NeuroBiology & Genetics Group
"To educate and inspire through discoveries"
RESEARCH FOCUS
Neuroscience is one of the most fascinating endeavours of biology research today, seek to understand how a brain function in health and disease. Our research group is interested in unraveling the role of genetic factors and molecular networks that regulate the development and function of disease and normal mammalian brain. With the knowledge gained in fundamental science, ultimately, we aimed to advance towards translational research (bench-to-bedside). Our group place a great emphasis in three main areas of research; (1) neurological disorders, (2) non-coding RNA roles in brain development and function and (3) technology transfer and development on gene delivery platform.
NBGG is involved in deciphering the genetic landscape leading to disrupted molecular pathways and processes responsible for Down syndrome pathology (trisomy 21) and associated disorders (defective neurogenesis and intellectual disability). Currently, we employed the Ts1Cje, a mouse model for Down syndrome to facilitate genetic dissection of the learning, behavioural and neurological abnormalities in Down syndrome.In addition to the brain development, our interest also extends to identifying the molecular mechanism responsible for hypotonia (decrease in muscle tone), neurogenic-to-gliogenic shift, and neuroinflammation in Down syndrome. The ultimate aim of our research is to determine the effect of the additional gene dosage in the trisomic model. In the long term, NBGG aims to that may improve the quality of life among Down syndrome patients. Moving on, we aim to venture the iPSC model, a powerful technology for human disease modeling, targeting various neurological disorders including Down syndrome, bipolar disorder, and Alzheimer’s disease. Taking advantage of the emerging CRISPR/Cas system and RNA seq to develop the RNA-targeting molecular therapies in the iPSC model.
Following are some examples of data published by the group in the past years.
Figure 1: Functional clustering of differentially expressed genes in Ts1Cje postnatal brains indicates global disruption of interferon-related molecular networks.
(Image was taken from Ling, K.-H., Hewitt, C. A., Tan, K.-L., Cheah, P.-S., Vidyadaran, S., Lai, M.-I., Lee, H.-C., Simpson, K., Hyde, L., Pritchard, M. A., Smyth, G. K., Thomas, T., & Scott, H. S. (2014). Functional transcriptome analysis of the postnatal brain of the Ts1Cje mouse model for Down syndrome reveals global disruption of interferon-related molecular networks. BMC Genomics, 15(1), 624. https://doi.org/10.1186/1471-2164-15-624)
Figure 2: Behavioural assessment of muscle weakness in the Ts1Cje mouse. (a) Grip strength test, (b) hanging wire – survival test, (c) hanging wire – falling test and (d) accelerated speed rotarod test.
(Image was taken from Bala, U., Leong, M. P. Y., Lim, C. L., Shahar, H. K., Othman, F., Lai, M. I., Law, Z. K., Ramli, K., Htwe, O., Ling, K. H., & Cheah, P. S. (2018). Defects in nerve conduction velocity and different muscle fibre-type specificity contribute to muscle weakness in Ts1Cje Down syndrome mouse model. PLoS ONE, 13(5), 1–13. https://doi.org/10.1371/journal.pone.0197711)
Figure 3: The illustration depicts the (a) role of microglia and astrocytes response to neuroinflammation and (b) how JAK-STAT signalling pathway are involved in the activation process.
(Image was taken from Lee, H.-C., Tan, K.-L., Cheah, P.-S., & Ling, K. H. (2020). JAK-STAT Signaling Pathway and Gliosis in Neuroinflammatory Diseases. In R. Goswami (Ed.), JAK-STAT Signaling in Diseases (pp. 83–101). Taylor & Francis.)
Figure 4: Pipeline for miR-3099 target gene prediction and functional characterization based on DAVID analysis (based on Gene Ontology, Biocarta, KEGG and tissue expression databases) and comparison with the Allen Brain Atlas in situ hybridization profile.
(Image was taken from Abidin, S. Z., Leong, J.-W., Mahmoudi, M., Nordin, N., Abdullah, S., Cheah, P.-S., & Ling, K.-H. (2017). In Silico Prediction and Validation of Gfap as an miR-3099 Target in Mouse Brain. Neuroscience Bulletin, 33(4), 373–382. https://doi.org/10.1007/s12264-017-0143-0)
STATS
- Total no. of grants obtained: 20
- Total funding obtained: RM2,406,116
- Ongoing grants: 4
- Completed grants: 16
ONGOING FUNDING
2024-2025
Industrial Grant – RM47,000
Developmental and functional evaluation of CEXCI on Down syndrome human iPSC derived neural models. PI: Prof Dr. Michael Ling
2022-2024
Putra Grant IPS, UPM – RM25,000
Investigation of lithium effect on REST expression and reactive astrocyte in Down Syndrome. PI: AP Dr. Michael Ling (Postgraduate: Dr Huang Tan)
2022-2025
Fundamental Research Grant Scheme, MOHE – RM165,036
Investigation of cell-specific REST expression and its repression on JAK-STAT signalling pathway to revert the neurogenic-to-gliogenic shift in Down syndrome cerebral organoids model. PI: AP Dr. Michael Ling
2022-2024
Putra Grant (GPB), UPM – RM120,000
Targeting JAK-STAT signalling pathway to revert neurogenic-to-gliogenic shift and connective deficits in the brain of Ts1Cje mouse model for Down syndrome. PI: AP Dr. Pike-See Cheah
COMPLETED PROJECTS
2021-2024
Fundamental Research Grant Scheme, MOHE – RM157,000
Investigation of lithium-mediated neuroprotection in Down syndrome via REST restoration. PI: AP Dr. Pike-See Cheah
2021-2023
IBRO Return Home Grant – EURO20,000
The interplay between REST and JAK-STAT in the neurogenic-to-gliogenic shift in Down syndrome. PI: AP Dr. Michael KH Ling
2021-2023
ISN Return Home Grant – USD10,000
Profiling of cell-specific REST expression and its repression on JAK-STAT signaling in Down syndrome cerebral organoids. PI: AP Dr. Michael KH Ling
2017-2018
Putra Grant (IPS), UPM – RM20,000
Identification and validation of a novel human orthologue for miR-3099 known as mds-21. PI: Dr. Michael KH Ling (Postgraduate: Mr. Shahidee Zainal Abidin)
2015-2017
Sciencefund, MOSTI – RM293,523
TargetingJAK-STAT signaling pathwayto revertneurogenic-to-gliogenic shift in the brain of Ts1Cje Mouse Model for Down syndrome. PI: Dr. Michael KH Ling
2015-2017
Fundamental Research Grant Scheme, MOHE – RM139,000
Role of the JAK-STAT signaling pathway during neurogenic-to-gliogenic shift in the brain of Ts1Cje Mouse Model for Down syndrome. PI: Dr. Pike-See Cheah
2014-2016
Putra Grant (Interdisciplinary), UPM – RM273,100
Psychosocial risk factors, BDNF and DAT1 Polymorphism and Risk of Major Depressive Disorder. PI: Joint between Prof. Dr. Normala Ibrahim with Dr. Michael KH Ling
2015-2016
Putra Grant (Postgraduate), UPM – RM15,000
Protein and gene expression profile of skeletal muscles in Ts1Cje Mouse Model of Down Syndrome : an insight to muscle weakness. PI: Dr. Pike-See Cheah (Postgraduate: Mr. Usman Bala)
2013-2015
Putra Grant, UPM – RM198,963
Molecular, metabolic and functional characterization of adult skeletal muscle in Down syndrome mouse model : insights into the muscle weakness seen in human condition. PI: Dr. Pike-See Cheah
2012-2015
Putra Grant, UPM – RM176,994
Identification of molecular mechanism responsible for hypotonia in adult Ts1Cje mouse model of Down syndrome. PI: Dr. Michael KH Ling
2013-2015
Putra Grant (Postgraduate), UPM – RM15,000
The association of CDKL5 and STXBP1 gene mutations in paediatric patients with early-onset epileptic encephalopathy in Malaysia. PI: Dr. Michael KH Ling (Postgraduate: Ms Ameerah Jaafar)
2012-2015
ERGS, MOHE – RM119,000
In vivo analysis of a novel miRNA, M1181, during mouse cerebral corticogenesis using in utero electroporation (IUE) approach. PI: Dr. Pike-See Cheah
2012-2015
FRGS, MOHE – RM81,000
A mouse embryonic stem cell culture system with stable and regulatable expression for a novel microRNA, miR3099: An in vitro approach towards functional genomics study. PI: Dr. Michael KH Ling
2013-2015
RUGS (Postgraduate), UPM – RM10,000
Expression profiling of a novel microRNA, miR3099, during neuronal development using an in vitro system. PI: Dr. Michael KH Ling (Postgraduate: Mr. Wei-Hong Siew)
2012-2014
Sciencefund, MOSTI – RM263,500
Establishment of the first ‘superelectroporator’ platform in Malaysia for the delivery of bicistronic expression vectors with shRNA and GFP open reading frames into the cerebral cortex of mouse model for Down syndrome. PI: Dr. Pike-See Cheah
2011-2013
RUGS, UPM – RM168,000
The identification of disrupted molecular networks involved in brain maturation and function in the Ts1Cje mouse model of Down Syndrome. PI: Dr. Pike-See Cheah