Dr. Xiao-Hong Lu, Assistant Professor of Pharmacology, Toxicology and Neuroscience, received a $750,000 grant from NASA Biological and Physical Sciences Division’s Space Biology Program to develop a novel genetic engineering technology to evaluate the impact of space radiation on the human brain.
Xiao-Hong Lu, PhD
Associate Professor of Pharmacology, Toxicology and Neuroscience
Dr. Lu’s research focuses on the molecular genetics and therapy of neurodegenerative and psychiatric disorders and the development of innovative neuroscience technologies. Dr. Lu completed his postdoctoral training in molecular genetics and neuroscience and was appointed as an Assistant Researcher at the Center for Neurobehavioral Genetics of the University of California, Los Angeles (UCLA). Dr. Lu developed the first BAC transgenic Parkinson’s disease (PD) mouse model that recapitulates the cardinal features of PD (licensed by Sanofi Aventis for drug discovery). His translational study of Huntington’s disease (HD) identified a novel therapeutic strategy (Science Translational Medicine, 2015; Highlighted in Nature Review Drug Discovery, and was selected as the most influential paper of 2015). Dr. Lu invented single-cell BAC transgenic technology (MORF, Mosaicism with Repeat Frameshift) that received support from the first round of the Brain Initiative award and was recently highlighted in NIH director's blog. Funded by a NARSAD Young Investigator Award, Lu lab generated the next-generation mouse model for schizophrenia (Mol Psychiatry-Nature, 2019). Lu lab recently developed a genetic sensor of DNA damage response, termed PRISM, exploiting virus-host DNA damage response interaction (Science Advances, 2022). Lu lab also explores the future of medicine and invented a robust method for efficient and precise CRISPR/Cas9 mediated genome editing in the adult mammalian brains. Dr. Lu is funded by grants from NIEHS, NASA, and NIGMS.
Lab and research methods
Genetic Engineering, BAC Transgenesis, CRISPR/Cas9, Single Neuron Genetics (MORF), Artificial Intelligence and Deep Learning, Wireless Optogenetics, Two-Photon Microscopy, Pharmacogenetics, Tissue Clearing and Volume Imaging, Preclinical Drug Trial, AAV and gene therapy, Miniature Microscope, NGS and Single-Cell Omics, Human iPSc derived neurons, Human Brain Organoid and Tissue Reprogramming, IVIS in vivo imaging.
|Mission to Mars and the Risk of Neurodegeneration (Funded by NASA 80NSSC21K0273).
As NASA plans future exploration missions to the Martian surfaces, there is growing concern that space radiation exposure during long-term exploration missions to Mars or other destinations may initiate or accelerate the progression of cognitive decline and neurodegeneration. To use the genetic sensor to visualize space radiation induced neurodegeneration, we invented a method employing an unsupervised deep learning network to augment the quality of volume imaging in the tissue-cleared whole brains. Our studies will support Human Space Exploration by contributing the first genetic biodosimetry for quantifying brain DNA instability and neurodegenerative changes to predict clinical health outcomes in human spaceflight crews and the utility of available ground-based analogs to realize basic mechanisms that can lead to the development of biologic countermeasures. Postdocs or graduate students working on this project will have the opportunity to apply NASA fellowship and work at NASA facility at Brookhaven National Laboratory.
Environmental and viral trigger of aging-dependent cognitive decline and neurodegenerative disorders (Funded by NIEHS R21ES031211-01A1 and intramural SARS-COV-2 awards)
Does the exposure to weed killer or SARS-CoV-2 infection increase our risk of developing Parkinson's disease (PD)? The majority of all PD cases have no identifiable inheritance and occur in a sporadic form. Environmental risk factors (e.g., virus infection, pesticide/herbicides, exposure to metals, solvents and polychlorinated biphenyls (PCBs), and head trauma) have been speculated as a trigger to the sporadic PD. To explore the pathogenic significance of environmental toxicant and virus exposure in sporadic neurodegenerative disorders, we designed a novel single-neuron genetic sensor termed PRISM . Our project also invented a small animal model with the faithful recapitulation of human ACE2 expression that is more valuable than most of the existent human ACE2 mouse models for studying pathogenesis, clinical complications, and developing exciting countermeasures for SARS-CoV-2 infection and long-haul COVID.
Can immunity dictate our social behavior? A VIP link between immune dysfunction and autism (Funded by NIGMS P20GM134974-01A1).
From an evolutionary perspective, for many millions of years, human behavior, especially sociality, has been shaped by two ancient battling forces: pathogens and the immune system. Sickness behavior or avoidance of social interaction in Autism could thus be viewed as an immune input into the brain to evade the spreading of pathogens. Our study begins to quest if immune inputs can indeed affect neural circuits and behavior. This project addresses the critical questions of whether, when, and how a dysfunctional immunity can cause social deficits? Besides, whether the immune system can be therapeutically targeted to ameliorate social symptoms in autism? In this project, we will develop next generation of antipsychotic drugs using a highly potent small molecule antagonist developed in our lab in an ongoing collaboration with the National Center for Advancing Translational Sciences (NCATS) and determine its efficacy to ameliorate social deficits.
Non-invasive Therapeutic Brain Genome Editing in Non-Human Primates (Collaboration with MD Anderson and Caltech)
CRISPR technology, a gene-editing tool that can be used to splice and alter the DNA inside a cell, has been hailed as the future of medicine. However, due to the complex anatomy, cell-type diversity, lack of simple, noninvasive delivery methods, and the challenge to evaluate the outcome, therapeutic genome editing in the central nervous system (CNS) has been largely limited. In order to overcome these hurdles, our lab has developed a neurotropic genome editing approach for a noninvasive, wide-scale, and dose-dependable genome editing method in adult mammalian brains. In collaboration with MD Anderson, for the first time, Lu lab is realizing brain genome editing in Non-Human Primates.
Selected Publications (out of more than 40)
1. Madison Wynne El-Saadi, Xinli Tian, Mychal Grames, Michael Ren, Kelsea Keys, Hanna Li, Erika Knott, Hong Yin, Shile Huang, Lu XH, Tracing brain genotoxic stress in Parkinson’s disease with a novel single-cell genetic sensor. Science Advances (Impact factor: 16.419), Vol 8, Issue 15 • DOI: 10.1126/sciadv.abd1700, 2022
2. Xinli Tian, Adam Richard, Madison Wynne El-Saadi, Aakriti Bhandari, Isabella Van Savage, Kevlyn Holmes, Ronald L. Klein, Donard Dwyer, Nicholas E. Goeders, X. William Yang, Lu XH*. Dosage sensitivity intolerance of VIPR2 microduplication is disease causative to manifest schizophrenia-like phenotypes in a novel BAC transgenic mouse model. Molecular Psychiatry-Nature (Impact factor: 15.99). Aug 23. doi:10.1038/s41380-019-0492-3. Link
3. Adam Richard; Xinli Tian; Madison W El-Saadi; Lu XH. Erasure of striatal chondroitin sulfate proteoglycan associated extracellular matrix rescues aging-dependent decline of motor learning, Neurobiology of aging, 2018 Jul 23;71:61-71. doi: 10.1016/j.neurobiolaging.2018.07.008.
4. Richard AD, Lu XH. “Teaching old dogs new tricks”: targeting neural extracellular matrix for normal and pathological aging-related cognitive decline. Neural Regen Res 2019;14:578-81.
5. Grames, M. S., Dayton, R. D., Jackson, K. L., Richard, A. D., Lu XH., Klein, R. L. Cre-dependent AAV vectors for highly targeted expression of disease-related proteins and neurodegeneration in the substantia nigra. FASEB J. 2018 Mar 7:fj201701529RR
6. Lu XH, Yang XW. Genetically-directed Sparse Neuronal Labeling in BAC Transgenic Mice through Mononucleotide Repeat Frameshift. Scientific Report. 2017 Mar 8;7:43915 (Featured in NIH director's blog).
7. Lu XH, Mattis VB, Wang N, Al-Ramahi I, van den Berg N, Fratantoni SA, Waldvogel H, Greiner E, Osmand A, Elzein K, Xiao J, Dijkstra S, de Pril R, Vinters HV, Faull R, Signer E, Kwak S, Marugan JJ, Botas J, Fischer DF, Svendsen CN, Munoz-Sanjuan I, Yang XW. Targeting ATM ameliorates mutant Huntingtin toxicity in cell and animal models of Huntington's disease. Science Translational Medicine (Impact factor: 17.99). 2015; Highlighted in Nature Review Drug Discovery (Impact factor: 84.69). Huntington Disease: Banking on ATM. 2015;14(2):92-3; Selected as the most influential paper of 2014-2015 by HD insight.
8. Wang N, Gray M, Lu XH, Cantel J, Greiner E, Gu X, Shirasaki D, Cepeda C, Holey S. Dong H, Levine M, Yang XW. Neuronal Targets of Mutant Huntingtin Genetic Reduction to Prevent HD Pathogenesis in Mice. Nature Medicine (Impact factor: 53.44), 20, 536–541 (2014)
9. Langfelder, P., Cantle, J.P., Chatzopoulou, D., Wang, N., Gao, F., Al-Ramahi, I., Lu, X.H., Ramos, E.M., El-Zein, K., Zhao, Y., Deverasetty, S., Tebbe, A., Schaab, C., Lavery, D.J., Howland, D., Kwak, S., Botas, J., Aaronson, J.S., Rosinski, J., Coppola, G., Horvath, S., and Yang, X.W. (2016). Integrated genomics and proteomics define huntingtin CAG length-dependent networks in mice. Nature Neuroscience (Impact factor: 24.88). 19: 623-633.
10.Lu XH and Yang XW. “Huntingtin Holiday”: Progress towards an antisense therapy for Huntington’s disease. Neuron (Impact factor: 17.17), 74(6):964-6, 2012
11. Veldman, M.B., Rios-Galdamez, Y., Lu, XH., Gu, X., Qin, W., Li, S., Yang, X.W. and Lin, S. (2015). The N17 domain mitigates nuclear toxicity in a novel zebrafish Huntington’s disease model. Molecular Neurodegeneration (Impact factor: 14.2). 10: 1-16.
12. Peñagarikano O, Lázaro MT, Lu XH, Gordon A, Dong H, Lam HA, Peles E, Maidment NT, Murphy NP, Yang XW, Golshani P, Geschwind DH. Exogenous and evoked oxytocin restores social behavior in the Cntnap2 mouse model of autism. Science Translational Medicine (Impact factor: 17.99), 2015 21;7(271):271ra8.
13 Haustein MD, Kracun S, Lu XH, Jackson-Weaver O, Tong X, Xu J, Yang XW , Marvin J, Looger L & Khakh BS: Conditions and constraints for astrocyte calcium excitability in a neuronal circuit. Neuron (Impact factor: 17.17) 2014 Apr 16;82(2):413-29.12.
14. Lu XH, Fleming SM, Meurers B, Ackerson LC, Mortazavi F, Lo V, Hernandez D, Sulzer D, Jackson GR, Maidment NT, Chesselet MF, Yang XW. BAC transgenic mice expressing a truncated mutant parkin exhibit age-dependent hypokinetic motor deficits, dopaminergic neuron degeneration, and accumulation of proteinase K-resistant alpha-synuclein. J. Neuroscience, 29: 1962–1976, 2009 (Highlighted by J Neurosci 2009 Jun 10;29(23):7392-4. Mice expressing mutant parkin exhibit hallmark features of Parkinson's disease).
15. Lu XH. Book title: Novel Approaches to Studying Basal Ganglia and Related Neuropsychiatric Disorders. Publisher: Elsevier Science, 2009. Hardcover ISBN: 9780123748942; eBook ISBN: 9780080953878,
Dr. Xiao-Hong Lu’s research team will use the NASA Space Radiation Laboratory (NSRL) at Brookhaven National Laboratory to simulate cosmic radiation in space vehicles and on the Martian surface to determine if long-term exposure to radiation causes adverse consequences to the brain.
One of the most important populations to genetic researchers is right here in Louisiana? It’s the Acadians. Dr. Xiao-hong Lu, a researcher at LSU Health Shreveport, talks about Gene Editing in this episode of "The Gene & The Acadians".
Dr. Lu was interviewed and featured by SPECTRUM news on Lu's lab's recently developed new genome editing method to treat brain disorders.
A discovery by Lu lab was selected from 14,000 abstracts as a Hot Topic by the Society for Neuroscience.
Lu Lab's research was published in Molecular Psychiatry-Nature and was selected as a featured cover article.
Today is the big day! Being one of the most sucessful gradaute students, Adam received his PhD degree with flying colors!
Molecular Psychiatry is a Nature journal, ranked fourth among 142 journals in the category "Psychiatry".
We are currently recruiting Post-doctoral Fellows for multiple funded projects. To enquire about opportunities, contact Dr. Lu at firstname.lastname@example.org.
We are currently recruiting Graduate Students for multiple funded projects. To enquire about opportunities, contact Dr. Lu at email@example.com.
Medical Students, Residents, and Fellows
The Lu laboratory has a number of research projects available for any Medical Students, Residents, and Fellows interested in performing neuroscience research.