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Duke University


Duke Medical Center

Chay T. Kuo, MD, PhD
BS, M.I.T.
MD, University of Chicago
PhD, University of Chicago

George W. Brumley Assistant Professor,
Dept. of Cell Biology,
Pediatrics, Neurobiology

Chay Kuo

    Understanding regenerative capacities in the nervous system
There are currently few, if any, effective treatment options for patients who have suffered traumatic brain injuries or stroke. Following injuries, patients are often faced with challenging roads ahead to reverse the often debilitating neurological/cognitive deficits. Since mature neurons in the brain, once damaged, do not proliferate, neuronal replacement therapy offers a promising and much needed treatment strategy for patients. Neurons are made from neural stem cells. There has been a great deal of interest in using neural stem cells as therapeutic agents. But beside neurons, neural stem cells also make astrocytes and oligodendrocytes. These glial cells are critically important for maintaining normal nervous system function, but in the context of brain injury, it is often believed that making more neurons from stem cells is the desirable outcome. My laboratory is interested in understanding regenerative capacities in the nervous system, in particular how postnatal/adult neural stem cells and their progeny modify brain homeostasis. Our research projects are centered around understanding the cellular and molecular pathways regulating generation/integration of new neurons and glia in the brain, in health and after injury. A better understanding of these processes may lead to future therapies that can accelerate tissue repair after brain injuries.

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Email: chay.kuo@duke.edu
366 Nanaline Duke Bldg.
451 Research Dr. Box 3709
Duke Univ. Medical Center Durham, NC 27710

 Telephone: (919) 684-4612
Fax: (919) 684-5481

NIH Director's New Innovator
David & Lucile Packard Fellow
Sontag Fellow
 
    Control of neurogenic niche homeostasis and neuronal production
For most of our experiments, we use the rodent postnatal/adult subventricular zone (SVZ) neurogenic niche as a model system. This is a brain area that contains robust self-renewing neural stem cell populations. Early on, we developed some of the first inducible genetic tools to modulate SVZ niche function in vivo, and have continued to work in this area by merging mouse genetics with optical and physiology tools. As it was unclear how new neuron production was sustained in the postnatal/adult brain, we recently uncovered that cellular properties within multiciliated ependymal cells, part of the neurogenic niche, provide critical cues to sustain neurogenesis in the postnatal/adult brain. Currently, a major focus in the lab is to elucidate important pathways regulating adult neural stem cell homeostasis within the functional niche - we are particularly interested in how this niche architecture is generated and maintained during the postnatal period, and in the application of this knowledge to formulate general principles guiding new neuron production. We use a variety of techniques including building novel mouse models, development of new imaging platforms, whole-cell recordings, and collaborations with bioengineers to study these processes. We are conducting both in vivo and in vitro-based screens to identify new pathways that regulate postnatal/adult neurogenesis.

    Contribution of stem cells and their progeny to brain repair and remodeling after injury
Postnatal disruptions of the SVZ neurogenic niche revealed that resident stem cells and their progeny have considerable plasticity and can participate in local remodeling and tissue repair. We are actively investigating the molecular mechanisms regulating this plasticity. We are interested in how environmental cues may transform differentiation capacities of newborn progeny from postnatal/adult neural stem cells, and how this process can functionally impact brain homeostasis in both health (integration of immature neurons into mature neural circuits) and after brain injury (migration/integration of neurons and glia following cortical stroke and traumatic brain injury). Our ability to precisely label and modify stem cell progeny under different environmental conditions, and to then follow their migration and differentiation gives us unique opportunities to tackle these challenging and medically important problems. We believe that a deeper understanding of resident stem cells’ innate responses to pathological conditions such as brain injury will accelerate therapeutic development for patients. Our approaches include a combination of mouse genetics, molecular biology, live-cell imaging, in vivo circuit tracing, electrophysiology, and collaborations with neural trauma colleagues.

Selected Publications
Benner, EJ, Luciano, D, Jo, R, Abdi, K, Paez-Gonzalez, P, Sheng, H, Warner, DS, Liu, C, Eroglu, C, and Kuo, CT. 2013. Protective astrogenesis from the SVZ niche after injury is controlled by Notch modulator Thbs4. Nature, DOI 10.1038/nature12069.

Paez-Gonzalez, P, Abdi, K., Luciano, D, Liu, Y, Soriano-Navarro, M, Rawlins, E, Bennett, V, Garcia-Verdugo, JM, and Kuo, CT. 2011. Ank3-dependent SVZ niche assembly is required for the continued production of new neurons. Neuron 71: 61-75. (Cover Story) -PDF-

Kuo, CT, Mirzadeh, Z, Soriano, M, Rasin, M, Wang, D, Shen, J, Sestan, N, Garcia-Verdugo, J, Alvarez-Buylla, A, Jan, LY, and Jan, YN. 2006. Postnatal deletion of Numb/Numblike reveals repair and remodeling capacity in the subventricular neurogenic niche. Cell 127: 1253-64. (Research Highlights in Nature) -PDF-

Kuo, CT, Zhu, SJ, Younger, S, Jan, LY, and Jan, YN. 2006. Identification of E2/E3 ubiquitinating enzymes and caspase activity regulating Drosophila sensory neuron dendrite pruning. Neuron 51: 283-90. (Research Highlights in Nature Rev. Neurosci.)

Yu, FW, Kuo, CT, and Jan, YN. 2006. Drosophila neuroblast asymmetric cell division: recent advances and implications for stem cell biology. Neuron 51: 13-20.

Kuo, CT and Jan, YN. 2005. The hand that rocks the spindle. Nature Cell Biol. 7: 858-9.

Kuo, CT, Jan, LY, and Jan, YN. 2005. Dendrite-specific remodeling of Drosophila sensory neurons requires matrix metalloproteases, ubiquitin-proteasome, and ecdysone signaling. PNAS 102: 15230-5.

Buckley, AF, Kuo, CT, and Leiden, JM. 2001. Transcription factor LKLF is sufficient to program T cell quiescence via a c-Myc-dependent pathway. Nature Immunol. 2: 698-704. (Accompanied News & Views in Nature Immuol.)

Kuo, CT and Leiden, JM. 1999. Transcriptional Regulation of T Lymphocyte Development and Function. Annu. Rev. Immunol. 17: 149-187.

Kuo, CT, Veselits, ML, Barton, KP, Lu, MM, Clendenin, C, and Leiden, JM. 1997. The LKLF transcription factor is required for normal tunica media formation and blood vessel stabilization during murine embryogenesis. Genes & Dev. 11: 2996-3006. (Cover Story)

Kuo, CT, Veselits, ML, and Leiden, JM. 1997. LKLF: A transcriptional regulator of single positive T cell quiescence and survival. Science 277: 1986-1990. (Accompanied Perspective in Science)

Kuo, CT, Morrisey, EE, Anandappa, R, Sigrist, K, Lu, MM, Parmacek, MS, Soudais, C, and Leiden, JM. 1997. GATA4 transcription factor is required for ventral morphogenesis and heart tube formation. Genes & Dev. 11: 1048-1060. (Cover Story)


Lab personnel
Chay T. Kuo, MD, PhD (principle investigator)
Patricia Paez-Gonzalez, PhD, (postdoc)
Khadar Abdi, PhD (postdoc)
Brent Asrican, PhD (postdoc)
Ryan Andersen, PhD (postdoc)
Nick Luciano, (grad student, Neurobiology)
Erica Rodriguez, (grad student, Neurobiology)
Dawn Fromme (technician)
Samantha Collins (technician)

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