Dr. Lu was interviewed and featured by SPECTRUM news on Lu's lab's recently developed new genome editing method to treat brain disorders.
Xiao-hong Lu, PhD
Assistant Professor of Pharmacology, Toxicology and Neuroscience
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".
The overarching goal of Dr. Lu’s research is to combine genetics and pharmacology to develop neural circuit-selective therapies for neuropsychiatric disorders. Trained as a psychiatrist and neuropharmacologist, Dr. Lu completed his postdoctoral training in molecular genetics and was appointed as an Assistant Researcher at 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. His translational study of Huntington’s disease (HD) identified a novel therapeutic strategy (Sci. Transl. Med., 2015; Highlighted in Nat Rev Drug Discov. and was selected as the most influential paper of 2015 by HD insight). Dr. Lu co-invented a single-cell transgenic technology (MORF, Mosaicism with Repeat Frameshift) that received support from the first round of the Brain Initiative award. Funded by a NARSAD Young Investigator Award, Lu lab generated a novel BAC transgenic mouse model of a copy number variation associated with schizophrenia (Mol Psychiatry, 2019). Recently, Dr. Lu’s lab invented a robust method for efficient and precise CRISPR/Cas9 mediated genome editing in the adult mammalian brain via intravascular administration of a neurotropic AAV. His team is now actively pursuing therapeutic genome editing for devastating brain disorders, such as Down syndrome.
Genetic Animal Models of Neuropsychiatric Disorders
To dissect pathogenic mechanisms and to identify therapeutic targets for neuropsychiatric disorders (Parkinson’s disease, Huntington’s disease, Schizophrenia, Depression, Stress and Drug Addiction) in genetically-engineered animal models generated using gene targeting/editing (CRISPR/Cas9) and Bacterial Artificial Chromosome (BAC) transgenesis.
Molecular Genetic Tools for Neurocircuit and Single Neuron Manipulation
Employ molecular genetic tools (Designer Receptors Exclusively Activated by Designer Drug (DREADD), optogenetics, DHFR etc) to pinpoint the mechanism of action of pharmacotherapies to genetically defined neuronal population or circuits.
Drug Discovery and Preclinical Trial
In vivo single neuron pharmacology and preclinical trial to study therapeutics for basal ganglia related neuropsychiatric disorders.
1. 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, Xiao-Hong Lu*. Dosage sensitivity intolerance of VIPR2 microduplication is disease causative to manifest schizophrenia-like phenotypes in a novel BAC transgenic mouse model. Molecular Psychiatry-Nature. Aug 23. doi:10.1038/s41380-019-0492-3. Link
2. 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. Link
3. Adam Richard; Xinli Tian; Madison W El-Saadi; Xiao-Hong Lu. 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. link
4. David J. McGee, Xiao-Hong Lu, and Elizabeth A. Disbrow, Stomaching the possibility of a pathogenic role for Helicobacter pylori in Parkinson’s disease. Journal of Parkinson's disease, 2018;8(3):367-374. doi: 10.3233/JPD-181327. Press Release, ScienceDaily, Parkinsonsnewstoday
5. Grames, M. S., Dayton, R. D., Jackson, K. L., Richard, A. D., Lu, X., 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
7. Xu, J., Bernstein, A., Wong, A., Lu, X., Khoja, S., Yang, X.W., Davies, D.L., Micevych, P., Sofroniew, M.V., Khakh, B.S. (2016). P2X4 Receptor Reporter Mice: Sparse Brain Expression and Feeding-Related Presynaptic Facilitation in the Arcuate Nucleus. J Neuroscience. 36: 8902-8920.
8. 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 Neurosci. 19: 623-633.
9. 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. Sci Transl Med. 2015; Highlighted in Nat Rev Drug Discov. Huntington Disease: Banking on ATM. 2015;14(2):92-3; Selected as the most influential paper of 2014-2015 by HD insight.
10. Veldman, M.B., Rios-Galdamez, Y., Lu, X.H., 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. Mol Neurodegener. 10: 1-16.
11. 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. Sci Transl Med. 2015 21;7(271):271ra8.
12. 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 20, 536–541 (2014)
13. Wang N*, Lu XH*, Sandova S, Yang XW. An Independent Study of the Preclinical Efficacy of C2-8 in the R6/2 Transgenic Mouse Model of Huntington's Disease. Journal of Huntington's disease, 2(4): 1879-6397, 2013 (*Co-First author)
14. 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 2014 Apr 16;82(2):413-29.
15. Lu XH and Yang XW. “Huntingtin Holiday”: Progress towards an antisense therapy for Huntington’s disease. Neuron, 74(6):964-6, 2012
16. Cantle, J.P., Lu, X.H., Gu, X.F., Yang, X.W. Cellular and molecular mechanisms implicated in pathogenesis of selective neurodegeneration in Huntington’s Disease. Frontiers in Biology, 459-476, 2012
17. Yang XW, Lu XH, Molecular and Cellular Basis of OCD-like Behaviors: Emerging View from Mouse Models. Current Opinion in Neurology, 114-118, 2011.
18. Tao J, Wu H, Lin Q, Wei W, Lu XH, Cantle JP, Ao Y, Olsen RW, Yang XW, Mody I, Sofroniew MV, Sun YE. Deletion of astroglial dicer causes non-cell-autonomous neuronal dysfunction and degeneration. J Neuroscience 31:8306-19, 2011.
19. 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, Highlighted in SciBX: Science-Business eXchange, Feb, 2009)
20. Lu XH. BAC to degeneration: Bacterial Artificial Chromosome (BAC)-mediated transgenesis for modeling basal ganglia neurodegenerative disorders. Int Rev Neurobiol. 2009;89:37-56
21. Gray M, Shirasaki D, Cepeda Carlos C, Andre VM, Wilburn B, Lu XH, Tao J, Yamazaki Y, Li SH, Sun YE, Li XJ, Levine MS, Yang XW. Full length human mutant Huntingtin with a stable polyglutamine repeat can elicit progressive and selective neuropathogenesis in BACHD mice. J. Neuroscience, 28: 6182-95, 2008
22. Zuo J, Liu Z, Ouyang X, Liu H, Hao Y, Xu L, Lu XH. Distinct neurobehavioral consequences of prenatal exposure to sulpiride (SUL) and risperidone (RIS) in rats. Prog Neuropsychopharmacol Biol Psychiatry. 2008 Feb 15;32(2):387-97. 2007
23 Lu XH, Dwyer DS. Second-generation antipsychotic drugs, olanzapine, quetiapine, and clozapine enhance neurite outgrowth in PC12 cells via PI3K/AKT, ERK, and pertussis toxin-sensitive pathways. J Mol Neurosci. 2005;27(1):43-64.
24. Ardizzone TD, Lu XH, Dwyer DS. Calcium-independent inhibition of glucose transport in PC-12 and L6 cells by calcium channel antagonists. Am J Physiol Cell Physiol, 2002 Aug;283(2):C579-86
25. Lu XH, Bradley RJ and Dwyer DS. Olanzapine produces trophic effects in vitro and stimulates phosphorylation of Akt/PKB, ERK1/2, and the mitogen-activated protein kinase p38. Brain Res. 2004 Jun 11;1011 (1):58-68.
26. Dwyer DS, Lu XH, Bradley RJ. Cytotoxicity of conventional and atypical antipsychotic drugs in relation to glucose metabolism. Brain Res. 2003 May 2;971(1):31-9.
27. Dwyer DS, Lu XH, Freeman A M. Neuronal glucose metabolism and schizophrenia: therapeutic prospects? Expert Rev. Neurotherapeutics. 2002
28. Lu XH, Li LJ, Li CQ, Luo XG. Effects of psychological stress on immediate gene c-fos expression and HPA axis regulation in rats. Chinese Journal of Mental Health. 2000; 14(1):10-13
29. Lu XH, Li LJ. Immediate gene c-fos and the molecular mechanism of psychological stress. Chinese Journal of Behavioral Medical Science. 1998, 7(1): 77-79
30. Lu XH, Li LJ, Li CQ, Luo XG. Potential anxiolytic role of c-fos antisense oligonucleotide in social-defeated rats. Bulletin of Xiangya Medical University, 2000 Dec 28;25(6):535-8
31. Lu XH. Antisense technology and the application in psychopharmacology. Journal of International Psychiatry. 1997, 24(4). 222-227
32. Lu XH. Social construction of brain. Journal of International Psychiatry. 1996, 23(3). 167-171
33. Chapter II, Neuropsychopharmacolog of Child and Adolescent Psychiatry. In Textbook of Child and Adolescent Psychiatry, Hunan Science and Technology Publisher, China (2013)
34. Yang XW and Lu XH. Chapter 19. The BAC transgenic approach to study Parkinson’s disease in mice. In “Parkinson’s Disease: Pathogenic and therapeutic insights from toxin and genetic models” (Edited by Richard Nass and Serge Przeborski). Elsevier: San Diego, 2008
35. Lu XH, Dwyer DS., Chapter IX. Neurotrophic effects of Psychoactive drugs: Significance for schizophrenia and other neurodevelopmental disorders. in Trends in Schizophrenia Research, Nova Science Publisher, New York, 2005
While we are not currently recruiting Post-doctoral Fellows, quality candidates will always be considered. To enquire about opportunities, contact Dr. Lu at firstname.lastname@example.org.
Graduate students interested in conducting research in the Orr lab should review the current laboratory research directions and contact Dr. Lu at email@example.com.
Undergraduate Research Assistants
We are not currently hiring any additional undergraduates. However, positions can become available during the summer.
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 atherosclerosis research.