side-effects and tolerance. Therefore, new potential drug targets and their agonists or antagonists are under investigation and development.
- What are the most causes of periphery nerve injury? Is there a preventative measure?
Peripheral nerves could be damaged by direct injury such as accident cut, abnormal physical compression, and pathological invasion of tumors. We can take certain preventative measures to avoid the progressive pathological changes. For example, if patients experience pain in the leg, they have to seek for medical advice from their doctors and to examine whether the pain is due to nerve compression by pathological changes of the spine, bone or muscle, and to administer or undergo suitable medical treatments, and to pay attention to reduce the pressure to the spine and the muscle damage in daily life.
- Are there any contributions that we are able to understand about pain from occupational-induced injuries? For instance, football players are very prone to injuries at the head and foot. Ballerinas often experience discomfort at the soles and muscles.
It is difficult to avoid injury to the nerve, particularly for some occupations. However, based on our understanding of the causes of nerve damage and the possible consequences, including changes in the gene expression pattern of the somatosensory neurons, people who spend long-hours in the office and in-front of the computers are recommended to change their seating positions and take short-interval breaks to prevent from the long-term pressure on their neck and lumbar spine.
- Is it possible for a healthy individual to build up tolerance for pain? And why?
First of all, nociceptive response is an essential function to protect us from further damage. It is difficult to say whether a healthy individual could gain a tolerance for nociceptive stimuli. People might build up tolerance to pain, because long-term noxious stimulation could alter the gene expression in both peripheral and central nervous systems. Moreover, the sensitive to the same nociceptive stimulus could be different among people, due to the genetic background, living and working environments, and even education.
- How would your research work contribute to pain management? And morphine tolerance among patients?
Our work contributes to the understanding of the molecular and cellular mechanisms of pain modulation. For example, we found the Na+/K+-ATPase (Na+/K+ pump) activator, follistatin-like 1 (FSTL1), in the nociceptive neurons. Na+/K+ pump is critical for maintaining the Na+ and K+ gradients across the plasma membrane to generate the resting membrane potential in neurons. We identified the first endogenous activator of Na+/K+ pump, and found that the nerve injury-induced decrease of FSTL1 was involved in neuropathic pain. Another example is to understand how opioid receptors act in the pain signaling pathway. It is known that the analgesic tolerance could occur when people take morphine and other opioid analgesics to reduce pain. Several mechanisms for morphine tolerance have been proposed. We have found that the formation and trafficking of opioid receptor heteromers in the nociceptive neurons after drug treatments is an important mechanism for tolerance towards morphine. Nerve injury-induced neuropathic pain and cancer pain can become morphine-insensitive and this is due to the changes in gene expression in sensory neurons, and more specifically in the reduced expression of μ-opioid receptors. Therefore, our work contributes to the pain management by finding novel mechanisms of pain modulation and evaluating the drug targets and pain therapies.
- Please share with us on the progress of your recent research work, and on the likelihood of it being a treatment option.
We are trying to reveal the mechanisms for chronic pain including inflammatory, neuropathic and cancer pain, and to identify suitable targets for drug development. A better understanding of the sensory mechanisms will lead to a better therapy of chronic pain. During the past decades, our work was mostly based on the data collected with the gene microarray, which shows the molecules are markedly increased or decreased in the dorsal root ganglion and spinal cord after peripheral nerve injury or inflammation. Now, we perform the neuron-typing using single-cell RNA sequencing combined with functional analysis, to explore how many types of somatosensory neurons under normal circumstance, and the changes of neuron types in pathological conditions such as peripheral nerve injury. These large-scale analysis and database construction will change not only our view about the sensory mechanisms, but also the way of our research. We have identified several membrane proteins as potential drug targets. We are co-operating with companies to test the chemical compounds targeting at these targets to see whether they are able to reduce chronic pain. We hope that these efforts will lead to the development new method and drug for pain therapies.
- Who are your close collaborative partners? Particularly, when your findings or products are ready to enter clinical phase trials and to be made as first-line of treatment for pain modulation.
For basic study on the pain mechanisms, we closely cooperate with a long list of research groups in China and abroad, because the integration of different technologies and knowledge is critical for us to understand the pain mechanism. For application study, we currently cooperate with some companies for preclinical study, and hope to broaden cooperation with other companies in the near future. We would like to cooperate with pharmaceutical companies to perform clinical phase trials of our drug candidates.
- Are you accepting undergraduate or postgraduate research placement students to work in your laboratory?
We certainly accept graduate students and post-doc fellows, and have good research projects for them. We also welcome young people in bioinformatics, computational biology and genetics to join us, because analyzing the transcriptome of neurons and the genome of neurological disorders is one of the major projects in my laboratory.