Karin Hochrainer, Ph.D.
Assistant Professor of Neuroscience
Finbar and Marianne Kenny Research Scholar in Neurology
Post-ischemic cell death is still poorly understood and remains a severe clinical problem. We aim to identify and better characterize cellular responses to ischemic stroke on a molecular level and eventually harness this knowledge to improve the treatment of stroke and other neurological disorders.
Research Directions and Goals:
My laboratory studies immediate changes in the proteome of brain cells after cerebral ischemic injury that we believe may represent adaptations that are crucial for cell fate determination under this severe stress condition. We are especially interested in the timeframe early after ischemia when protein synthesis and degradation machineries are shut down to preserve energy, as this forces cells to deal with the ischemic stress using the existing protein pool.
In particular we are investigating changes in:
A) Post-translational modifications of proteins, with special emphasis on ubiquitination. Under stress conditions, the ubiquitin proteasome system becomes increasingly important as it allows for a rapid response to the changing environment by both functional adaptation and turnover of the existing cellular protein pool. We have established that cerebral ischemia leads to a vast induction of protein ubiquitination after blood flow reintroduction that is reversible and does not portend cell death (Hochrainer et al, Stroke 43(8): 2229-35, 2012).
Using mass-spectrometry we have now identified proteins that are targeted by ubiquitination after ischemia. In current studies we are investigating the impact of ubiquitin-conjugation to selected substrate proteins.
B) The solubility pattern of proteins. Apart from the ubiquitin-focused research we have also with mass spectrometry identified proteins that migrate from a soluble to insoluble state early after ischemia. Specifically, we find that proteins involved in RNA metabolism are distinctively enriched in inclusions after ischemia. Among these proteins are TDP43, FUS and hnRNPA1, RNA-binding proteins also found in inclusions in ALS and frontotemporal dementia. Unlike in neurodegenerative diseases, in which aggregates are irreversibly formed over the course of decades and may be a sign of forthcoming cell death, their accumulation after ischemia appears to be rapid and transient. We are currently investigating the role of RNA-binding proteins and their accumulation in the stress response after ischemic stroke.
Our ischemia models include A) an in vivo mouse model of middle cerebral artery occlusion (MCAO), and B) an in vitro oxygen and glucose deprivation (OGD) model used on organotypic hippocampal slice cultures and on primary mouse brain cells, both of which we isolate from mouse embryos and/or pups. We combine these models with molecular, cell biology and biochemical approaches to address the above raised questions.
Current Lab Members:
-Gianfranco Racchumi, Research Specialist
-Victoria Palfini, Research Technician
Past Lab Members:
-Victoria Olaseun, Intern from Lehman College (5/2013-8/2013)
-Mehmet Kaplan, Intern from Ege University (Turkey) (7/2013-9/2013) - now PhD student at Medical University of Innsbruck (Austria)
-Reunet Rodney-Sandy, Research Technician (8/2014-7/2016) - now Research Associate at the Icahn School of Medicine at Mount Sinai
-Juhi Baskar, Intern from SASTRA University (India) (1/2015-6/2015) - now Lead Project Engineer at LVPEI Center for Innovation (India)
-Habib Zahir, Intern from Hunter College (6/2015-8/2015) - now Medical Student at College of Osteopathic Medicine
-Vaishali Balachandran, Intern from SASTRA University (India) (1/2016-6/2016) - now Masters Student at Cornell University
-Nefertari Duversaint, Intern from CUNY (6/2016-8/2016)
-Mohan Harihar Milaganur, Intern from SASTRA University (India) (1/2017-6/2017)- now graduate student at the University of Michigan
-Ismary Blanco, Research Technician (8/2016-6/2018) – now PhD student at Georgetown University
-Shilpa Swaminathan, Intern from SASTRA University (India) (1/2018-6/2018)
- Kahl A, Blanco I, Jackman K, Baskar J, Milaganur Mohan H, Rodney-Sandy R, Zhang S, Iadecola C and *#Hochrainer K. Cerebral ischemia induces the aggregation of proteins linked to neurodegenerative diseases. Sci Rep. 2018; 8(1): 2701. DOI:10.1038/s41598-018-21063-z. (*corresponding and #senior author).
- *#Hochrainer K. Protein modifications with ubiquitin as response to cerebral ischemia-reperfusion injury. Transl Stroke Res. 2018; 9(2): 157-173. (*corresponding and #senior author).
- *Hochrainer K, Pejanovic N, Olaseun VA, Zhang S, Iadecola C and Anrather J. The ubiquitin ligase HERC3 attenuates NF-κB-dependent transcription independently of its enzymatic activity by delivering the RelA subunit for degradation. Nucleic Acids Res. 2015; 43(20): 9889-904. (*corresponding author).
- *Hochrainer K, Jackman K, Benakis C, Anrather J and *Iadecola C. SUMO2/3 is associated with ubiquitinated protein aggregates in the mouse neocortex after middle cerebral artery occlusion. J Cereb Blood Flow Metab 2015; 35(1): 1-5. (*corresponding authors).
- Abe T, Zhou P, Jackman K, Capone C, Casolla B, Hochrainer K, Kahles T, Ross ME, Anrather J and Iadecola C: Lipoprotein receptor-related protein-6 protects the brain from ischemic injury. Stroke 2013; 44(8): 2284-91.
- Hochrainer K, Racchumi G and Anrather J: Site-Specific phosphorylation of the p65 protein subunit mediates selective gene expression by differential NF-kB and RNA Polymerase II promoter recruitment. J Biol Chem 2013; 288(1): 285-93.
- Hochrainer K, Jackman K, Anrather J and Iadecola C. Reperfusion rather than ischemia drives the formation of ubiquitin aggregates in the mouse neocortex after middle cerebral artery occlusion. Stroke 2012; 43(8): 2229-2235.
- Hochrainer K, Racchumi G, Zhang S, Iadecola C and Anrather J: Monoubiquitination of nuclear RelA negatively regulates NF-κB activity independent of proteolysis. Cell Mol Life Sci. 2012; 69(12): 2057–2073.
- Kunz A, Abe T, Hochrainer K, Shimamura M, Anrather J, Racchumi G, Zhou P and Iadecola C: Nuclear factor-kappaB activation and postischemic inflammation are suppressed in CD36-null mice after middle cerebral artery occlusion. J Neurosci. 2008; 28(7): 1649-1658.
- Hochrainer K, Racchumi G and Anrather J: Hypo-phosphorylation leads to nuclear retention of NF-kappaB p65 due to impaired IkappaBalpha gene synthesis. FEBS Lett. 2007; 581(28): 5493-5499.
National Institute of Neurological Disorders and Stroke
American Heart Association
Sackler Brain and Spine Institute
Feil Family Foundation
Presidents Council of Cornell Women