McNair Scholars

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.

Associate Professor of Neurosurgery
Appointed McNair Scholar March 2023

In biology, structure and function are inextricably linked. Much of neuronal function is determined by anatomical connections - the brain’s "wiring diagram." Moreover, most brain disorders are understood to be problems not confined to the cells of a particular region, but distributed through the communication among multiple brain regions. Thus, they are essentially connectionist disorders. My laboratory’s ultimate goal is to build the wiring diagram of the human brain.

My training prepared me well for these tasks. I was a graduate student at Duke University in Dr. Michael Platt’s lab, where I recorded from single neurons as nonhuman primates carried out learning and decision-making tasks. I then moved on to my postdoctoral training with Dr. Suzanne Haber at the University of Rochester. There, I learned traditional and cutting-edge neuroanatomy. I used anatomical connectivity to establish principles of white matter organization and to determine rodent-primate homologies in frontal cortical areas. This work had substantial translational impact.

As faculty, I have established an active research laboratory spanning methodologies. One of these is anatomical tract-tracing, which is the gold standard for determining neuronal anatomical connectivity. Unfortunately, tract-tracing cannot be performed in humans. Can advanced imaging technologies solve this problem? Diffusion magnetic resonance imaging (dMRI) takes advantage of the differential diffusion of water molecules along axons to estimate connectivity between populations of neurons. Unfortunately, dMRI does not accurately match anatomical connections. Overcoming this hurdle depends on matching the tracts generated by dMRI with underlying white matter anatomy. In collaboration with Dr. Jan Zimmermann and other members of the University of Minnesota’s Center for Magnetic Resonance Research, I have developed a pipeline to combine non-invasive, dMRI-derived measures of brain connectivity with anatomical tract-tracing. I perform both anatomical tract-tracing and dMRI in nonhuman primates, and then I apply the lessons learned about dMRI’s failures to human data. Furthermore, in collaboration with Dr. Taner Akkin, I am combining tract-tracing and polarization-sensitive optical coherence tomography. At the conclusion of these studies, we hope to build toward an accurate wiring diagram of nonhuman primate and human brains.

With these maps in hand, we expect to link structure (in the form of anatomical connectivity) with function (from electrophysiology and neuroimaging). We have already published one study demonstrating the value of this approach. In collaboration with Dr. Ben Hayden, I examined functional properties of neurons in orbitofrontal and posterior cingulate cortices that were structurally distinguished on the basis of anatomical connectivity.

Another way of approaching brain connectivity is via functional connectivity, which measures how correlated neural signals are across regions over time. Functional connectivity is a useful and popular tool in human MRI; however, its biological basis is poorly understood. My goal is to improve the interpretability of functional connectivity by chemogenetically manipulating circuits and measuring the effects on functional connectivity. I characterized the anatomical distribution of viral expression in the nonhuman primate brain to guide our usage of chemogenetic tools. I also helped to develop a robust pipeline for measuring functional connectivity in nonhuman primates at 10.5T. I expect these experiments will significantly contribute to our understanding of functional connectivity MRI work in human populations.

Rodents are essential nonhuman animal models in the field of neuroscience. Unfortunately, rodent brains are certainly not human brains. I use connectivity as a defining metric of brain regional similarity across species. In my laboratory’s first published work on this subject, we analyzed anatomical connectivity between the rat posteromedial cortex and various prefrontal cortical and striatal regions. The coming years will require comparing these connectivity maps to those from nonhuman primates and humans, as well as expanding them to other regions, to establish translational value.

Finally, neuromodulation tools like deep brain stimulation and transcranial magnetic stimulation offer the tantalizing possibility of manipulating brain connections in order to treat psychiatric and neurological disorders. With my recent move to ��, I plan to use the accurate wiring diagrams we are generating to inform targeting for neuromodulation solutions for human brain disorders.

Assistant Professor of Neurology
Appointed McNair Scholar January 2023

Our cognitive functions arise from the orchestrated activity of highly interconnected circuits of neurons. In a healthy brain, neural activity levels are maintained in an optimal range. In epilepsy, healthy circuit activity patterns are disturbed and replaced by hypersynchronous activity that interfere with cognitive functions and can transform into seizures.

Epilepsy affects 50 million people worldwide. Current treatment options (including medication and surgical resection) leave more than one third of people with epilepsy without adequate seizure control. The shared underlying cause of epilepsies, whether of genetic or acquired origins, is neuronal hyperexcitability. Such hyperexcitability is a pathomechanism of epilepsy and several related brain disorders, including Alzheimer’s disease and autism. Therefore, developing treatments for hyperexcitability is critically important. However, the precise mechanisms that cause epileptic circuit activity remain poorly understood. As a result, despite decades of research, multiple generations of antiseizure medications have failed to reduce the proportion of patients with treatment-resistant epilepsy.

Our mission at the Laboratory of Neural Circuit Modulation is to advance a mechanistic understanding of the circuit mechanisms that regulate neuronal activity to enable developing neuromodulatory interventions for inhibiting epilepsy. In the following years, we will primarily focus on the inhibitory circuit elements involved in the generation and termination of seizures.

Inhibition is often described as a counterweight to excitation, and impaired inhibition contributes to epilepsy. However, inhibition is complicated. There are dozens of types of GABAergic inhibitory interneurons, with important cellular and molecular differences. Our prior research identified functionally distinct interneuron types that are recruited in distinct brain states, including physiological brain states during behavior, and pathological states (seizures) in epilepsy.

We aim to develop innovative approaches that will allow us and the field to map the recruitment of distinct inhibitory cell types in seizures and target such types (including types that remained out of reach) with neuromodulatory intervention. We use rodent models of epilepsy along with non-epileptic controls and carry out large-scale, cell type-specific recording of neuronal activity using in vivo 2-photon microscopy. This approach uses a multiphoton microscope to take high-resolution images of fluorescence reporters inside the brain of awake, behaving mice at a rate of dozens of frames per second. Genetically encoded fluorescent reporters of neuronal activity (calcium, neurotransmitters, neuromodulators and endocannabinoids) are expressed in the cell types of interest using genetic targeting. Optical recordings are combined with correlated measurement of electrical activity (such as depth EEG) and behavioral features to detect and ultimately predict seizures. There are three advantages of this approach critical for our mission: First, the ability to simultaneously record from hundreds of neurons is realized without losing the ability to distinguish between neuronal types. Second, the procedures that establish our optical access to the brain enable the application of both invasive and non-invasive neuromodulatory interventions during recording. Optogenetic methods use genetically encoded light-sensitive ion channels, and low-intensity focused ultrasound takes advantage of the differences in cell-intrinsic properties between cell types and cell states. These stimuli allow selectively activating or inhibiting the targeted cell types. Moreover, stimuli can be triggered by a closed loop system, enabling strategies that aim to prevent or interrupt seizures without interfering with baseline brain activity. Lastly, as these experiments are carried out in awake mice, the approach allows us to challenge the subjects with behavioral tasks during recording and stimulation. Thus, the impact of the neuromodulatory interventions on both seizures and cognitive function can be evaluated with great resolution and specificity.

Assistant Professor of Molecular and Human Genetics and Pediatrics
Appointed McNair Scholar February 2019

As a physician-scientist, my efforts are primarily focused on understanding the genetic and neuro-physiologic underpinnings of neurodevelopmental disorders such as intellectual disability, epilepsy, autism, schizophrenia and other neuropsychiatric conditions. In particular, one emerging theme in the field is that disrupted inhibitory neuronal development and function has been found in association with many neurologic and psychiatric disorders. This would be consistent with the growing body of knowledge that inhibitory neurons are highly diverse and key for virtually all aspects of neurobiology from neural circuit development to information processing. Therefore, elucidating the genetic etiologies of inhibitory neuronal development and function has great potential to advance our understanding of inhibitory neurobiology in health and disease. However, determining the genetic cause is only the first step. The critical advance needed for translation of human genetic studies into clinical applications is to identify the consequences of genetic alterations at the molecular, cellular, neural network and whole-organism levels. This mechanistic dissection of neurodevelopmental disorders bridges molecular function to disease pathogenesis, which is crucial for the development of effective targeted therapeutics. Types of genetic alterations we study in the lab impact transcriptional regulation, protein translation, cell-type specific specification. synapse formation, and neurotransmitter release.

Our goal is to determine the role of cerebro-cerebellar excitatory and inhibitory neuronal dysfunction in the pathogenesis of neurodevelopmental and neuropsychiatric disorders by deciphering how genetic alterations perturb neurotransmission in the brain, impact neural development and lead to abnormal neurologic output. In the Chao Lab, we integrate cross-species approaches in humans to uncover the genetic etiologies of neurodevelopmental disorders, fruit flies to elucidate the molecular pathways and mice to explore the cascade of events in the mammalian brain and develop pre-clinical studies. A variety of approaches and techniques are employed in our laboratory including comprehensive human phenotyping and multiomics studies, genetically engineered mouse and fruit fly models, functional analyses with electrophysiology, imaging, transcriptomics, molecular and cellular assays and behavioral profiling.

In addition to the laboratory research activities, our team leads an Epilepsy Genetics Initiative at the Duncan NRI to identify genetic determinants of undiagnosed developmental and epileptic encephalopathies and we established a multidisciplinary EBF3-related autism spectrum, ataxia, and other neurodevelopmental disorders clinic at TCH. We now follow the largest group of EBF3-related HADDS and 10q26 deletion syndrome patients to date in a single institution and conduct comprehensive phenotypic-genotypic analysis with neurocognitive profiling and neuroimaging. Finally, we are leading a Phase 0 natural history study for STXBP1-related epileptic encephalopathy with the goal of continuing to Phase 1 gene therapy studies. The findings from the clinical studies also inform our laboratory research efforts to understand how gene disruptions alter inhibitory and excitatory neuronal development, perturb neural network activity and lead to cognitive and behavioral abnormalities in neurodevelopmental and psychiatric disorders.

Professor of Molecular & Human Genetics and Biochemistry & Molecular Biology | Program in Integrative
Molecular and Biomedical Sciences and Program in Developmental Biology
Appointed McNair Scholar May 2017

Cancers are driven by genomic and epigenetic alterations that result in the activation of cellular proto-oncogenes and the inactivation of tumor suppressor genes. Although high-throughput genomic approaches have begun to establish extensive catalogs of gene alterations in human tumors, the genes that control tumor genesis, progression and response to therapies are often concealed by the complex chromosomal instability in cancer cell genomes. This challenge is exacerbated by the lack of functional annotation for the vast majority of genes in the human genome. Thus, functional approaches are critical for identifying the genetic programs underlying cancer pathogenesis. Our laboratory applies genome-wide RNA interference (RNAi) and other technologies to the unbiased discovery of cancer genes and networks. Specifically, we focus on four areas of cancer gene discovery: Discovering new oncogene-induced “stress pathways” and translating these pathways into cancer therapies

The cancer community has largely studied the effects of oncogenes and tumor suppressors and how they contribute to the “pro-tumorigenic” hallmarks of cancer cells. However, it’s also become clear that oncogenes themselves induce a variety of stresses in cancer cells such as metabolic reprogramming, oxidative pressures, mitotic instability and proteomic imbalance. These stress phenotypes, sometimes collectively referred to as oncogenic stress, can serve to antagonize tumor growth and survival. The idea that oncogenes confer a highly stressed state onto cancer cells predicts that strategies to exacerbate one or more of these oncogene-induced stresses could conceivably tilt this balance in favor of killing cancer cells. We have been interested in exploiting the idea of oncogene-induced stresses for therapeutic discovery by tackling three poorly understood questions:

What are the molecular mechanisms by which prominent oncogenes (ex. Myc, Ras, etc.) induce these stresses?
How do cancer cells tolerate these stresses?
Are these stress support pathways different in normal and tumor cells?

By using forward genetic approaches, we have made surprising discoveries about the endogenous cell pathways that are required to tolerate predominant oncogenic drivers like c-Myc (ex. Kessler et al, Science 2012). We are now extending these studies by elucidating the stress support pathways that enable cancer cells to tolerate other prominent drivers. Repositioning anti-cancer therapies for triple-negative breast cancer

Breast cancer is a collection of diseases with distinct clinical behaviors and heterogeneous molecular features. Among these disease subtypes, triple-negative breast cancer (TNBC) is the most aggressive, and the molecular determinants of TNBC are poorly understood. Recently, our group discovered a new tumor suppressor network that is disrupted in more than 70% of TNBCs (Sun et al, Cell 2011), with the tyrosine phosphatase PTPN12 acting as a core component of this network. Importantly, disruption of this tumor suppressor network leads to the concerted hyper-activation of a class of receptor tyrosine kinases. These kinases work together to drive TNBC and probably other cancers. Importantly, we have shown that pharmacologic inhibition of these collaborating kinases leads to tumor regression of primary TNBCs in vivo. We are currently dissecting the mechanism(s) by which these signaling pathways cooperate, and translating these discoveries into new clinical trials for TNBC patients at BCM. Identifying new oncogene / tumor suppressor networks via functional genetic screens

With the explosion of genomic data emerging from TCGA, COSMIC and other annotations of cancer genomes, there are fundamental challenges in:

Discerning which mutant genes are critical cancer drivers
How are these drivers connected in genetic / signaling networks and
Are there key drivers that have not been uncovered by these genomic analyses

We are addressing these important questions by developing genetic screens in human and mouse systems for new tumor suppressors and oncogenes. By combining new genetic technologies and engineered cell systems, we are uncovering new signaling networks that control tumor initiation and progression. For instance, a series of our genetic screens in breast cancer have uncovered an interconnected network of over 40 new tumor suppressor (PTPN12, REST, INPP4B, etc.) and oncogenes (PLK1, TEX14, etc.) with unappreciated roles in human cancer (ex. Westbrook et al, Nature 2008; Sun et al., Cell 2011; Pavlova et al., eLife 2013). We are systematically applying genetic, cell biologic, and biochemical approaches to understand the functions of these gene networks in controlling malignant transformation. Understanding drug resistance in breast cancer

Targeted therapies have revolutionized cancer treatment. These new medicines antagonize the survival and progression of tumors by inhibiting cancer-driving oncogenes. However, despite the early success of these therapies, there is substantive heterogeneity in the initial and long-term response of tumors to these therapies. A major goal in our group is to discover the mechanisms governing how tumors respond to targeted therapies and translating these discoveries into better ways of predicting patient response. Using new genetic screening technologies and methods, we have developed an approach to identify signaling networks that govern how cancer cells respond to targeted therapies. By using this approach, we are dissecting both the mechanisms of drug-action and pathways to resistance for agents that are in the clinic as well as drugs soon to be approved as new cancer therapies.

Professor in the Department of Molecular and Human Genetics and the Lester and Sue Smith Breast Center
Appointed McNair Scholar October 2016

Dr. Zhang received his Ph.D. degree in Molecular Genetics from the Chinese Academy of Sciences followed by a postdoctoral training in bioinformatics at the Oak Ridge National Laboratory. Before joining �� in August 2016, he had been a faculty member in the Department of Biomedical Informatics at the Vanderbilt University for 10 years.

During his tenure at Vanderbilt, Dr. Zhang has established an internationally recognized research program in cancer proteogenomics, focusing on integrating genomic and proteomic data to better understand cancer biology. Innovative bioinformatics methods and tools developed by his group enabled the first integrative proteogenomic characterization of human cancer, which was published in Nature. This landmark study demonstrated that integrated proteogenomic analysis provides functional context to interpret genomic abnormalities, and that proteogenomics holds great potential to enable new advances in cancer biology, diagnostics and therapeutics.

Dr. Zhang has more than 70 publications in the areas of bioinformatics, proteomics and cancer systems biology. He has served as principal investigator, bioinformatics director, or co-investigator on more than 10 federal grants. He serves frequently as program committee member in international conferences and as reviewer for NIH study sections. He also serves on the editorial board of multiple journals including Molecular & Cellular Proteomics and Clinical Proteomics. He has been honored with local, national and international awards in recognition of his research activities, including an award from the National Library of Medicine (NLM) for Innovative Uses of NLM Information. Dr. Zhang is a funded scholar of the Cancer Prevention and Research Institute of Texas.

The long-term goal of Zhang’s research is to use proteogenomics and multi-omics data to better understand cancer biology and to improve cancer care.

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