The Baoji Xu Laboratory at The Scripps Research Institute Florida

Research Projects

Control of body weight

Over 30% of adults and 16% of children are obese in the United States. 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 obesity. Understanding the molecular, cellular, and physiological processes regulating energy balance will provide opportunities to develop novel interventions for obesity.

Our goal is to identify neural circuits that regulate appetite and energy expenditure. We will then find specific proteins in these circuits with the hope of treating obesity by pharmacologically modulating the activity of the circuits through these proteins.

We currently focus on understanding how brain-derived neurotrophic factor (BDNF) regulates body weight. Mutations in the gene for BDNF or its receptor cause marked overeating and severe obesity in both humans and mice. We have discovered a few neuronal populations that mediate the inhibitory effect of BDNF on appetite and the stimulatory effect of BDNF on energy expenditure.

Regulation of protein synthesis

Over 50% of human genes produce multiple mRNAs with different lengths of 3’ untranslated regions (3’ UTRs) but encoding exactly the same proteins. For example, the BDNF gene produces two pools of mRNA with either a short 3’ UTR (0.35 kb) or a long 3’ UTR (2.9 kb) due to alternative polyadenylation. It had been a puzzle why a cell needs more than one mRNA species if they encode the same protein.

We are the first to demonstrate that mRNAs with different 3’ UTRs have distinct functions in cells. We have discovered that short 3’ UTR BDNF mRNA is restricted to neuronal cell bodies, whereas long 3’ UTR BDNF mRNA is also transported to dendrites for local protein synthesis. Furthermore, we have found that BDNF synthesized in dendrites have functions that are distinct from BDNF synthesized in cell bodies. We are currently investigating how mRNAs are transported to dendrites. Because dendrites have few Golgi complexes, we are interested in uncovering the dendritic secretory pathway for proteins synthesized in dendrites. We are also investigating the possibility that 3’ UTRs regulate the localizationand stability of proteins synthesized in cell bodies.

Molecular mechanism of synaptic maturation and elimination

Once a neural circuit is formed following the guidance of developmental cues, it has to be sculpted in an activity-dependent process to increase the preciseness and efficiency of its neuronal connections. At the synapse level, this refinement is associated with loss and maturation of synapses. Deficits in synaptic maturation and elimination could be the bases for some neurodevelopmental disorders such as autism spectrum disorders. Furthermore, synaptic loss has also emerged as a central pathology in neurodegenerative diseases. We are investigating the molecular pathway that controls synaptic maturation and elimination in the cerebral cortex and hippocampus. We have discovered that BDNF synthesized in dendrites is essential for this critical developmental process.

Identification of compounds that potentiate BDNF production for treatment of neurodegenerative diseases

No disease-modifying treatment is currently available for Alzheimer’s disease (AD) and Huntington’s disease (HD). In light of the failure of recent clinical trials that target Ab, there is an urgent need to develop drugs that target the pathophysiology of neurodegenerative diseases, i.e. dysfunction and loss of synapses followed by neuronal loss. Since BDNF promotes neuronal survival and stimulates synaptogenesis and synaptic plasticity, increasing BDNF levels could halt or reverse the progress of these diseases by enhancing the function of existing synapses, inducing formation of new synapses, and preventing additional neuronal loss. We are interested in developing small molecules that are able to stimulate BDNF production in neurons.