Neuroscience is one of the escalating and most fascinating endeavours of biology research today. Neuroscience research has advanced knowledge on how a brain functions, how a neurone behaves and how damaged neuronal networks may lead to various neurological disorders. In Universiti Putra Malaysia (UPM), neuroscience research is now one of the priority niche areas. Besides, steps have been taken to gather both the scientists and clinicians who venture in the field by pooling resources and practicing knowledge sharing. Our research group, known as NeuroBiology and Genetics Group (NBGG), is interested in unraveling the role of genetic factors and molecular networks that regulate the development and function of the mammalian brain. 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). With limited access to Down syndrome patient tissues and the lack of comprehensive investigations at the molecular level, we have employed Ts1Cje, a mouse model for Down syndrome to facilitate genetic dissection of the learning, behavioural and neurological abnormalities in Down syndrome. In collaboration with Professor Hamish Scott from the University of Adelaide, South Australia, we profile gene expression pattern at various regions of the Down syndrome brain at different stages of development. Spatiotemporal comparisons of gene expression profiles between the normal and Down syndrome brains provide a great genetic overview that may provide clues on what has gone wrong in the Down syndrome brain. In addition to the brain development, our interest also extends to identifying the molecular mechanism responsible for hypotonia (decrease in muscle tone), a cardinal feature, in Down syndrome. Our group plans to generate a comprehensive catalogue of molecular and cellular properties that affect locomotor functions and vesicle recycling mechanism at the neuromuscular junction of the Ts1cje mouse model. 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 develop molecular therapies that may improve the quality of life among Down syndrome patients.
A different branch of NBGG research is to understand the role of non-coding RNAs in regulating the development of the mammalian brain. Our group has a special interest in characterising the molecular role of a few novel microRNAs (miRNAs), that are found to be expressed throughout embryonic development especially in the brain. miRNAs are short RNA sequences with 18-24nt in length. miRNAs target mainly at the 3’ UTR of mRNA to either repress translation processes or promote mRNA degradation. In both cases, miRNAs will influence the level of protein synthesis. When the phenomenon happens at a global scale, changes of the amount of proteins synthesised may affect the phenotypic characteristics of the cell. In the context of a developing brain, miRNAs may play a crucial role in regulating neurogenesis, neuronal differentiation and function. To dissect the molecular role of these novel miRNAs, NBGG plans to use various techniques such as in situ hybridisation, stemloop-RT-qPCR, overexpression studies, Western blotting and luciferase assay analysis in various models such as mouse embryonic stem cells, differentiated neurones, primary neuronal cultures and brain sections.
To complement our efforts in elucidating the role of various candidate genes and miRNAs in brain development or function, our group is in the midst of establishing a “super electroporator” platform for the delivery of charged particles into specific regions of the mouse brain. Charged particles such as DNA constructs with Green Fluorescent Protein (GFP) as traceable gene reporter system have been established in our laboratory and are ready to be electroporated into the developing mouse brain in utero. The platform will facilitate us to trace the formation of defective migratory routes of neurones in the Down syndrome brain in the presence or absence of selected candidate trisomic genes. The platform also enables us to study the function of novel miRNAs in a spatiotemporal manner throughout the development and maturation of the brain.
Our group also works with clinicians to screen for aberrations of selected genes in Parkinson’s disease and infantile spastic patients. In addition, we look forward to any queries regarding our research projects and welcome any potential collaborators to work on the following extended research topics:
a) Advancement of the ‘super electroporator’ platform and its applications in in utero, in vitro as well as in vivo delivery of charged particles.
b) Identification and characterisation of natural products that may improve the learning and memory capability in Ts1Cje mouse model.
c) Exploration of the role of novel miRNAs in early embryo development.
d) Characterisation of candidate noncoding RNAs in human Down syndrome induced pluripotent stem cell (iPSC)-derived neurones.
e) Elucidation of long noncoding RNAs roles in gene expression regulation in the mammalian brain via bioinformatics and genomics approaches.
Dr. Michael KH Ling:
[email protected] +603-89472564
Dr Ling’s Scientific Malaysian profile: https://www.scientificmalaysian.com/scimy/members/michaelling/
Dr. Pike-See Cheah:
[email protected] +603-89472355
Dr Cheah’s Scientific Malaysian profile: https://www.scientificmalaysian.com/scimy/members/pikesee/
My main research interests revolve entirely around Neural Computation. Together with several PhD students and collaborators, I am trying to unravel what computations are being carried out by different neural systems, and how and why they are being implemented. Therefore, I am interested in both biological and artificial aspects of neural computation.
On the biological side, my work falls mostly within the field of Computational Neuroscience concerned with how different biological neural systems solve different types of computational problems. In terms of problem domains, I have mostly been involved in the research of visual functions and therefore Computer Vision and Image Processing are central to my investigations. I am currently focusing on the simulation-modelling of the biological retina, through which I hope to:
1) answer several questions pertaining to the structure and function of different retinae,
2) propose new image processing techniques for low-level functions such as illumination normalization and colour correction, and
3) propose new designs for retinal prostheses.
So far, our models of the outer retina have revealed that the relatively simple micro-circuits established between photoreceptors, horizontal cells and bipolar cells are capable of a significant number of distinct image processing functions such as denoising, contrast and saturation enhancement, edge detection and colour normalization (see Figure 1 for an example of local illumination normalization and denoising). We are currently in the process of extending our models of the retina, by adding several amacrine and ganglion cell types, with the aim of understanding retinal colour coding and processing. This understanding should guide us towards achieving the goal of enhancing retinal prostheses for allowing users to experience coherent colour perception.
On the artificial or applied side we are developing new types of hybrid artificial neural networks with a particular emphasis on functional diversity, i.e., Neural Diversity Machines (NDM). The notion of diversity is borrowed from biological neural systems where we observe a significant diversity of neurons in terms of morphology, connectivity, electrophysiology, and other properties. The case of the retina, where on average (across species) there are approximately 55 different types of neuron, is one simple illustration of this point. Initial experiments have shown some promising results and our current priority is to improve the speed and reliability of optimization methods for NDM.
Although NDMs are intended to be general and have already been tested on several unrelated benchmarks from the UCI Machine Learning Repository, one of the target domains which ties NDMs with our more biologically oriented research pertains to the segmentation of histological images of the retina for automated or semi-automated reconstruction of retinal circuits (i.e. connectomics research). The motivation behind this application is to bridge one gap in the chain from biological specimens through data acquisition up to computational modelling. To completely bridge the gaps in this chain means that one day we will be able to scan a neural tissue (e.g., retina) and automatically generate computational insights. As collaboration is essential (e.g., biologists and computer scientists), I look forward to receiving any potential queries from interested parties.
Figure 1: Examples of image processing by a neural model of the outer retina.
Scientific Malaysian Profile:
 Research page – http://baggins.nottingham.edu.my/~kcztm/Research.html
 Interdisciplinary Computing and Complex Systems research group – http://icos.cs.nott.ac.uk/
 Cognitive and Sensory Systems research group – http://www.nottingham.edu.my/Psychology/Research/CognitiveandSensorySystemsGroup.aspx