ABOUT THE RESEARCHER

OVERVIEW

Our lab seeks to understand the molecular and cellular basis of human brain disorders in order to ultimately develop therapeutics. Many brain disorders, including neurodevelopmental disorders, epilepsy, and brain cancer, arise from gene expression abnormalities that alter the molecular makeup of cells and deficits in cellular function and circuit connectivity. Unfortunately, very few therapeutic options that target the relevant disease risk genes are available in the clinic for the treatment of these brain disorders. Targeted therapy development continues to be challenging due to a general lack of knowledge about the molecular mechanisms that regulate the expression of risk genes. Until disease models faithfully recapitulate the human disease condition and discovery methodologies unbiasedly identify effective therapeutics, precision medicine for brain disorders will remain elusive.

Our lab is dedicated to advancing precision medicine for brain disorders using genome-edited human stem cells. We leverage cutting-edge technologies including single-cell RNA sequencing, CRISPR gene editing, human stem cells, and high-throughput screening methodologies, to create physiologically-relevant models of human brain diseases for mechanistic investigation, and to develop drug discovery platforms for the screening of precision medicine therapeutics that regulate the expression of disease risk genes for neurodevelopmental disorders, epilepsy, and brain tumor. The goal of our work is to yield actionable scientific insights that help to fill the gap between basic science and therapeutics development for the clinical treatment of brain disorders.

Research Direction 1: Restoring excitation/inhibition balance to treat brain disorders

Epileptic seizure manifests as the main symptom or as a comorbidity for variety of brain diseases spanning from neurodevelopmental disorders to brain cancer, which suggests that a common disease mechanism of impaired balance between excitation and inhibition (E/I balance) in brain circuits is involved. In previous work, we created a high-throughput drug screening platform based on gene-edited human stem cell-derived neurons to discover the first group of small molecule drugs that activate the expression of KCC2, a neuronal chloride transporter that plays a pivotal role in maintaining the E/I balance. We then demonstrated the in vivo therapeutic efficacy of the discovered KCC2 expression-enhancing compounds (KEECs) in a mouse model of neurodevelopmental disorder in which KCC2 expression is reduced in the brain (Tang et al., Science Translational Medicine, 2019).

Leveraging the KEECs we have pioneered and a KCC2 conditional knockin mouse we have recently generated, we will rigorously investigate a novel therapeutic avenue that targets KCC2 to treat brain disorders that manifest impaired E/I balance, including developmental and epileptic encephalopathy and tumor-associated epilepsy.

Research Direction 2: Elucidating the uncharacterized roles of FLT3 kinase pathway in brain development and neuroinflammation

In our previous work, we utilized an unbiased drug screening approach to identify drugs that activate KCC2 gene expression. We unexpectedly discovered a number of FLT3 kinase pathway inhibitors drugs, which are approved by the FDA to treat blood cancer but have not been well studied in the brain. We further performed mRNA sequencing experiments to investigate the changes in gene expression induced by FLT3 kinase inhibitors in mouse and human neurons, which uncovered previously unknown roles of the FLT3 kinase pathway in promoting synapse development and reducing neuroinflammation. We will employ a combination of research techniques including genome-engineered human cells and mouse models, RNA sequencing, and genome-wide CRISPR screening, to elucidate the potentially diverse roles of the FLT3 pathway in modulating signal transduction and gene expression in brain cell types. We will further map the mechanistic insights gained from these discoveries onto brain function and dysfunction to drive the development of therapeutics.

Research Direction 3: Blocking malignant interactions between brain tumors and their microenvironments to suppress brain cancer growth

Brain tumors closely interact with the surrounding tissue to promote their growth and to evade immune surveillance. For example, recent work has uncovered bi-directional interactions between neurons and tumors through electrochemical synapses and paracrine factors, and demonstrates that tumor-induced KCC2 expression reduction and resulting epilepsy in turn provides trophic support to the tumors and further promotes their growth. Therefore, tumor-induced KCC2 reduction results in a ‘vicious cycle’ that involves a positive feedback between brain hyperexcitability and tumor growth, which represents a potential target for therapeutic intervention.

Our goals are:

  1. To devise pharmacological approaches to reduce tumor-associated epilepsy
  2. To enhance the capability for microglia cells to detect and destroy brain tumor. Our approach is to establish models of brain and spinal cord cancer through tumor xenograft transplantation or organoid culture to investigate the signaling mechanisms underlying malignant tumor-brain interactions. We will leverage mechanistic insights to devise drug and cell therapies that break the ‘vicious cycle’ of malignant tumor-brain interactions and, in that way, have the potential of advancing to the clinic to benefit both pediatric and adult brain cancer patients.

Selected Publications

  1. Tang, X., Jaenisch, R., Sur, M.. The role of GABAergic signalling in neurodevelopmental disorders. Nat Rev Neurosci. 2021, PMID: 33772226
  2. Li, C.H., Coffey, E.L., Dall’Agnese, A., Hannett, N.M., Henninger, Tang, X., J.E., Oksuz, O., Zamudio, A.V., Schuijers, J., Liu, X.S., Markoulaki, S., Svoboda, D.S., Wogram, E., Lee, T.I., Jaenisch, R., Young, R.A., Dual roles for MeCP2 in heterochromatin condensate formation and separation from transcriptional condensates, Nature, PMID: 32698189.
  3. Tang, X., Drotar, J., Li, K., Clairmont, CD., Brumm, AS., Wu, H., Liu, XS., Wang, J., Gray, NS., Sur, M., Jaenisch, R.. Pharmacological Enhancement of KCC2 Gene Expression Exerts Therapeutic Benefits on Human Rett Syndrome Neurons and Mecp2 Mutant Mice, Science Translational Medicine, 2019. PMID: 31366578. (highlighted by F1000Prime and Nature Reviews Drug Discovery)
  4. Tang, X., Kim, J., Zhou, L., Wengert, E., Zhang, L., Wu, Z., Carromeu, C., Muotri, AR., Marchetto, MC., Gage, FH., Chen, G.. KCC2 rescues functional deficits in human neurons derived from patients with Rett syndrome, Proceedings of the National Academy of Sciences, 2016. PMCID: PMC4725523. (highlighted by F1000Prime)
  5. Banerjee, A., Rikhye, RV., Breton-Provencher, V., Tang, X., Li, C., Li, K., Runyan, CA., Fu, Z., Jaenisch, R., Sur, M.. Jointly reduced inhibition and excitation underlies circuit-wide changes in adult cortical processing in vivo, Proceedings of the National Academy of Sciences, 2016. PMCID: PMC5135376.
  6. Zhu, S., McGrath, BC., Bai, Y., Tang, X., Cavener, DR.. PERK regulates Gq protein-coupled intracellular Ca2+ dynamics in primary cortical neurons, Molecular Brain, 2016. PMCID: PMC5045583.
  7. Wu, Z., Foster, AC., Staubli, U., Wu, X., Sun, C., Tang, X., Li, YX., Chen, G.. Effects of 3-aminoglutarate, a “silent” false transmitter for glutamate neurons on synaptic transmission and epileptiform activity. Neuropharmacology, 2015. PMCID: 26002626.
  8. Tang, X., Zhou, L., Wagner, AM., Marchetto, MC., Muotri, AR., Gage, FH., Chen, G.. Astroglial cells regulate the developmental timeline of human neurons differentiated from induced pluripotent stem cells. Stem Cell Research, 2013, PMCID: PMC397996. (cover story)
  9. Fan, Y., Tang, X., Vitriol, E., Chen, G., Zheng, JQ.. Actin Capping Protein is required for Dendritic Spine Development and Synapse Formation. Journal of Neuroscience, 2011. PMCID: PMC3138183.
  10. Zhou, L., Tang, X., Li, X., Bai, Y., Buxbaum, JN., Chen, G.. Identification of transthyretin as a novel interacting partner for the δ subunit of GABAA receptors. PLOS One, 2019. PMCID: PMC6322723.
  11. Wang, R., McGrath, BC., Kopp, RF., Roe, MW., Tang, X., Chen, G., Cavener DR.. Insulin Secretion and Ca2+ Dynamics in β-Cells Are Regulated by PERK (EIF2AK3) in Concert with Calcineurin. Journal of Biomedical Chemistry, 2013. PMCID: PMC3837125.
  12. Harel, NY., Song, KH., Tang, X., Strittmatter, SM.. Nogo receptor deletion and multimodal exercise improve distinct aspects of recovery in cervical spinal cord injury. Journal of Neurotrauma, 2010. PMCID: PMC2978056.
  13. Gu, J., Lee, CW., Fan, Y., Komlos, D., Tang, X., Sun, C., Yu, K., Hartzell, HC., Chen, G., Bamburg. JR., Zheng, JQ.. ADF/Cofilin-Mediated Actin Dynamics Regulate AMPA Receptor Trafficking during Synaptic Plasticity. Nature Neuroscience, 2010. PMCID: PMC2947526.

BACKGROUND

Xin Tang received his Ph.D. in neurobiology from Pennsylvania State University. He completed his postdoctoral training at the Whitehead Institute for Biomedical Research at MIT. He was the recipient of the Bridge to Independence career transition award from the Simons Foundation Autism Research Initiative and served as chief editor of the book ‘Neuronal chloride transporters in health and disease’. He currently is an assistant professor in the Department of Neurosurgery and the F.M. Kirby Neurobiology Center at Boston Children's Hospital, Harvard Medical School.

Dr. Tang is committed to proactively support diversity, equity, and inclusion at Boston Children’s Hospital and the F.M. Kirby Neurobiology Center. His personal experience as an immigrant scientist studying and working in the US gave him first-hand knowledge about the importance of these values. He feels very fortunate about the opportunities he has received, and am committed to provide them to the next generations of researchers. It’s his cherished belief that scientific research effort that aims to understand universal truths is by definition a global collaboration, and should provide a fair, merit-based, safe and collegial forum for anyone to access, communicate and contribute to. His lab and himself will strive to ensure that every talented individual, regardless of their gender, ethnic background, religion, sexual orientation, and nationality, is given equal opportunities to excel in their scholarly activities.

Throughout his career, he has been deeply engaged in teaching and mentoring students and young scientists from diverse backgrounds and at different stages of their career. As a lab leader, he is committed to recruiting and training students and postdocs from underrepresented minorities in order to foster diversity in his lab, and to train the next generation of scientists coming from diverse background so they can become role models for their community. He will ensure the scientific progress and career development of his trainees by securing funding to support under-represented and international students and provide mentorship for their research programs.

PUBLICATIONS

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  1. The role of GABAergic signalling in neurodevelopmental disorders. Nat Rev Neurosci. 2021 05; 22(5):290-307. View abstract