Michal Hetman, M.D., Ph.D.

Michal Hetman headshotProfessor, Department of Neurological Surgery and Department of Pharmacology & Toxicology
Endowed Professor of Molecular Signaling

Laboratory of Neural Signaling

Telephone: 502-852-3619
E-mail Michal Hetman

 

 


Research Focus:

Our laboratory uses various molecular/cell neurobiology approaches to address two major questions.

Question #1: What is the contribution of a nuclear substructure, the nucleolus and the nucleolus-based process of ribosome biogenesis to the regulation of neuronal gene expression programs as well as neuronal damage response? We are particularly interested in mechanisms that underlie requirement of neuronal ribosome synthesis for development and maintenance of the dendritic tree. In addition, we investigate role of ribosomal biogenesis stress (also known as nucleolar stress) in immature neuron apoptosis that is triggered by neurotropic RNA viruses such as Zika virus.

Question #2: What are the mechanisms that mediate loss and/or maladaptive changes in neural cells after traumatic spinal cord injury? Our efforts are focused on determining role of the integrated stress response pathway in injury-induced death of oligodendrocytes, and, consequently, injury-associated loss of the spinal cord white matter. In addition, we are also interested in comprehensive analysis of gene expression programs that mediate oligodendrocyte- or sensory neuron responses to injury including identification of the master transcription factors driving such responses.

To answer those questions we use cultured cells (neurons, oligodendrocytes or neuroprogenitors from rats, mice or human induced pluripotent stem cells) as well as whole mice (both wild type and various transgenic lines). Dendritic morphometry, apoptosis/cell survival analysis, mRNA/rRNA/protein expression analysis, DNA transfections, RNASeq, qRT-PCR, and immunofluorescence analysis are routinely applied to those experimental systems.

Selected publications with greatest relevance to our current research are listed below. Hetman lab trainees are underlined, summer students/rotating medical students and interns are indicated by *. The complete bibliography can be accessed with the following link:  Pubmed - M. Hetman.

    Click to view all of Dr. Graves's publications on PubMed

    Key Publications:

    1: Ohri SS, Bankston AN, Mullins SA, Liu Y, Andres KR, Beare JE, Howard RM, Burke DA, Riegler AS, Smith AE, Hetman M, Whittemore SR. Blocking autophagy in oligodendrocytes limits functional recovery after spinal cord injury. J Neurosci. 2018 May 23. pii: 0679-17. doi: 10.1523/JNEUROSCI.0679-17.2018. [Epub ahead of print] PubMed PMID: 29793971.

    2: Vashishta A, Slomnicki LP, Pietrzak M, Smith SC, Kolikonda M*, Naik SP*, Parlato R, Hetman M. RNA Polymerase 1 Is Transiently Regulated by Seizures and Plays a Role in a Pharmacological Kindling Model of Epilepsy. Mol Neurobiol. 2018 Mar 15.doi: 10.1007/s12035-018-0989-9. [Epub ahead of print] PubMed PMID: 29546592.

    3: Slomnicki LP, Hallgren J, Vashishta A, Smith SC, Ellis SR, Hetman M. Proapoptotic Requirement of Ribosomal Protein L11 in Ribosomal Stress-Challenged Cortical Neurons. Mol Neurobiol. 2018 Jan;55(1):538-553. doi: 10.1007/s12035-016-0336-y. Epub 2016 Dec 14. PubMed PMID: 27975169.

    4: Slomnicki LP, Chung DH, Parker A*, Hermann T*, Boyd NL, Hetman M. Ribosomal stress and Tp53-mediated neuronal apoptosis in response to capsid protein of the Zika virus. Sci Rep. 2017 Nov 30;7(1):16652. doi: 10.1038/s41598-017-16952-8. PubMed PMID: 29192272; PubMed Central PMCID: PMC5709411.

    5: Kilanczyk E, Saraswat Ohri S, Whittemore SR, Hetman M. Antioxidant Protection of NADPH-Depleted Oligodendrocyte Precursor Cells Is Dependent on Supply of Reduced Glutathione. ASN Neuro. 2016 Jul 21;8(4). pii: 1759091416660404. doi:10.1177/1759091416660404. Print 2016 Aug. PubMed PMID: 27449129; PubMed Central PMCID: PMC4962338.

    6: Slomnicki LP, Malinowska A, Kistowski M, Palusinski A, Zheng JJ, Sepp M,Timmusk T, Dadlez M, Hetman M. Nucleolar Enrichment of Brain Proteins with Critical Roles in Human Neurodevelopment. Mol Cell Proteomics. 2016 Jun;15(6):2055-75. doi: 10.1074/mcp.M115.051920. Epub 2016 Apr 6. PubMed PMID: 27053602; PubMed Central PMCID: PMC5083102.

    7: Slomnicki LP, Pietrzak M, Vashishta A, Jones J*, Lynch N*, Elliot S*, Poulos E*, Malicote D*, Morris BE*, Hallgren J, Hetman M. Requirement of Neuronal Ribosome Synthesis for Growth and Maintenance of the Dendritic Tree. J Biol Chem. 2016 Mar 11;291(11):5721-39. doi: 10.1074/jbc.M115.682161. Epub 2016 Jan 12. PubMed PMID: 26757818; PubMed Central PMCID: PMC4786710.

    8: Hallgren J, Pietrzak M, Rempala G, Nelson PT, Hetman M. Neurodegeneration-associated instability of ribosomal DNA. Biochim Biophys Acta. 2014 Jun;1842(6):860-8. doi: 10.1016/j.bbadis.2013.12.012. Epub 2014 Jan 2. PubMed PMID: 24389328; PubMed Central PMCID: PMC3985612.

    9: Ohri SS, Hetman M, Whittemore SR. Restoring endoplasmic reticulum homeostasis improves functional recovery after spinal cord injury. Neurobiol Dis. 2013 Oct;58:29-37.  doi: 10.1016/j.nbd.2013.04.021. Epub 2013 May 6. PubMed PMID: 23659896; PubMed Central PMCID: PMC3748169.

    10: Hetman M, Pietrzak M. Emerging roles of the neuronal nucleolus. Trends Neurosci. 2012 May;35(5):305-14. doi: 10.1016/j.tins.2012.01.002. Epub 2012 Feb 2. Review. PubMed PMID: 22305768; PubMed Central PMCID: PMC3348388.

    11: Ohri SS, Maddie MA, Zhao Y, Qiu MS, Hetman M, Whittemore SR. Attenuating the endoplasmic reticulum stress response improves functional recovery after spinal cord injury. Glia. 2011 Oct;59(10):1489-502. doi: 10.1002/glia.21191. Epub 2011 Jun 2. PubMed PMID: 21638341; PubMed Central PMCID: PMC3391751.

    12: Gomes C, Smith SC, Youssef MN*, Zheng JJ, Hagg T, Hetman M. RNA polymerase 1-driven transcription as a mediator of BDNF-induced neurite outgrowth. J Biol Chem. 2011 Feb 11;286(6):4357-63. doi: 10.1074/jbc.M110.170134. Epub 2010 Nov 23. PubMed PMID: 21098478; PubMed Central PMCID: PMC3039349.

    13: Pietrzak M, Rempala G, Nelson PT, Zheng JJ, Hetman M. Epigenetic silencing of nucleolar rRNA genes in Alzheimer's disease. PLoS One. 2011;6(7):e22585. doi: 10.1371/journal.pone.0022585. Epub 2011 Jul 22. PubMed PMID: 21799908; PubMed Central PMCID: PMC3142181.

    14: Kalita K, Makonchuk D, Gomes C, Zheng JJ, Hetman M. Inhibition of nucleolar transcription as a trigger for neuronal apoptosis. J Neurochem. 2008 Jun 1;105(6):2286-99. doi: 10.1111/j.1471-4159.2008.05316.x. PubMed PMID: 18315559; PubMed Central PMCID: PMC2909334.