Translational Research Projects

The Hsieh laboratory focuses on 4 major areas: (1) epilepsy-in-a-dish, (2) 3D cerebral organoids, (3) patient recruitment, and (4) mechanisms of adult neurogenesis:


Epilepsy-in-a-dish

Severe epilepsies of childhood pose specific difficulties in diagnosis and treatment as they are typically refractory to conventional therapies, associated with poor developmental outcomes, and co-morbid with cerebral palsy, autism, and other neuropsychiatric conditions. Single gene epilepsy syndromes, so-called genetic epileptic encephalopathies, provide a window to study these diseases using patient specific models. In collaboration with Dr. Jay Schneider’s lab, we are making patient-derived induced pluripotent stem cells to study monogenic epilepsies. We are employing several novel cell culture innovations, including 3D neuronal cultures called “cerebral organoids”. Use of CRISPR gene-editing technology allows for creation of isogenic controls facilitating analysis of molecular phenotypes attributable to the specific genetic mutation. We hope to translate our findings to educate treatment of these challenging diseases.

3D cerebral organoids and optic cup

Using human embryonic stem (hES) cells and organoid technology, we are modeling human brain development, including photoreceptor and retinal pigmented epithelium in vitro. Currently we are elucidating the biology of in vitro optic cup formation using retinoblastoma gene (RB) knockout hES cells. Our goal is to identify the developmental biology of the formation of retinal layers and model human disease with genetic etiology, such as juvenile macular degeneration and Leber congenital amaurosis.


Patient recruitment

We have a research protocol for recruiting patients with rare genetic diseases for which there is no cure. We hope to develop disease models to further our understanding of these diseases and ultimately influence treatment. If you are interested in learning more about our research in genetic diseases, please contact Drew.Thodeson@UTSouthwestern.edu.

Sage and his family with Dr. Drew Thodeson. Sage is a delightful 10-year-old boy who loves Tex-Mex food. He has epilepsy, a complicated movement disorder, and autism. He is our first patient we have recruited for our epilepsy-in-a-dish study.

Mechanisms of adult neurogenesis in physiological and pathological conditions

Adult mammalian neural stem cells in the hippocampal dentate gyrus are a subject of intense study based on their biological properties and potential medical significance. Neural stem cells can self-renew and differentiate into neurons and glial cells (astrocytes and oligodendrocytes) during development and in the adult central nervous system. After a severe brain insult, neural stem cells proliferate and migrate aberrantly and contribute to epilepsy progression. We are interested in the identification of the cellular and molecular mechanisms regulating self-renewal and fate specification of adult neural stem cells and plasticity of newborn neurons in both physiological and pathological contexts, such as epilepsy. Our laboratory is using an integrated approach to investigate rodent and human neural stem cells both in vitro and in animal models utilizing techniques in molecular biology, cell biology, virology, neuroscience, and imaging.