Marta M. Lipinski
Anatomy and Neurobiology
Shock,Trauma and Anesthesiology Research (STAR) Center; Center for Stem Cell Biology and Regenerative Medicine; Center for Biomolecular Therapeutics
- BA: Indiana University, Bloomington, IN
- PhD: Massachusetts Institute of Technology, Cambridge, MA
- Postdoctoral training: Harvard Medical School, Boston, MA
Autophagy is a catabolic process mediating the turnover of bulk cytoplasmic constituents including organelles and protein aggregates in a lysosome-dependent manner. It is necessary for cellular homeostasis and protects organisms from a variety of diseases, including neurodegeneration and aging. Accumulation of autophagosomes has been observed following traumatic brain injury (TBI) and spinal cord injury (SCI), but its mechanisms and function in those contexts remain unknown. We use in vivo and in vitro models to examine the role of autophagy after TBI and SCI, and to delineate the molecular mechanisms involved. Our data demonstrate that although autophagosomes accumulate in the brain and spinal cord after TBI and SCI, respectively, autophagic degradation cannot proceed to completion. This block of autophagy is especially apparent in neurons and correlates with markers of neuronal cell death. Thus defective autophagy may contribute to neuronal cell death in TBI and SCI. We are currently investigating potential methods to re-activate autophagy flux as a treatment for TBI and SCI.
Additionally, we are using in vitro models, including human induced pluripotent stem (iPS) cells, to examine function and mechanisms of USP24, a novel gene associated with Parkinson’s disease (PD). Our long-term goal is to define novel target molecules and pathways for safe and effective modulation of autophagy as a treatment against neurodegeneration induced by both acute (trauma) and chronic (neurodegenerative diseases) causes.
Consequences and mechanisms of autophagy dysfunction after traumatic brain injury:
We are using transgenic mice and in vitro models to determine the mechanisms leading to lysosomal damage and disruption of autophagy flux following traumatic brain injury (TBI). Specifically, we are focusing on the function of cellular phospholipase cPLA2 in mediation of lysosomal membrane damage after TBI. We are also investigating the effects of inhibition of autophagy on neuronal cell death and neuroinflammation after TBI as well as testing whether restoration of autophagy can be used as a treatment to improve functional outcomes after brain trauma.
Effects of autophagy disruption on neuronal cell death and functional recovery after spinal cord injury:
In collaboration with Dr. Junfang Wu (Anesthesiology) and Dr. Eugene Koh (Orthopedics) we are using transgenic mouse mice and in vitro models to determine the influence of disruption of lysosomal function and autophagy flux on apoptotic and non-apoptotic neuronal cell death mechanisms following spinal cord injury (SCI). We are also investigating potential involvement of inhibition of autophagy in axonal damage observed after SCI. Furthermore we are testing whether enhancing autophagy may have beneficial effects on functional outcomes after SCI.
Mechanisms of the PARK10 gene USP24 in regulation of autophagy:
USP24 is a gene located in the PARK10 locus associated with late onset Parkinson's disease. We identified USP24 as a novel negative regulator of autophagy and are using cell-based models including human iPS cells differentiated into dopaminergic neurons to investigate its function and mechanisms. We are also investigating whether inactivation of USP24 may be a potential future target for treatment of PD and other neurodegenerative conditions.
Active Grant Support:
The Function and Mechanisms of Autophagy in Spinal Cord Injury
NIH R01 NS094527 (PI: Junfang Wu)
06/01/2016 – 05/31/2021
Function and Mechanisms of Autophagy-lysosomal Pathway in Traumatic Brain Injury
NIH R01 NS091218 (PI: Marta Lipinski)
03/01/2015 – 02/29/2020
The PARK10 Gene USP24 Affects Parkinson's Disease Via Regulation of Autophagy
NIH R03 NS087338 (PI: Marta Lipinski)
09/01/2014 – 08/31/2016
Neuronal differentiation of iPS cells by autophagy induction in oxidative environment to treat TBI
Maryland Stem Cell Research Grant 2016-MSCRFE (PI: Chinmoy Sarkar)
07/01/2016 – 06/30/2018
- Chinmoy Sarkar, PhD, Research Associate
- Shuo Liu, MD-PhD, Postdoctoral Fellow
- Julia Peter, Graduate Student
- Nivedita Hegdekar, Graduate Student
A complete list of Dr. Lipinkski's published work can be found on PubMed.
- Barekat A, Gonzalez A, Mauntz R, Kotzebue R, Molina B, El-Mecharrafie N, Conner C, Garza S, Melkani G, Joiner W, Lipinski M, Finley K and Ratliff E. Using Drosophila as an integrated model to study mild repetitive traumatic brain injury. Scientific Reports. 2016; 6:25252. PMID: 27143646.
- Wu J, Zhao Z, Kumar A, Lipinski MM, Loane DJ, Stoica BA, Faden AI. ER stress and disrupted neurogenesis in the brain are associated with cognitive impairment and depressive-like behavior after spinal cord injury. Journal of Neurotrauma. 2016; 33:1-17. PMID: 27050417.
- Ratliff E, Barekat A, Lipinski M, Finley K. Brain trauma and autophagy: What flies and mice can teach us about conserved responses. Autopahgy. 2016; accepted.
- Klionsky DJ, Abdelmohsen K, Abe A, Abedin MJ, Abeliovich H, Acevedo Arozena A, Adachi H, Adams CM, Adams PD, Adeli K, Adhihetty PJ, Adler SG, Agam G, Agarwal R, Aghi MK, Agnello M, Agostinis P, Aguilar PV, Aguirre-Ghiso J, Airoldi EM, Ait-Si-Ali S, Akemat. Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy. 2016; 12(1):1-222. PMID: 26799652.
- Liu S, Sarkar C, Dinizo M, Faden AI, Koh EY, Lipinski MM#, Wu J#. Disrupted Autophagy After Spinal Cord Injury is Associated With ER Stress and Neuronal Cell Death. Cell Death & Disease. 2015; 6:e1582. PMID: 25569099. #co-senior authors
- Lipinski M, Wu J. Modification of Autophagy-lysosomal Pathway as a Treatment After Spinal Cord Injury. Neural Regeneration Research. 2015; 10(6):892-3. PMID: 26199601.
- Awad O, Sarkar C, Panicker LM, Miller D, Zeng X, Sgambato JA, Lipinski MM, Feldman RA. Altered TFEB-mediated Lysosomal Biogenesis in Gaucher Disease iPSC-derived Neuronal Cells. Human Molecular Genetics. 2015; 24(20):5775-88. PMID: 26220978.
- Wu J, Sabirzhanov B, Stoica BA, Lipinski MM, Zhao Z, Zhao S, Ward N, Yang D, Faden AI. Ablation of the Transcription Factors E2F1-2 Limits Neuroinflammation and Associated Neurological Deficits After Contusive Spinal Cord Injury. Cell Cycle. 2015; 14(23):3698-712. PMID: 26505089.
- Zhang T, Dong K, Liang W, Xu D, Xia H, Geng J, Najafov A, Liu M, Li Y, Han X, Xiao J, Jin Z, Peng T, Gao Y, Cai Y, Qi C, Zhang Q, Sun A, Lipinski M, Zhu H, Xiong Y, Pandolfi PP, Li H, Yu Q, Yuan J. G-protein Coupled Receptors Regulate Autophagy by ZBTB16-Mediated Ubiquitination and Proteasomal Degradation of Atg14L. eLife. 2015; 4:06734. PMID: 25821988.
- Lipinski MM, Wu J, Faden AI, Sarkar C. Function and Mechanisms of Autophagy in Brain and Spinal Cord Trauma. Antioxidants & Redox Signaling. 2015; 23(6):565-77. PMID: 25808205.
- Srakar C, Zhao Z, Aungst S, Sabirzhanov B, Faden AI, and Lipinski MM. Impaired Autophagy Flux is Associated With Neuronal Cell Death After TBI. Autophagy. 2014; 10(12):1418-30. PMID: 25484084.
- Zhao Z, Faden AI, Loane DJ, Lipinski MM, Sabirzhanov B, Stoica BA. Neuroprotective Effects of Geranylgeranylacetone in Experimental Traumatic Brain Injury. Journal of Cerebral Blood Flow and Metabolism. 2013; 33(12):1897-908. PMID: 23942364.
- Xu Y, Yuan J, Lipinski MM. Live Imaging and Single-cell Analysis Reveal Differential Dynamics of Autophagy and Apoptosis. Autophagy. 2013; 9(9):1418-30. PMID: 23748697.
- Py BF, Jin M, Desai BN, Penumaka A, Zhu H, Kober M, Dietrich A, Lipinski MM, Henry T, Clapham DE, Yu. Caspase-11 Controls Interleukin-1Beta Release Through Degradation of TRPC1. Cell Reports. 2013; 6(6):1122-8. PMID: 24630989.
- Ofengeim D, Shi P, Miao B, Fan J, Xia X, Fan Y, Lipinski MM, Hashimoto T, Polydoro M, Yuan J, Wong S. Identification of Small Molecule Inhibitors of Neurite Loss Induced by ABeta Peptide Using High-content Screening. The Journal of Biological Chemistry. 2012; 287(12):8714-23. PMID: 22277654.
2011 and before
- Kepp O, Galluzzi L, Lipinski M, Yuan J, Kroemer G. Cell Death Assays for Drug Discovery. Nature Reviews Drug Discovery. 2011; 10(3):221-37. PMID: 21358741.
- Boyce M, Lipinski MM, Py B.F., and Yuan J. Endoplasmic Reticulum Stress Response in Cell Death and Cell Survival. Reed JC, Green DR, eds. Apoptosis: Physiology and Pathology. Cambridge University Press, 2011.
- Lipinski MM, Zheng B, Lu T, Yan Z, Py BF, Ng A, Xavier RJ, Li C, Yankner BA, Scherzer CR, Yuan J. A Genome-wide Analysis Reveals Mechanisms Modulating Autophagy in Normal Brain Aging and in Alzheimer's Disease. Proceedings of the National Academy of Sciences of the United States of America. 2010;107(32):14164-9. PMID: 20660724.
- Lipinski MM. Towards the Global Understanding of the Autophagy Regulatory Network. Autophagy. 2010; 6(8):1218-20. PMID: 20953147.
- Lipinski MM, Hoffman G, Ng A, Zhou W, Py BF, Hsu E, Liu X, Eisenberg J, Liu J, Blenis J, Xavier RJ, A Genome-wide SiRNA Screen Reveals Multiple MTORC1 Independent Signaling Pathways Regulating Autophagy Under Normal Nutritional Conditions. Developmental Cell. 2010; 18(6):1041-52. PMID: 20627085.
- Furuya T, Kim M, Lipinski M, Li J, Kim D, Lu T, Shen Y, Rameh L, Yankner B, Tsai LH, Yuan J. Negative Regulation of Vps34 by Cdk Mediated Phosphorylation. Molecular Cell. 2009;38(4):500-11. PMID: 20513426.
- Huang Y, Zhou X, Miao B, Lipinski M, Zhang Y, Li F, Degterev A, Yuan J, Hu G, Wong ST. A Computational Framework for Studying Neuron Morphology From in Vitro High Content Neuron-based Screening. Journal of Neuroscience Methods. 2009;190(2):299-309. PMID: 20580743.
- Huang Y, Zhou X, Miao B, Lipinski M, Xia Z, Hu G, Degterev A, Yuan J, Wong ST. An Image Based System Biology Approach for Alzheimer's Disease Pathway Analysis. IEEE/NIH Life Science Systems and Applications Workshop. IEEE/NIH Life Science Systems and Applications Workshop. 2009;2009:128-132. PMID: 20585413
- Py BF*, Lipinski MM*, Yuan J. Autophagy Limits Listeria Monocytogenes Intracellular Growth in the Early Phase of Primary Infection. Autophagy. 2007; 3(2):117-25. PMID: 17204850. *first co-authors
- Zhang Y, Zhou X, Degterev A, Lipinski M, Adjeroh D, Yuan J, Wong ST. Automated Neurite Extraction Using Dynamic Programming for High-throughput Screening of Neuron-based Assays. NeuroImage. 2007; 35(4):1502-15. PMID: 17363284.
- Zhang Y, Zhou X, Degterev A, Lipinski M, Adjeroh D, Yuan J, Wong ST. A Novel Tracing Algorithm for High-throughput Imaging Screening of Neuron-based Assays. Journal of Neuroscience Methods. 2006; 160(1):149-62. PMID: 16987551.
- Lipinski MM, Yuan J. A Cellular Response to an Internal Energy Crisis. Cell. 2005; 123(1):3-5. PMID: 16213206.
- Lipinski MM, Yuan J. Mechanisms of Cell Death in Polyglutamine Expansion Diseases. Current Opinion in Pharmacology. 2004; 4(1):85-90. PMID: 15018844.
- Yuan J, Lipinski M, Degterev A. Diversity in the Mechanisms of Neuronal Cell Death. Neuron. 2003; 40(2):401-13. PMID: 14556717.
- Lipinski MM, Macleod KF, Williams BO, Mullaney TL, Crowley D, Jacks T. Cell-autonomous and Non-Cell-Autonomous Functions of the Rb Tumor Suppressor in Developing Central Nervous System. The EMBO Journal. 2001; 20(13):3402-13. PMID: 11432828.
- Lipinski MM, Jacks T. The Retinoblastoma Gene Family in Differentiation and Development. Oncogene. 2000; 18(55):7873-82. PMID: 10630640.