1. Intrinsic mechanisms critical for reactivation of neural stem cells
Wang Hongyan, NBD
Neural stem cells switch between a quiescent (non-dividing or slow-dividing) vs. proliferative states. Neural stem cells in the quiescent state have limited capacity in generating neurons. It is critical to understand how the switch is regulated during brain development, so that it can be applied to stem cell-based therapy to treat neurodegenerative diseases caused by neuronal loss. Similar to mammalian neural stem cells, fruit fly Drosophila melanogaster larval brain neural stem cells transit from a quiescent to reactivated state in response to both intrinsic and extrinsic stimuli. However, intrinsic cues that allow cell cycle re-entry of quiescent neural stem cells are unknown. Our goal is to identify intrinsic cues that control reactivation of neural stem cells.
2. Bacterial hijacking of host iron acquisition pathways
Bindu Sukumaran, EID
Urinary tract infections (UTIs) are common and costly infectious diseases, affecting half of all women. Many women suffer from recurrent UTIs, for which no effective therapy currently exists. Intracellular persistence within bladder epithelial cells (BEC) by uropathogenic E. coli (UPEC) contributes to recurrent UTI in mouse models of infection. We specifically asked whether and how UPEC co-opt any of the host proteins regulating vesicular trafficking for intracellular infection. We demonstrated a novel mechanism by which UPEC exploit a host endocytic recycling pathway protein (Rab35) to acquire the critical nutrient iron and to prevent lysosomal degradation, thereby promoting intracellular survival within BEC. In this proposal, we aim to further characterize this pathway in detail by using in vitro, in vivo and also recurrent UTI patient samples. The results of this study may highlight new avenues for therapeutic intervention in recurrent UTI. In addition, knowledge gained from this study can also be extended to understand the general principles by which other intracellular bacterial pathogens acquire essential nutrients, leading to additional strategies to combat these infectious diseases.
3. Systems for assessing mutation signatures in-vitro and discovering mutagenic exposures in tumors
Steven Rozen, CSCB
Exposures to mutation-causing chemicals and radiation are major causes of cancer, and cancers undergo genetic mutations during their development. The advent of inexpensive genome sequencing has created opportunities for (1) improved testing for mutagenicity and safety, (2) determination of the characteristic mutation signatures of different mutagens, and (3) vastly better understanding of how mutagenic carcinogens increase cancer risk and of which carcinogens pose the most severe risks. There are unmet needs for both improved mutagenicity testing and for improved assessment of the roles of mutagens in causing cancer. This project will create a robust cell-culture-based platform for assessing mutagenicity and determining the characteristic extended mutation signatures of mutagens, i.e. patterns of DNA mutations in their larger sequence contexts. We will apply this platform to known and suspected mutagens. Novelty stems not only from development of the platform, but also from new knowledge of the extended mutation signatures of mutagens. In addition, this project will develop and apply new computational tools to identify known mutation signatures in worldwide databases of somatic mutations from >12,000 tumors, thereby revealing hitherto unknown mutagenic exposures that cause cancer. The results of this project will offer new opportunities for cancer prevention.
4. Characterizing dynamic functional connectivity in the adult and developing brain using concurrent fMRI-EEG
Helen Zhou Juan, NBD
The architecture of the human brain undergoes dramatic changes during development. Functional connectivity derived from functional magnetic resonance imaging (fMRI) maps large-scale neural network function and dysfunction. Recent studies found distinct functional connectivity changes in patients with neuropsychiatric disorders. Nevertheless, emerging work suggested that the assumption of static brain state over time is insufficient to understand brain connectivity. It remains unclear how these brain regions interact dynamically and support cognition during development. We propose to employ concurrent fMRI and electroencephalography techniques to examine functional connectivity and its underlying neural oscillations in healthy individuals aged 12-26 years old. We will develop novel dynamic functional connectivity approaches to examine the temporally varying coordination and competition among neural systems. We will test the performance of the new methods based on repeat scans of adults within one month. We will examine the effect of age on functional connectivity and neural oscillations cross-sectionally and investigate the longitudinal changes in a subset of healthy adolescents at 18 months follow-up. This study will provide novel insights on how dynamic interactions between brain regions mature with age. It will lay the foundation for future studies to identify aberrant dysconnectivity patterns in neurodevelopmental disorders.
5. Understanding disease pathology and mechanisms for Rett Syndrome and other Autism Spectrum Disorders
Eyleen Goh, NBD
Understanding complex neuropsychiatric disorders such as autism spectrum disorders (ASD) is a daunting task because there is no available animal model or in vitro model that fully recapitulates the disease-associated dysfunctions of the human brain. This is largely due to the unknown etiology of ASD and the wide spectrum of genes that have implicated in ASD. The genetics of ASD is complex and hundreds of genes have been linked to increased risk of ASD. Therefore, studies on ASD rely on rodent models that exhibit one or more behavioral deficits that are characteristic of ASD. Rett syndrome (RTT) is a rare form of ASD that has an unusually strong genetic component and therefore provides an excellent system/model to study cognitive functions related to Rett and to the broader ASD. Sporadic mutations in methyl-CpG binding protein 2 (MeCP2) have been detected in more than 80-90% of RTT patients. Rodent models with various Mecp2 null mutations and deletions exhibited RTT-like behavioral phenotypes, such as impaired learning and memory, poor social recognition, and social avoidance Neurons in Mecp2 null mice can survive until adulthood but show defects in neuronal development and circuitry. These findings suggest the possibility of reversing the neurological phenotypes of RTT by appropriate therapeutic interventions. Impairments in both neuronal structure and synaptic function have been implicated in the brain defects found in RTT animal models. The proposed experiments will use in vitro neuronal culture systems, animal studies and induced pluripotent stem (iPS) cells derived from human RTT patients to compare causal relationships between genetic, cellular, circuitry and behavioral defects in RTT. These results will aid in screening and finding potential therapeutics that can reverse RTT phenotypes.
6. The interplay of phosphorylation and dephosphorylation regulates accurate chromosome segregation and the spindle assembly checkpoint
Lee Sang Hyun, CSCB
Mitosis is one of the most basic and essential processes in living organisms. It is a highly ordered process comprising multiple steps that mediate dramatic changes to the cell architecture. Events such as cell rounding, chromatin condensation, nuclear envelope disassembly, centrosome separation, bipolar spindle assembly, chromosome segregation, contractile ring formation and cleavage furrow ingression for cytokinesis involve numerous proteins, which are tightly coordinated by mitotic kinases and phosphatases. Mitotic defects inevitably generate chromosome alterations that fuels tumorigenesis and many genetic disorders. It also has a direct clinical relevance since the anti-microtubule drug Taxol is one of the most successful anti-cancer drugs, which disrupts chromosome segregation and promotes cancer cell death. We aim to uncover new mitotic signaling pathways for proper chromosome segregation that could be exploited to implement the appropriate defense to chromosome instability and tumorigenesis. Our studies will uncover new mitotic signaling pathways that could be exploited to implement the appropriate defence to chromosome instability (CIN) and tumorigenesis. Specific pharmaceutical targeting of such signaling pathways will also serve as a valuable strategy for anti-cancer therapy in clinic.
7. Using an Incentive Design with Fixed and Dynamic Target Number of Steps for a Family-based Walking Program
Semra Ozdemir Van Dyk, HSSR
Childhood obesity is one of the major challenges in developed countries, including Singapore. One of the main reasons behind growing childhood obesity is low levels of physical activity, and children may be patterning their levels of inactivity after their parents. Physical activity interventions that target children and parents could have a significant public health impact. Incentives for meeting activity goals can be effective in promoting sustained levels of physical activity. We propose to test two types of incentive strategies (fixed threshold versus a dynamic threshold based on peer effects). The proposed walking program will last 6 months and will focus on the family as a target of the intervention in efforts to make physical activity a family priority. Rewards will be based on the criteria that all participating family members need to meet their activity goals. We hypothesize that the average number of steps taken by children will be higher when incentives are offered than when they are not. We also hypothesize that the average number of steps taken by children will be higher when families are compared to other families in terms of physical activity than when they are not compared to other families.
8. The Role of Risk Factors in Influencing Inpatient Utilization and Costs: Evidence from linked Singapore Chinese Cohort Data
Nguyen Van Hai, HSSR
As Singapore becomes wealthier and its population ages, it is facing a dual health challenge: to expand access to insurance coverage and increase subsidy for its people while keeping healthcare costs in check. Several recent policy efforts (e.g. Medishield Life) have expanded insurance coverage to accommodate low income people and the elderly. These reforms raise the need to address a number of issues related to the costs of expanded access. This research aims to quantify elderly’s inpatient costs at their end-of-life stage. In particular, it focuses on estimating end-of-life inpatient costs associated with risk factors (such as physical activity, smoking, obesity, and so on) and chronic diseases that people acquired in their mid/late life. The study also investigates the implications of cost-control features in the MediShield program on healthcare utilization. Overall, this research will provide useful information to help forecast the cost burdens that the government and older adults will face in the future. This, in turn, will help them to make appropriate savings and investment decisions. This research will also provide useful information to assist current government efforts to revamp the Medishield.