NIH/NINDS RF1 Award Supports 4H Leukodystrophy Research
Our laboratory has received a $1.01 million National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS) RF1 award to support our research on 4H leukodystrophy, a rare neurogenetic disorder caused by dysfunction of RNA polymerase III.
The project, “Novel Zebrafish Models and Molecular Insights into 4H Leukodystrophy, Linking POLR3 Dysfunction to Disease Progression and Therapeutic Compound Discovery,” provides multi-year funding through August 2029.
Using zebrafish disease models, the project will investigate how POLR3 dysfunction affects neural development and myelination, examine RNA biology and cellular stress pathways associated with disease progression, and evaluate potential therapeutic compounds.
The award will also expand hands-on research and training opportunities for undergraduate and graduate students at Utah Tech University, giving them opportunities to participate directly in disease modeling, molecular biology, functional genomics, neuroscience, and therapeutic discovery.
The award represents the first NIH research award and the first R01-level NIH research award in Utah Tech University’s history, marking an important milestone in the growth of biomedical research and student-centered scientific discovery at the university.
see the news link: https://news.utahtech.edu/2026/10/07/nihgrant/
Research projects
RNA Polymerase III-Associated Leukodystrophy
4H leukodystrophy is a rare genetic disorder that primarily affects the white matter of the brain and is characterized by progressive neurological dysfunction. The name “4H” reflects three major clinical features: hypomyelination, hypodontia, and hypogonadotropic hypogonadism. Symptoms often begin in infancy or childhood and may include developmental delay, motor impairment, difficulties with coordination and balance, cognitive decline, and other neurological abnormalities.
The disease is caused by pathogenic variants in genes associated with RNA polymerase III, including POLR3A, POLR3B, POLR3K, and POLR1C. RNA polymerase III is responsible for producing several classes of essential non-coding RNAs, including transfer RNAs and other small RNAs required for normal cellular function. How disruption of RNA polymerase III selectively leads to abnormalities in myelination and nervous system development remains incompletely understood.
Our research focuses on developing and characterizing zebrafish models of POLR3-related leukodystrophy to uncover the molecular and cellular mechanisms that drive disease progression. We investigate how altered RNA biology, cellular stress responses, protein synthesis, neural development, and myelination contribute to disease phenotypes.
Because there is currently no curative treatment for 4H leukodystrophy, we also use our zebrafish models for therapeutic compound screening. Our goal is to identify candidate molecules that can rescue disease-associated phenotypes and ultimately contribute to the development of new treatment strategies for individuals and families affected by rare genetic disorders.
The integrated stress response (ISR) is a conserved cellular signaling pathway that helps cells adapt to environmental, metabolic, and proteotoxic stress. In response to diverse stressors, ISR signaling regulates protein synthesis and activates stress-responsive gene expression to restore cellular homeostasis. Although transient ISR activation can be protective, prolonged or dysregulated signaling can disrupt normal cell function and contribute to disease progression.
Our research investigates how abnormal ISR signaling contributes to neurological and genetic diseases, with a particular focus on neural development, myelination, and neurodegeneration. We study how disease-associated genetic changes alter stress sensing, translation, and cellular recovery, and how these changes influence cell survival and tissue function.
RNA Metabolism Regulation
RNA metabolism is a fundamental process that controls how genetic information is processed, transported, translated, and degraded within cells. Precise regulation of RNA is especially important during development, when cells must rapidly adjust gene expression in response to changing developmental and environmental signals.
Our research investigates how RNA processing, splicing, stability, degradation, and translation contribute to neural development and cellular homeostasis. We are particularly interested in RNA-binding and RNA-processing factors that regulate the fate of messenger RNAs and other RNA species.
Using zebrafish models, molecular genetics, imaging, and transcriptomic approaches, we examine how disruption of RNA metabolism affects nervous system development and disease-related pathways. We also study the roles of RNA-associated complexes, including factors involved in RNA degradation and RNA granule biology, to understand how cells maintain RNA quality and respond to stress.
Our long-term goal is to define how abnormal RNA regulation contributes to developmental and neurological disorders and to identify molecular pathways that may provide new opportunities for therapeutic intervention.
Validation of Gene Variants of Unknown Significance
Interpreting variants of uncertain significance (VUS) remains a major challenge in genomic research and clinical genetics. Although sequencing technologies can identify genetic variants efficiently, determining whether a specific variant disrupts gene function or contributes to disease often requires additional experimental evidence.
Our research uses molecular and functional approaches to evaluate the biological effects of candidate variants. Techniques such as PCR, Sanger sequencing, next-generation sequencing, gene expression analysis, and protein-based assays are used to confirm variants and examine their molecular consequences.
We also use zebrafish as an in vivo functional model to investigate how genetic variants affect development, cellular pathways, and disease-associated phenotypes. By combining genomic analysis with functional validation, our goal is to provide experimental evidence that improves variant interpretation and strengthens our understanding of the relationship between genotype and disease.
Our Team
Hung-Yu Shih
Principle Investigator
Dr. Hung-Yu, Principal Investigator and molecular geneticist, serves as an assistant professor in Utah Tech University’s Department of Biological Sciences. Following his degree from Chang Gung University (Taiwan) and postdoctoral fellowship at the University of Utah, he balances his academic career with fishing, gardening, and family meals.
Yu-Chien Liu
Program coordinator
Research: Yu-Chien Liu focuses on establishing zebrafish disease models of Wolfram Syndrome 2 while mentoring undergraduates in biotechniques for zebrafish care and lab maintenance.
Bio: Taiwan-native Liu coordinates Utah Tech University’s Zebrafish Research Lab, enjoying basketball, badminton, and volleyball, which balance her work and foster collaborations.
Corbin Arnold
Research Associate
Research: Corbin is a Research Associate studying thrombosis and vascular biology. He earned his B.S. degree in Spring 2026 and continues to build his research experience through laboratory experimentation, study design, and data analysis while contributing to ongoing projects in the lab.
Bio: Originally from Los Angeles, Corbin relocated to Utah in 2020. He is pursuing a career in medicine and aspires to become a surgeon. Outside the lab, he enjoys fitness, outdoor activities, and all things Star Wars.
Marli Wakefield
Graduate Student
Research: Marli is a graduate student investigating RNA splicing and RNA degradation in development and disease. Her work focuses on understanding how disrupted RNA-processing pathways affect cellular function and contribute to neurodevelopmental phenotypes. She is developing expertise in molecular and cellular techniques while contributing to ongoing RNA biology projects in the lab.
Bio: Born and raised in Mesquite, Nevada, Marli is pursuing graduate training at Utah Tech University. She is interested in biomedical research and medicine. Outside the lab, she enjoys outdoor activities and spending time with family and friends.
Zach Christiansen
Graduate Student
Research: Zach uses CRISPR technology in zebrafish to investigate the role of a co-chaperone protein in nonalcoholic fatty liver disease (NAFLD), with a focus on how its loss may contribute to cellular stress and lipid accumulation in the liver.
Bio: Originally from St. George, Utah, Zach is a Biotechnology student pursuing his Master’s in Genomics at Utah Tech University. He has a passion for genomics and cancer biology and hopes to pursue a career as a medical geneticist, with a focus on precision medicine. Outside the lab, he enjoys playing pickleball and tennis and spending time with his dogs.
Julia Hyer
Graduate Student
Research: Julia is a graduate student investigating the pathological mechanism of 4H Leukodystrophy and how the ATF family of genes contributes to 4H pathogenesis. She is continually improving her skills in molecular biology techniques and experimental design while contributing to ongoing lab projects.
Bio: Originally from Salt Lake, Julia has enjoyed her time at Utah Tech, where she began studying in 2023. She is interested in pursuing biomedical research and medicine. Outside the lab, she enjoys playing pickleball, being outside, and spending time with friends and family.
Nyx Morehead
Undergraduate student
Research: Nyx is an undergraduate researcher studying the functional impact of MBD4 genetic variants associated with blood disorders. Using molecular and zebrafish-based approaches, he is evaluating how disease-associated variants may alter MBD4 function and contribute to hematologic abnormalities.
Bio: Born and raised in Anchorage, Alaska, Nyx is currently majoring in Biotechnology. Afterward, he intends to pursue a career in medical research. Outside of research, he enjoys skiing, music, and spending time outdoors.
Shaina Jessop
Undergraduate student
Research: Shaina is an Undergraduate Research student majoring in biomedical sciences. In the lab, she is studying the underlying cellular mechanisms of RNA polymerase III-related leukodystrophies. She continues to build her research experience and education by gaining hands-on experience in study design and experimental techniques while contributing to the lab’s ongoing research.
Bio: Originally from Arizona, Shaina relocated to Utah in 2025. She is pursuing a healthcare career and aspires to become a trauma surgeon. Outside the lab, she enjoys backpacking, swimming, and anything that’s outside!
Audrey Eno
Undergraduate student
Research: Eno is an undergraduate research student who is using gateway cloning to investigate overexpression of particular genes in an NAFLD/MASLD model that may have a connection to the disease. They are gaining valuable hands-on experience in experimental techniques as they contribute to research done in the lab.
Bio: Born and raised in Southwest Utah, Eno is majoring in biotechnology. Outside of the lab they enjoy creative and physical activities and being at home.
Former lab members
Youssef Harraq (undergraduate)
Rosemary Mwithiga (undergraduate)
Kaleb Corbett (undergraduate)
Raul Ruiz (undergraduate)
Reagan McKee (undergraduate)
Reign Krieger (undergraduate)
Jared Thiriot (undergraduate)
Isadora Mageo (undergraduate)
Isabel Rhodes (high school student)
Avery Zentner (undergraduate)
Syrus Miner (undergraduate)
Kaisa Poulson (undergraduate)
Tyler Kline (undergraduate)
David Shropshall (undergraduate)
Isabelle Kenworthy (undergraduate)
Lorena Hardy (high school student)
Publications
Publications
1. Hung-Yu Shih, Quentin Raas, Joshua L. Bonkowsky (2024). Progress in leukodystrophies with zebrafish. Development, Growth & Differentiation, 66(1):21–34.
2. Hung-Yu Shih, Hao-Yuan Chen, Yin-Cheng Huang, Tu-Hsueh Yeh, Yi-Chieh Chen, Yi-Chuan Cheng (2023). Etv5a Suppresses Neural Progenitor Cell Proliferation by Inhibiting sox2 Transcription. Stem Cells and Development, 32(17-18):524–538.
3. Hung-Yu Shih, Chia-Wei Chang, Yi-Chieh Chen, Yi-Chuan Cheng (2023). Identification of the Time Period during Which BMP Signaling Regulates Proliferation of Neural Progenitor Cells in Zebrafish. International Journal of Molecular Sciences, 24(2):1733.
4. Sheng-Jia Lin, Yin-Cheng Huang, Hao-Yuan Chen, Jia-You Fang, Shu-Yuan Hsu, Hung-Yu Shih, Yu-Chien Liu, Yi-Chuan Cheng (2021). RGS2 suppresses melanoma growth via inhibiting MAPK and AKT signaling pathways. Anticancer Research, 41(12), 6135–6145.
5. Alexa Derksen, Hung-Yu Shih, Diane Forget, Lama Darbelli, Luan T Tran, Christian Poitras, Kether Guerrero, Sundaresan Tharun, Fowzan S Alkuraya, Wesam I Kurdi, Cam-Tu Emilie Nguyen, Anne-Marie Laberge, Yue Si, Marie-Soleil Gauthier, Joshua L Bonkowsky, Benoit Coulombe, Geneviève Bernard (2021). Variants in LSM7 impair LSM complexes assembly, neurodevelopment in zebrafish and may be associated with an ultra-rare neurological disease. Human Genetics and Genomics Advances, 2(3), 100034. (co-first author).
6. Matthew D Keefe, Haille E Soderholm, Hung-Yu Shih, Tamara J Stevenson, Kathryn A Glaittli, D Miranda Bowles, Erika Scholl, Samuel Colby, Samer Merchant, Edward W Hsu, Joshua L Bonkowsky (2020). Vanishing white matter disease expression of truncated EIF2B5 activates induced stress response. eLife, 9:e56319. (co-first author).
7. Yen-Che Hsieh, Ming-Chang Chiang, Yin-Cheng Huang, Tu-Hsueh Yeh, Hung-Yu Shih, Han-Fang Liu, Hao-Yuan Chen, Chien-Ping Wang, Yi-Chuan Cheng (2018). Pparα deficiency inhibits the proliferation of neuronal and glial precursors in the zebrafish central nervous system. Developmental Dynamics, 247(12):1264–1275.
8. Tu-Hsueh Yeh, Han-Fang Liu, Yu-Wen Li, Chin-Song Lu, Hung-Yu Shih, Ching-Chi Chiu, Sheng-Jia Lin, Yin-Cheng Huang, Yi-Chuan Cheng (2018). C9orf72 is essential for neurodevelopment and motility mediated by Cyclin G1. Experimental Neurology, 304:114–124.
9. Yi-Hsuan Wu, Ying-Hsuan Lee, Hung-Yu Shih, Shih-Hsiang Chen, Yi-Chuan Cheng, Daniel Tsun-Yee Chiu (2018). Glucose-6-phosphate dehydrogenase is indispensable in embryonic development by modulation of epithelial-mesenchymal transition via the NOX/Smad3/miR-200b axis. Cell Death & Disease, 9(1):10.
10. Sheng-Jia Lin, Ming-Chang Chiang, Hung-Yu Shih, Kun-Chun Chiang, Yi-Chuan Cheng (2017). Spatiotemporal expression of foxo4, foxo6a, and foxo6b in the developing brain and retina are transcriptionally regulated by PI3K signaling in zebrafish. Development Genes and Evolution, 227(3):219–230.
11. Yin-Cheng Huang, Sheng-Jia Lin, Hung-Yu Shih, Chung-Han Chou, Hsiao-Han Chu, Ching-Chi Chiu, Chiou-Hwa Yuh, Tu-Hsueh Yeh, Yi-Chuan Cheng (2017). Epigenetic regulation of NOTCH1 and NOTCH3 by KMT2A inhibits glioma proliferation. Oncotarget, 8(38): 63110–63120.
12. Hung-Yu Shih, Shu-Yuan Hsu, Pin Ouyang, Sheng-Jia Lin, Ting-Yun Chou, Ming-Chang Chiang, Yi-Chuan Cheng (2017). Bmp5 regulates neural crest cell survival and proliferation via two different signaling pathways. Stem Cells, 35(4):1003–1014.
13. Sheng-Jia Lin, Ming-Chang Chiang, Hung-Yu Shih, Li-Sung Hsu, Tu-Hsueh Yeh, Yin-Cheng Huang, Ching-Yu Lin, Yi-Chuan Cheng (2017). Regulator of G protein signaling 2 (Rgs2) regulates neural crest development through Pparδ-Sox10 cascade. Biochimica et Biophysica Acta (BBA) – Molecular Cell Research, 1864(3):463–474.
14. Feng-Chun Hung, Hung-Yu Shih, Yi-Chuan Cheng, Chuck C.-K. Chao (2015). Growth-arrest-specific 7 gene regulates neural crest formation and craniofacial development in zebrafish. Stem Cells and Development, 24(24):2943–51. (co-first author).
15. Yi-Chuan Cheng, Yin-Cheng Huang, Tu-Hsueh Yeh, Hung-Yu Shih, Ching-Yu Lin, Sheng-Jia Lin, Ching-Chi Chiu, Ching-Wen Huang, Yun-Jin Jiang (2015). Deltex1 is inhibited by the Notch–Hairy/E(Spl) signaling pathway and induces neuronal and glial differentiation. Neural Development, 10:28.
16. Yi-Chuan Cheng, Ming-Chang Chiang, Hung-Yu Shih, Tsu-Lin Ma, Tu-Hsueh Yeh, Yin-Cheng Huang, Ching-Yu Lin, Sheng-Jia Lin (2014). The transcription factor hairy/E(spl)-related 2 induces proliferation of neural progenitors and regulates neurogenesis and gliogenesis. Developmental Biology, 397(1):116–28.
17. Yin-Cheng Huang, Hung-Yu Shih, Sheng-Jia Lin, Ching-Chi Chiu, Tsu-Lin Ma, Tu-Hsueh Yeh, Yi-Chuan Cheng (2014). The epigenetic factor Kmt2a/Mll1 regulates neural progenitor proliferation and neuronal and glial differentiation. Developmental Neurobiology, 75(5):452–62. (co-first author).
18. Yi-Chuan Cheng, Paul J. Scotting, Li-Sung Hsu, Sheng-Jia Lin, Hung-Yu Shih, Fu-Yu Hsieh, Hui-Lan Wu, Chu-Li Tsao, Chia-Jung Shen (2013). Zebrafish rgs4 is essential for motility and axonogenesis mediated by Akt signaling. Cellular and Molecular Life Sciences, 70(5):935–50.
19. Shin-Yi Chen, Hung-Yu Shih, Sheng-Jia Lin, Chung-Der Hsiao, Zih-Cing Li, Yi-Chuan Cheng (2013). Etv5a regulates the proliferation of ventral mesoderm cells and the formation of hemato-vascular derivatives. Journal of Cell Science, 126(Pt 24):5626–34.
20. Fu-Yu Hsieh, Tsu-Lin Ma, Hung-Yu Shih, Sheng-Jia Lin, Ching-Wen Huang, Hsiao-Yun Wang, Yi-Chuan Cheng (2013). Dner inhibits neural progenitor proliferation and induces neuronal and glial differentiation in zebrafish. Developmental Biology, 375(1):1–12.
21. Yi-Chuan Cheng, Fu-Yu Hsieh, Ming-Chang Chiang, Paul J. Scotting, Hung-Yu Shih, Sheng-Jia Lin, Hui-Lan Wu, Han-Ting Lee (2013). Akt1 mediates neuronal differentiation in zebrafish via a reciprocal interaction with Notch signaling. PLOS ONE, 8(1):e54262.
22. Shu-Yuan Hsu, Yi-Chuan Cheng, Hung-Yu Shih, Pin Ouyang (2012). Dissection of the role of Pinin in the development of zebrafish posterior pharyngeal cartilages. Histochemistry and Cell Biology, 138(1):127–40.
2026 Lab luncheon
2026 DanioVision training
Lab exercise
2025 Dixie Tech visit
Courses
BTEC 2050 - Zebrafish Maintenance and Methodology
This course will give a broad introduction to zebrafish husbandry, maintenance, breeding, egg collection, and embryo microscopy. It will prepare students for advanced functional genomics coursework and research.
BTEC 3050 - CRISPR/Cas9 Technique
This course will introduce foundational techniques of gene knockout using the CRISPR/Cas9 System. Students will gain hands-on experience in a variety of techniques and carry out several experiments using CRISPR/Cas9. This class will prepare students for advanced functional genomics coursework and research.
BTEC 4040 - Techniques in Functional Genomics
This undergraduate laboratory course introduces foundational techniques used in functional genomics. Students will gain hands-on experience with RNA and protein analysis, including RNA purification, cDNA synthesis, quantitative PCR, protein quantification, Western blotting, and immunostaining. The course emphasizes accurate laboratory practice, data analysis, interpretation, and scientific documentation and prepares students for advanced functional genomics coursework and research.
BTEC 4050 - In Situ Hybridization
This course will introduce foundational techniques of in situ hybridization, and provide applied lab experiences in identifying abnormal phenotypes using in situ hybridization techniques. It will prepare students for advanced functional genomics coursework and research.
BTEC 4060 - Variant Validation in Zebrafish
This applied lab allows students to perform a functional genomics validation experiment in the zebrafish model. Students will be given a variant of unknown significance identified by hospital collaborators, and will carry out all steps required to validate the variant of unknown significance including: zebrafish mating and effective collection, microinjection, microscopic and in situ hybridization identification of phenotype, knockout rescue and variant validation.
BIOL-5910 - Genomics Seminar
This graduate paper-presentation seminar focuses on current research and emerging advances in genomics, functional genomics, bioinformatics, and precision medicine. Each week, student presenter(s) will critically analyze and present a peer-reviewed primary research paper, followed by faculty- and student-led discussion. Students not presenting that week must read the assigned paper and submit a brief reflection before class begins. The course emphasizes critical evaluation of scientific literature, clear oral communication, thoughtful scientific discussion, and integration of experimental and computational approaches. At the end of the semester, students will integrate the knowledge and critical perspectives developed through the paper presentations into a formal presentation of their proposed research project. The project proposal presentation is conducted during the seminar but is evaluated as part of the student’s Capstone Project and is not included in the BIOL-5910 Seminar course grade.
Capstone Project-Master's program
The Master of Science in Genomics Capstone Project is a first-stage, project-based experience in which students begin developing the research or applied project that will guide their work across the M.S. program. Because this course occurs in the first semester, the primary emphasis is not on producing a large body of preliminary data. Instead, students will identify a meaningful biological, biomedical, computational, or translational question; define the knowledge gap; establish a scientifically justified project direction; and build a feasible plan for carrying the project forward over the subsequent two years.
Students will progress from reviewing the literature and defining the problem to developing a focused research question, hypothesis, or project objective; identifying potential experimental, computational, bioinformatic, or analytical methodologies; evaluating feasibility, resources, controls, and alternative strategies; and constructing a realistic two-year project timeline. Preliminary observations or pilot data may be included when available, but they are not required to complete the course successfully. Projects may include experimental functional genomics, bioinformatics, genomic data analysis, precision medicine, model-organism research, or other areas consistent with the M.S. in Genomics program.
Consistent with Utah Tech University’s polytechnic and hands-on educational philosophy, the Capstone emphasizes learning through authentic application. Students are expected to move beyond reproducing established laboratory or computational exercises and instead apply technical, analytical, and professional skills to real scientific questions. The course therefore serves as an education-to-research-to-workforce bridge, preparing students for internships, research employment, biotechnology and genomics careers, and advanced doctoral or professional training.
Office Hours
Sunday
- Closed.
Monday
- 9:00 am - 5:00 pm
Tuesday
- 9:00 am - 5:00 pm
Wednesday
- 9:00 am - 5:00 pm
Thursday
- 9:00 am - 5:00 pm
Friday
- 9:00 am - 5:00 pm
Saturday
- Closed.
Contact Us
The Shih Lab is always seeking new opportunities for collaboration with potential partners in the academic and industry sectors. We also share our fish lines and materials for other researchers to use in their projects. If you are interested in working together or would like to request research materials, please contact us via phone, or email.
Hung-Yu Shih, PhD
Assistant Professor of Biology
Email: hung.yu.shih@utahtech.edu
Phone: 435-652-7752
Office: SET 510/ Lab: SET 303