Assistant Professor, Medicine – Endocrinology
Appointed McNair Scholar June 2024
Obesity and diabetes remain significant global health challenges, contributing to high rates of morbidity and mortality worldwide. Compelling evidence has revealed an active dialogue between the nervous system and metabolic tissues and organs in orchestrating physiological processes to maintain metabolism and glucose homeostasis. The appropriate detection of metabolic inputs by sensory neurons is a crucial initial step in the neuromodulation of metabolism. However, it is still unclear how distinct metabolic cues are represented in the nervous system and how they achieve precise neural control of metabolism. My research uses state-of-the-art technologies to uncover the sensory mechanisms that control pancreatic physiology, map the underlying neural pathways, and explore the role of neuromodulation in regulating metabolism and diabetes. A molecular and functional dissection of the pancreas-brain crosstalk will open up new vistas in neural control of metabolism and may bring novel concepts and therapeutic targets into the field of diabetes intervention and prevention.
The vagus nerve, a major component of the parasympathetic nervous system, serves as a crucial physical and functional link between the body and the brain. Vagal neurons project to a large variety of visceral organs including thoracic tissues like heart and lung, and abdominal tissues like stomach, intestine, pancreas, and liver, and controls cardiovascular, respiratory, digestive, memory, cognitive, and many other functions. Vagus nerve stimulation has the potential to regulate physiology and pathophysiology associated with its targets. For example, vagus nerve stimulation can treat patients with drug-resistant refractory epilepsy and recurrent depression. Neuromodulation of the vagus nerve is currently being investigated as a potential treatment for obesity. The advantages of vagal targets are not only that they act peripherally and do not need to cross the blood-brain barrier, but also the inherent plasticity of vagal neurons allows them to be rewired. However, the vagus nerve itself contains multiple types of intermingled sensory and motor neurons with different electrophysiological properties, peripheral targets, genetic identities, and physiological and pathophysiological roles. Without specificity and precision, disrupting vagal signaling will likely generate mixed results and unwanted side effects.
As a critical organ for maintaining systemic metabolic homeostasis, the pancreas receives enriched innervation from the peripheral nervous system. In my previous study (Zhao et al, Nature, 2022.), I defined pancreas-innervation vagal sensory neurons (VSNs) using ‘Projection-seq’, a powerful technique that I developed. I then predicted their interactions with the pancreas through analysis of cell-cell signaling, highlighting the potential importance of neuromodulation of pancreatic function. VSNs are anatomically, genetically, and functionally heterogeneous. Genetically distinct VSNs form morphologically distinct nerve terminal structures in the same organ and can mediate opposing physiological functions. This heterogeneity underlies the conflicting results that vagal electrical stimulation and transection studies have produced in the control of the pancreas. Therefore, defining distinct VSNs and unraveling the precise molecular and cellular mechanisms underlying vagal control of the pancreas will be essential to successfully leverage the potential for vagal neuromodulation in treating diabetes. My aim is to dissect the vagal pancreas-to-brain neurons at molecular and functional levels. Using powerful AAV-guided anatomical tracing, whole mount tissue clearing, and volumetric imaging, I was able to systematically examine the innervation of the pancreas by vagal afferents and use different transgenic mouse lines to specifically label distinct nerve terminal structures. I will apply powerful genetic tools, including optogenetics, chemogenetics, cell-type specific ablation, and pharmacological manipulation to investigate the functional roles of distinct VSNs in regulating pancreatic islet health, insulin secretion, and glucose homeostasis. This approach can be extended to VSNs’ impact on other organs, other aspects of physiology, and animal behaviors. Potential effects of gender and left- vs right-sided vagal nerves will also be examined. The aforementioned powerful genetic tools will greatly improve specificity and precision. To further explore the mechanistic basis underlying the vagal pancreas interactions, I will perform proximity labeling studies to define the proteomic profiles of these vagal pancreas-to-brain neurons. Moreover, I will investigate the impact of diabetes on the vagal-pancreas interaction and vice versa, exploring how their interplay influences the development and progression of diabetes using various mouse models. This will be followed by studies to understand how the brain processes and integrates the vagal pancreatic inputs to modulate metabolism. These studies will provide a framework for understanding pancreas-brain crosstalk and its importance in maintaining pancreatic function and metabolic homeostasis, as well as a rational basis for neuromodulatory interventions.
Overall, I aim to determine how the nervous system senses pancreatic cues to achieve precise neuromodulation of metabolism at molecular, cellular, and circuit levels and further promote the development of novel therapeutic strategies for diabetes intervention. My research aligns well with the mission of the McNair Scholars Program, which is to pursue collaborative and transformational research in the areas of breast and pancreatic cancer, juvenile diabetes, and the neurosciences.
