Rehana K. Leak, Ph.D.

 HPP355: Human Physiology and Pathology

 GPSC576: Neuronal Pharmacology and General Toxicological Principles

 GPSC572: Methods of Evaluation of Drug Action and Toxicity

 GPSC695: Oral and Written Presentation Skills in Pharmacology

RESEARCH INTERESTS

The Leak laboratory uses primary neurons, primary glia, cell lines, and naturally aged animals for 4 major projects:

Project 1: Our goal is to understand how neurons and glia adapt to stress, a capacity that may be reduced in neurodegenerative diseases such as Alzheimer's and Parkinson's. The phenomenon of adaptation to sublethal stress is termed preconditioning. In lay terms, "what does not kill you makes you stronger," but only if you are relatively healthy and young. Adaptations to sublethal stress have been studied for many years. However, recent studies in Dr. Leak's lab have shown for the first time that even severely stressed cells that manage to survive the original insult are protected against subsequent challenges (Titler et al., 2013; Cell Tissue Res, In Press). In astrocytes, the mechanism of this stress-resistance is glutathione dependent.

Project 2: Our goal is to understand why subregions of the cerebral cortex are differentially vulnerable to Parkinson's and Alzheimer's disease. For example, no one knows why the primitive allocortex is so vulnerable to protein aggregations and cell death and why the phylogenetically modern neocortex is resistant. Dr. Leak's lab has recently shown that the allocortex is more vulnerable to proteasome inhibition than the neocortex and that it has a different antioxidant profile with aging (Posimo et al., 2013; PLoS One, In Press). The mechanism underlying neocortical stress-resistance is still under investigation.

Project 3: Our goal is to characterize natural adaptations to the minor stress of aging. We are currently characterizing compensatory rises in heat shock protein expression as a function of age in brain regions vulnerable to Parkinson's and Alzheimer's disease. Many heat shock proteins are anti-apoptotic chaperones that refold misfolded proteins or guide irreparably damaged proteins to the proteasome for degradation. A rise in heat shock proteins therefore reflects an adaptive response to mild cellular stress. Heat shock proteins are important to study because neurodegenerative diseases are primarily diseases of protein misfolding.

Project 4: Our goal is to characterize the mechanism of protection of the dietary supplement N-acetyl cysteine. N-acetyl cysteine is well known to be a glutathione precursor and has been shown to benefit patients with Alzheimer's disease. Recent research in our lab has shown that N-acetyl cysteine can protect neuronal cells in both glutathione-dependent (Unnithan et al., 2012; Neurochem Int. 61: 356-368) and glutathione-independent manners. For example, N-acetyl cysteine may also work in a heat shock protein-dependent manner in our astrocytic and neuroblastoma models.

Students interested in conducting research can contact Dr. Leak at leakr@duq.edu. We also welcome patient and caregiver visits to the laboratory.

HONORS / AWARDS

1. Voted Professor of the Year by the PY1 Duquesne Pharmacy students (2012)
   Recognized by the American Association of Colleges of Pharmacy as Teacher of the Year
2. Grant: Impact of N-acetyl cysteine on heat shock protein 70
   Source: Commonwealth Universal Research Enhancement (C.U.R.E.), Pennsylvania Dept of Health (2013 – 2014)
   Principal Investigator: RK Leak
3. Grant: Adaptations to paraquat toxicity in a model of Parkinson's disease in vivo
   Source: Faculty Development Funds, Duquesne University (2011 - 2013)
   Principal Investigator: RK Leak
4. Grant: Adaptation to cellular stress in cortical regions involved in Parkinson's disease
   Source: Parkinson's and Movement Disorders Foundation (2010 -2011)
   Principal Investigator: RK Leak
5. Grant: Endogenous adaptations to cellular stress; implications for Alzheimer's and Parkinson's diseases
   Source: Hunkele Dreaded Diseases Foundation (2010 - 2012)
   Principal Investigator: RK Leak
6. Grant: Exercise, trophic factors, and Parkinsonism; A behavioral and biological analysis (2P50 NS19608)
   Source: National Institute of Neurological Disorders and Stroke (NINDS; 2009 - 2013)
   Co-Investigator: RK Leak
7. Scholarship for Cold Spring Harbor Course on Advanced Techniques in Molecular Neuroscience (2009)
8. Grant: Preconditioning neuroprotection in models of Parkinson's disease
   Source: American Parkinson's Disease Association (APDA; 2006 - 2007)
   Principal Investigator: RK Leak
9. Michael J. Fox Foundation Fellowship (2004 - 2006)
10. NINDS Scientific Career-Reentry Fellowship (2004 - 2006)
    Source: National Institute of Neurological Disorders and Stroke (NINDS)
11. NINDS Post-doctoral Training Fellowship (2001)
    Source: National Institute of Neurological Disorders and Stroke (NINDS)
12. National Science Foundation Graduate Fellowship (1994 - 1997)
    University of Pittsburgh
13. National Science Foundation Summer Research Fellowship (1992)
    University of Virginia
14. Senior Thesis First Prize, Department of Biopsychology, Barnard College (1992)
15. German Language First Prize, Barnard College (1992)
16. Graduated Magna Cum Laude, Barnard College (1992)
17. Phi Beta Kappa Induction (1992)

PUBLICATIONS SINCE 2006

1. Posimo JM^, Titler AM^, Choi H^, Unnithan AS^, and Leak RK* (2013) Neocortex and allocortex respond differentially to cellular stress in vitro and aging in vivo. PLoS One. In Press *Corresponding author; ^Undergraduate and graduate students
2. Titler AM^, Posimo JM^, and Leak RK* (2013) Astrocyte plasticity revealed by adaptations to severe proteotoxic stress. Cell Tissue Research. In Press *Corresponding author; ^Graduate students
3. Leak RK, Zhang L, Luo Y, Li P, Zhao H, Liu X, Ling F, Jia J, Chen J, and Ji X (2013) Peroxiredoxin 2 battles PARP1- and p53-dependent pro-death pathways following ischemic injury. Stroke. In Press
4. Leak RK, Zhang L, Stetler RA, Weng Z, Li P, Atkins GB, Gao Y, and Chen J (2013) HSP27 protects the blood-brain barrier against ischemia-induced loss of integrity. CNS & Neurological Disorders - Drug Targets. In Press
5. Stetler RA, Leak RK, Gao Y, and Chen J (2013) The dynamics of the mitochondrial organelle as a potential therapeutic target. Journal of Cerebral Blood Flow and Metabolism 33: 22-32 (By invitation)
6. Zhang M, An C, Gao Y, Leak RK, Chen J, and Zhang F (2013) Emerging roles of Nrf2 and phase II enzymes in neuroprotection. Progress in Neurobiology 100: 30-47
7. Wang G, Jiang X, Pu H, Zhang W, An C, Hu X, Kiou AKF, Leak RK, Gao Y, and Chen J (2013) Scriptaid, a novel histone deacetylase inhibitor, protects against traumatic brain injury via modulation of PTEN and AKT pathway. Neurotherapeutics 10: 124-142
8. Zhang M, Li W, Leak RK, Chen J, and Zhang F (2013) ATP induces mild hypothermia in rats but has a strikingly detrimental impact on focal cerebral ischemia. Free Radicals in Biology and Medicine. Epub ahead of print
9. Leak RK*, Garbett K, Dettmer AM, Mirnics K, Zhang Z, and Cameron JL (2012) Physical activity is linked to ceruloplasmin in the striatum of intact, but not MPTP-treated primates. Cell Tissue Research 350: 401-407 * Corresponding author
10. Unnithan AS^, Choi H^, Titler AM^, Posimo JM^, and Leak RK* (2012) Rescue from a two hit high-throughput model of neurodegeneration with N-acetyl cysteine. Neurochemistry International 61: 356-368 *Corresponding author; ^Undergraduate and graduate students
11. Leak RK* and Moore RY (2012) Innervation of ventricular and periventricular compartments. Brain Research 1463: 51-62 *Corresponding author
12. Stetler RA, Leak RK, Gao YQ, and Chen J (2012) Mitochondrial biogenesis contributes to ischemic neuroprotection afforded by LPS preconditioning. Journal of Neurochemistry 123(S2): 125-137 (By invitation)
13. Hu X, Li P, Guo Y, Wang H, Leak RK, Chen S, Gao Y, and Chen J (2012) Microglia/macrophage polarization dynamics reveal novel mechanism of injury expansion after focal cerebral ischemia. Stroke 43: 3063-3070
14. Zhang F, Wang S, Weng Z, Li P, Gan Y, Zhang L, Zhang M, Cao G, Gao Y, Leak RK, Sporn MB, and Chen J (2012). Pharmacological induction of heme oxygenase-1 by a triterpenoid protects against ischemic neuronal injury. Stroke 43: 1390-1397
15. Mitchell AC, Leak RK, Garbett K, Zigmond MJ, Cameron JL, and Mirnics K (2012) Physical activity-associated gene expression signature in non-human primate motor cortex. Obesity 20: 692-698
16. Li P, Leak RK, Gan Y, Hu X, Stetler RA, and Chen J (2012) How do subcellular organelles participate in preconditioning-conferred neuroprotection? Innate Tolerance in the CNS. Springer Series in Translational Stroke Research. (Ed. J Gidday). Springer. Ch 19: 387-428 (By invitation)
17. Hu X, Zhang M, Leak RK, Gan Y, Li P, Gao Y, and Chen J (2012) Delivery of neurotherapeutics across the blood brain barrier in stroke. Current Pharmaceutical Design 18: 3704-3720
18. Mitchell AC, Leak RK, Zigmond MJ, Cameron JL, and Mirnics K (2011) Gene transcripts associated with BMI in the motor cortex and caudate nucleus of calorie-restricted monkeys. Genomics 99: 144-151
19. Leak RK*, Castro SL, Jaumotte JD, Smith AD, and Zigmond MJ (2010) Assaying multiple biochemical variables from the same tissue sample. Journal of Neuroscience Methods 191: 234-238 *Corresponding author
20. Egaña L, Cuevas R, Baust T, Parra L, Leak RK, Hochendoner S, Peña K, Quiroz M, Hong W, Dorostkar M, Janz R, Sitte H, and Torres G (2009) Physical and functional interaction between the dopamine transporter and the synaptic vesicle protein Synaptogyrin-3. Journal of Neuroscience 29:4592-604
21. Requena DF, Parra LA, Baust TB, Quiroz M, Leak RK, Garcia-Olivares J, Torres GE. (2009) The molecular chaperone Hsc70 interacts with the vesicular monoamine transporter-2. Journal of Neurochemistry 110: 581-594
22. Zigmond MJ, Cameron JL, Leak RK, Mirnics K, Russell VA, Smeyne RJ and Smith AD (2009) Triggering endogenous neuroprotective processes through exercise in models of dopamine deficiency. Parkinsonism and Related Disorders: WFN World Congress on Parkinson's Disease Supplement 3:S42-45
23. Leak RK and Zigmond MJ (2008) Endogenous defenses that protect dopamine neurons: studies with 6-OHDA models of Parkinson's disease. Parkinson's Disease: Pathogenic and Therapeutic Insights from Toxin and Genetic Models. (Ed. R Nass and S Przedborski). Elsevier. Ch 13: 173 - 194
24. Leak RK*, Zigmond MJ, and Liou AKF (2008) Adaptation to chronic MG132 reduces oxidative toxicity by a CuZnSOD-dependent mechanism. Journal of Neurochemistry 106: 860-874 *Corresponding author
25. Liou AKF, Leak RK, Li L, and Zigmond MJ (2008) Wild-type LRRK2 but not its mutant attenuates stress-induced death via ERK pathway. Neurobiology of Disease 32: 116-124
26. Lindgren NL, Leak RK, Smith AD, and Zigmond MJ (2008) Role of ERK in the action of GDNF in a mouse model of Parkinson's disease. Journal of Neuroscience Research 86: 2039-2049
27. Lin E, Cavanaugh JE, Leak RK, Perez RG, and Zigmond MJ (2008) Rapid activation of ERK by 6-hydroxydopamine promotes survival of dopaminergic cells. Journal of Neuroscience Research 86: 108-117
28. Leak RK, Liou KF, and Zigmond MJ (2006) Effects of sublethal 6-hydroxydopamine on the response to subsequent oxidative stress in dopaminergic cells: evidence for preconditioning. Journal of Neurochemistry 99: 1151-1163

PRESENTATIONS SINCE 2006

1. Leak RK, Posimo JM, Titler AM, Choi H, and Unnithan AS (2012) Differential neo- and allocortical vulnerability to proteasome inhibition in vitro mimics topography of human neurodegeneration. Gordon Conference on Neurobiology of Brain Disorders. Stonehill College, MA
2. Choi H, Unnithan AS, Titler AM, Posimo AM, and Leak RK (2012) Synergistic toxicity of two proteasome inhibitor hits is dependent upon glutathione loss. American Society of Health-System Pharmacists Clinical Meeting. 2-331. Las Vegas, NV
3. Titler AM, Posimo JM, and Leak RK (2012) Astrocyte plasticity revealed by adaptations to severe proteotoxic stress. Society for Neuroscience. 63.15. New Orleans, LA
4. Posimo JM, Titler AM, and Leak RK (2012) Neocortical neurons are more vulnerable than allocortical neurons in a high-throughput model of proteotoxic stress. Society for Neuroscience. 64.18. New Orleans, LA
5. Titler AM, Posimo JM, and Leak RK (2012) Astrocyte plasticity revealed by adaptations to severe proteotoxic stress. 4th Annual American Association for Pharmaceutical Scientists Pittsburgh Chapter Student Research Symposium. Pittsburgh, PA
6. Posimo JM, Titler AM, and Leak RK (2012) Neocortical neurons are more vulnerable than allocortical neurons in a high-throughput model of proteotoxic stress. 4th Annual American Association for Pharmaceutical Scientists Pittsburgh Chapter Student Research Symposium. Pittsburgh, PA
7. Jiang Y, Rumble J, Posimo JM, Titler AM, Choi H, Unnithan AS, and Leak RK (2012) N-acetyl cysteine protects neuronal cells by a glutathione-independent and Hsp70-dependent mechanism. Summer Research Symposium. Duquesne University. Pittsburgh, PA
8. Choi H, Unnithan AS, Titler AM, Posimo JM and Leak RK (2012) Rescue from a two hit high-throughput model of neurodegeneration with N-acetyl cysteine. Duquesne University Undergraduate Research Symposium. Pittsburgh, PA
9. Harun R, Zhou H, Wagner AK, and Leak RK (2011) An examination of striatal c-Fos activation following controlled cortical impact in rats. National Neurotrauma Symposium. Hollywood, FL
10. Titler AM, Posimo JM, and Leak RK (2011) Pretreatment with MG132 protects primary astrocytes against subsequent toxic exposures. 3rd Annual American Association for Pharmaceutical Scientists Pittsburgh Chapter Student Research Symposium. Pittsburgh, PA
11. Leak RK (2011) Adaptation to cellular stress in models of Parkinson's disease. Slippery Rock Department of Biology Seminar Series. Pittsburgh, PA
12. Leak RK (2011) Adaptation to cellular stress in models of Parkinson's disease. Duquesne Department of Biology Seminar Series. Pittsburgh, PA
13. Posimo JM, Titler AM, and Leak RK (2011) Topographical differences in sensitivity to proteasome inhibition in mammalian cerebral cortex. 3rd Annual American Association for Pharmaceutical Scientists Pittsburgh Chapter Student Research Symposium. Pittsburgh, PA
14. Parra LA, Baust TB, Leak RK, Smith AD, Zigmond MJ, and Torres GE (2010) A novel role for the molecular chaperone Hsc70 in the regulation of tyrosine hydroxylase activity and subcellular distribution. Society for Neuroscience. 741.3. San Diego, CA
15. Lopresti BJ, Dettmer AM, Leak RK, Rockcastle NJ, Zigmond MJ, Mathis C, Zhang Z, and Cameron JL. (2010) Regular exercise training protects against MPTP-damage to nigrostriatal dopamine neurons in nonhuman primates. The Eighth International Symposium on Functional Neuroreceptor Mapping of the Living Brain - NRM 2010. Glasgow, Scotland
16. Mitchell AC, Leak RK, Garbett K, Greenough WT, Zigmond MJ, Cameron JL, and Mirnics K (2010) The effects of exercise on the brain transcriptome. Society for Neuroscience. 460.1. San Diego, CA
17. Dettmer AM, Lopresti BJ, Leak RK, Rockcastle N, Zigmond MJ, Mathis CA, Zhang A, and Cameron JL (2010) Physical activity protects the striatum against MPTP damage in nonhuman primates. Society for Neuroscience. 460.11. San Diego, CA
18. Posimo JM, Titler AM, Cavanaugh JE, and Leak RK (2010) Age-related increases in ceruloplasmin in the mouse mesencephalon. Metals and Ions in Biology conference at Duquesne University. Pittsburgh, PA. *Won Best Poster award
19. Titler AM, Posimo JM, and Leak RK (2010) Oxidative stress elicits refractory response to subsequent toxin exposure. Metals and Ions in Biology conference at Duquesne University. Pittsburgh, PA
20. Cameron JL, Rockcastle N, Zigmond MJ, Leak RK, Smith AD, Lopresti BJ, Mathis CA, Mirnics K, Williams NI, and Zhang Z (2009) Exercise protects the striatum against MPTP damage in nonhuman primates. Society for Neuroscience. 430.7. Chicago, IL **Abstract chosen for a press conference
21. Parra LA, Baust TB, Quiroz M, Leak RK, and Torres GE (2009) A novel interaction between the molecular chaperone Hsc70 and tyrosine hydroxylase. Society for Neuroscience. 131.9. Chicago, IL
22. Leak RK (2008) Adaptation to chronic MG132 reduces oxidative toxicity via CuZnSOD. Pittsburgh Area Ubiquitin-Proteasome Meeting. Pittsburgh, PA
23. Leak RK, Zhang Z, Castro SL, Lopresti BJ, Mathis CA, Zigmond MJ, and Cameron JL (2008) Impact of exercise in a non-human primate model of Parkinson's disease. Seventh International Symposium on Functional Neuroreceptor Mapping of Living Brain. Neuroreceptor Mapping '08. Pittsburgh, PA
24. Leak RK, Jaumotte JD, and Zigmond MJ (2008) Responses to low and high cellular stress in neuronal cortical cultures. Society for Neuroscience. 343.21. Washington, DC
25. Lopresti BJ, Zhang Z, Zigmond MJ, Leak RK, Mathis CA, and JL Cameron (2008) Increased survival of nigrostriatal dopaminergic neurons following a toxic MPTP insult in the exercising primate: A [11C]DTBZ PET study. Seventh International Symposium on Functional Neuroreceptor Mapping of Living Brain. Pittsburgh, PA
26. Leak RK, Wong MS, Zigmond MJ, and Liou KF (2007) Proteasome inhibition induces protection against oxidative stress in catecholaminergic cells. Society for Neuroscience. 382.7. San Diego, CA
27. Mirnics K, Garbett K, Mitchell AC, Sullivan E, Leak RK, Zigmond MJ, and Cameron JL (2007) Spontaneous activity and neocortical gene expression in non-human primates. Society for Neuroscience. 589.9. San Diego, CA
28. Leak RK, Zigmond MJ, and Liou KF (2007) Adaptation of catecholaminergic cells to MG-132 and reduced vulnerability to oxidative stress. 11th Annual National Conference of Morris K. Udall Centers for Excellence in Parkinson's Research. Pittsburgh, PA
29. Lindgren NL, Leak RK, Smith AD, and Zigmond MJ (2006) Role of MAP kinases in the neuroprotective effects of GDNF in vivo. Society for Neuroscience. 756.7. Atlanta, GA
30. Liou KF, Leak RK, Li L, Kotevski L, and Zigmond MJ (2006) Characterization of the functional differences between LRRK2 wild-type and Y1699C mutant genes. Society for Neuroscience. 173.9. Atlanta, GA