Program 3: Cellular and Molecular Mechanisms

Investigate and analyze the cellular and molecular mechanisms that mediate the tissue- and microenvironment-specific responses of cells and their optimization
Theme 1: Control of Cell Life and Death
Sub-Project CM.1.1: HEDLUND, Eva (KI)

Prof. Eva Hedlund and her team is investigating mechanisms of neuronal vulnerability and resilience in motor neuron disease with a particular focus on amyotrophic lateral sclerosis. Towards this purpose they have developed a technique, LCM-seq, to analyze the transcriptomes of cell somas, isolated from partially degraded tissues. They now apply LCM-seq to reveal the response of individual neurons to disease. The Hedlund team are also using induced pluripotent stem cells to generate in vitro model of the human neuromuscular junction which is an early pathological target in ALS. Here they also interrogate the transcriptomes of axons in health and ALS with a technique, Axon-seq, they recently developed to reveal early pathological changes. Her research is expected to reveal important information on the cellular and molecular disease mechanisms of ALS.

Theme 2: Epigenetics and Energy Metabolism
Sub-Project CM.2.1: WAN, Chao (CUHK) and LING, Samuel Ka-Kin (CUHK)

The Wan laboratory has extensive experience in molecular and cellular mechanisms of the oxygen sensing and growth factor pathways in skeletal development, degeneration and regeneration, and discovery of novel therapies for skeletal repair or regeneration. His CNRM project will target the energy metabolism pathway to investigate the precise conditions controlling the fate of chondroprogenitors for the design of 3D bioprinting- based engineering of cartilage that prevents chondrocyte hypertrophy both in vitro and in vivo. He will work with Prof. Ling Ka-kin (Co-I) to explore a phase 1 clinical trial using the procedure established in this study.

Theme 2: Epigenetics and Energy Metabolism
Sub-Project CM.2.2: WANG, Huating (CUHK) and WONG, Ronald Man-Yeung (CUHK)

Dr. Wang’s laboratory has longstanding interest in studying gene regulatory mechanisms using skeletal muscle cells and cancer cells as model systems. Current studies focus on the functional roles of non-coding RNAs in regulating gene expression in skeletal muscle stem cells and muscle regeneration. Her CNRM project will study how histone- alteration changes in skeletal muscle tissue drive remodeling of gene enhancers and muscle stem cell niche environment, and to characterize changes of transcriptome, chromatin accessibility and histone modifications in muscle stem cells from aging mouse. Additional focus will be on how caloric restriction and exercise may improve aging muscle stem cell function through modulating the above epigenetic hallmarks in mouse.

Theme 1: Control of Cell Life and Death
Sub-Project CM.2.3: Prof. CECCATELLI, Sandra and Prof. JOSEPH, Bertrand

Dr. Ceccatelli’ s group could show that high levels of glucocorticoid hormones (GC) affect the methylation state of genes regulating proliferation, differentiation, and migration as well as mitochondrial function and redox state. These findings point to epigenetic modifications being part of the developmental neurotoxicity mechanisms. In addition, in vivo rodent models revealed that prenatal excess GC alters hippocampal neurogenesis and induces depression-like behavior in adulthood that is preceded by long-lasting alterations in circadian patterns of activity. Collaborative clinical investigations show abnormal circadian activity patterns in depressed patients as well. Over the years, Dr Joseph's team has been working in several fields of research from the investigations of the cell death signaling pathways to the molecular mechanism controlling cell differentiation. In addition, these investigations were performed in various models of human diseases ranging from cancers, neurodevelopmental disorders to neurodegenerative disorders. His team discovered that autophagy is regulated by epigenetics and contributed to the concept of histone onco-modification. Dr Joseph has more than 15 years of experience working in the field of microglia, and an international recognition. Highlights of his research include the discovery of a role for killer caspases in microglia pro-inflammatory and tumor-supporting phenotypes and a contribution to the understanding of the transcriptional/epigenetic regulation of microglial activation states and the possibility to reprogram microglia toward distinct phenotypes. Lately, Dr Joseph has been arguing for the concept of microglia diversity, i.e., the existence of microglial subtypes.