Baoji Xu, PhD

Professor
Department of Neuroscience
Florida Campus


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Scripps Research Joint Appointments

Graduate Program
Professor, Department of Neuroscience
Faculty, Graduate Program

Other Joint Appointments

Affiliate Professor, Florida Atlantic University, Charles E Schmidt College of Medicine, Boca Raton, FL

Research Focus

The goal of our laboratory is to understand how both healthy and diseased brains work. We focus on the mechanisms by which growth factors such as brain-derived neurotrophic factor (BDNF) regulate the development and function of brain neural circuits that control body weight, learning, mood, and social behaviors. We hope that our research will lead to discovery of novel therapeutics for neurodegenerative diseases, neurodevelopmental disorders, and obesity.

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. 


Education

Ph.D., Molecular Biology, Stanford University, Stanford, California,
B.S., Biology, Xiamen University, Xiamen, Fujian, China,

Professional Experience

2013 - Professor, The Scripps Research Institute
2015 - Affiliate Professor, Florida Atlantic University, Charles E Schmidt College of Medicine, Boca Raton, FL
2013 - 2018 Adjunct Professor, Georgetown University Medical Center, Washington, DC
2009 - 2013 Associate Professor with tenure, Georgetown University Medical Center, Washington, DC
2003 - 2009 Assistant Professor, Georgetown University Medical Center, Washington, DC
2001 - 2002 Research Scientist II, Chiron Corporation, Emeryville, CA
1995 - 2001 Postdoctoral Fellow, University of California, San Francisco, CA 

Awards & Professional Activities

Rockefeller Foundation Predoctoral Fellowship
American Heart Association Scientist Development Award
Whitehall Foundation Award
Georgetown University Annual IPN Junior Faculty Award
Ad hoc member of NIH CNNT, MNPS, ZRG1 EMNR-B, and NSD-C Study Sections
Regular member of NIH Neurological Sciences and Disorders C (NSD-C) Study Section


Selected References

Xu ZX, Tan JW, Xu H, Hill CJ, Ostrovskaya O, Martemyanov KA, and Xu B. 2019. Caspase-2 promotes AMPA receptor internalization and cognitive flexibility via mTORC2-AKT-GSK3β signaling. Nat Commun. 10: 3622.

Liao GY, Kinney CE, An JJ, and Xu B. 2019. TrkB-expressing neurons in the dorsomedial hypothalamus are necessary and sufficient to suppress homeostatic feeding. Proc. Natl. Acad. Sci. USA 116: 3256-3261.

Xie X, Yang H, An JJ, Houtz J, Tan JW, Xu H, Liao GY, Xu ZX, and Xu B. 2019. Activation of anxiogenic circuits instigates resistance to diet-Induced obesity via increased energy expenditure.Cell Metab29: 917-931 (see comments here and here).

Chen CM, Orefice LL, Chiu SL, LeGates TA, Hattar S, Huganir RL, Zhao H, Xu B, and Kuruvilla R. 2017. Wnt5a is essential for hippocampal dendritic maintenance and spatial learning and memory in adult mice. Proc. Natl. Acad. Sci. USA 114: E619-E628.

Xu B, Xie X. 2016. Neurotrophic factor control of satiety and body weight. Nat Rev Neurosci. 17:282-292.

An JJ, Liao GY, Kinney CE, Sahibzada N, and Xu B. 2015. Discrete BDNF neurons in the paraventricular hypothalamus control feeding and energy expenditure. Cell Metab22:175-188.

Liao GY, An JJ, Gharami K, Waterhouse EG, Vanevski F, Jones KR, and Xu B. 2012. Dendritically targeted BdnfmRNA is essential for energy balance and response to leptin. Nat. Med.18: 564-571 (see comments here and here).

Baydyuk M, Russell T, Liao GY, An JJ, Reichardt LF, and Xu B. 2011. The TrkB receptor controls striatal formation by regulating the number of newborn striatal neurons. Proc. Natl. Acad. Sci. USA 108: 1669-1674 (see comments here).

Xie Y, Hayden MR, and Xu B. 2010. BDNF overexpression in the forebrain rescues Huntington’s disease phenotypes in YAC128 mice. J. Neurosci. 30: 14708-14718.

An JJ, Gharami K, Liao GY, Woo NH, Lau AG, Vanevski F, Torre ER, Jones KR, Feng Y, Lu B, and Xu B. 2008. Distinct role of long 3′ UTR BDNF mRNA in spine morphology and synaptic plasticity in hippocampal neurons. Cell 134: 175-187.

Xu B, Goulding EH, Zang K, Cepoi D, Cone RD, Jones KR, Tecott LH, and Reichardt LF. 2003. Brain-derived neurotrophic factor regulates energy balance downstream of melanocortin-4 receptor. Nat. Neurosci6: 736-742 (see comments here).

 


Links

Anxious to lose weight

Anxiety-induced weight loss

Scientists discover a brain molecule connecting anxiety to weight loss

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