Central control of eating behavior and obesity
Obesity has become a leading worldwide health problem because of its high prevalence. Obese children and adults are developing type-2 diabetes at high rates, and are at significant risk for life-threatening cardiovascular disease and cancer. Despite the enormous economic cost of obesity, there is currently no effective and safe treatment available for this health issue. Understanding the central mechanism that controls food intake and energy expenditure will provide opportunities to develop novel interventions for obesity.
Our group has played a leading role in discovering brain-derived neurotrophic factor (BDNF) as a key regulator of body weight by suppressing food intake and promoting energy expenditure. We and others have shown that disruption in BDNF-to-TrkB signaling leads to severe obesity in humans and mice. We are conducting studies to identify neural circuits that control appetite and energy expenditure in mice by using biochemical, behavioral, genetic, physiological and viral approaches. Identification of the circuits will allow us to further investigate what signals are generated upon eating to stimulate BDNF release from neurons in the brain, how the released BDNF alters the activity of the circuits, and how the circuits stop eating and stimulate energy utilization. This research project will help us understand not only how our body controls eating, a fundamental behavior, but also how the brain functions.
Autism spectrum disorders
Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental disorders with deficits in two core domains: social interaction and communication, and repetitive behaviors or restrictive behaviors. Prevalence of ASD is 1 in 68 children under 8 years of age in the USA and is higher in males (1 in 42) than in females (1 in 189). There is a strong genetic basis for ASD. Mutations in hundreds of genetic loci, including both germline and de novo mutations, have been implicated in underlying ASD. Because of this high genetic heterogeneity, it is essential to find common pathophysiology pathways in order to develop therapeutic strategies for ASD. One common pathophysiology pathway underlying ASD is likely to be exaggerated protein synthesis, as mutations in several negative regulators of protein synthesis, such as PTEN, TSC1, TSC2 and FMRP, cause ASD. We are interested in identifying groups of cells in which exaggerated translation causes ASD-like behaviors and elucidating molecular mechanisms by which exaggerated translation alters the function of the cells.
Alzheimer’s disease
Alzheimer’s disease (AD) is the most common neurodegenerative disease that causes problems with memory, thinking and behavior. Recent human genomic studies have implicated dysfunction of microglial cells, the resident immune cells in the brain, as an important cause for AD. Microglial dysfunction likely leads to deficits in clearance of toxic protein aggregates such as beta-amyloid (Ab) polymers and cell debris. We are interested in the cellular and biochemical process by which microglia sense and remove cell debris and protein aggregates in the brain. In addition, aging is the largest risk factor for AD and is associated with a reduction in uptake and metabolism of glucose, the main fuel source of the brain. We are also interested in elucidating biochemical pathways that regulate glucose metabolism in the brain and investigating how the activity of these pathways is reduced in aging brain.
Drug discovery
No disease-modifying treatment is currently available for AD. In light of the failure of recent clinical trials that target Ab, there is an urgent need to develop drugs that target the AD pathophysiology, i.e. dysfunction and loss of synapses followed by neuronal loss. It is well documented that BDNF promotes neuronal survival and stimulates synaptogenesis and synaptic plasticity. Thus, increasing BDNF levels could halt or reverse the progress of AD by enhancing the function of existing synapses, inducing formation of new synapses, and preventing additional neuronal loss. The proof of principle for this concept has been shown in AD animal models. However, BDNF is a poor therapeutic agent due to its pharmacological properties. It is also difficult to find small-molecule compounds (~500 Da) that mimic the action of 56-fold larger BDNF protein (~28 kDa in dimer). We are searching for small-molecule compounds that stimulate production of endogenous BDNF in neurons. Because reduced levels of BDNF are also associated with obesity, anxiety and other brain disorders, these BDNF-boosting compounds could be useful for other diseases.