Dr. Ben Bahr
Repair Mechanisms in the Brain
The 100,000 Gbyte hard-drive we call our brain is a challenge to study, also making it a challenge to find therapeutic treatments against the numerous diseases that disrupt memory encoding and other brain functions. In my lab, slices of brain tissue are kept alive to examine neuronal connections responsible for memory processing as well as cellular maintenance pathways, and to study their vulnerability to pathogenesis. While the brain’s incredible density of synaptic connections allows for extraordinary memory capacity, the abundant synapses are also vulnerable to pathogenic over-activation. Such excitotoxic brain damage can occur in many disease states including stroke, traumatic injury, and seizure events. We are studying the pharmacological enhancement of endogenous compensatory pathways to offset the damage, and we found that positive modulation of internal repair mechanisms protects against the damaging effects of seizures and stroke-type excitotoxic insults. Our other focus is to study age-related neurodegenerative disorders. Every 72 seconds someone in the U.S. develops Alzheimer’s disease (AD) due to suspected imbalances between protein production and protein clearance. Reducing Alzheimer-type protein accumulation is essential for slowing the progression of the disease. Lysosomes and their degradative enzymes (e.g. cathepsins) are known to respond to AD, likely in an attempt to offset the abnormal protein accumulations that cause a distinct cascade of synaptopathogenesis. To treat the impaired clearance of particular protein species, we discovered a new class of drugs that act as positive modulators of the lysosomal response, resulting in the up-regulation of cathepsins as well as neuroprotection in cultured brain slices and in mouse models of AD.
Members of the William C. Friday Laboratory
- Ben A. Bahr, Ph.D. (PI; Depts. of Biology and Chemistry & Physics)
- Heather Romine, M.B.A. (Lab Manager, Research Associate)
- Marquitta Smith, Ph.D. (Postdoctoral Fellow)
- Samuel Ikonne, Ph.D. (Research Assistant Professor)
- Natalie Emanuel, B.S. (Research Technician)
- Hollie Young, B.A., B.S. (Research Technician)
- Karen Farizatto; Universitária São Paulo, graduate student
- Wynne Kelly; graduate student
- Morgan Pait; undergrad RISE & PURC Research Fellow
- Lyndsie Elliott; undergrad
- Justin Floyd; undergrad
- Christopher Long; undergrad RISE Fellow
- Marcus Sherman; undergrad RISE Fellow
- Ziporia Swift; undergrad RISE Fellow
- Aaron Byrd; undergrad RISE Fellow
- Katherine Rentschler; undergrad
- Marilyn Louise Knotts; undergrad
- Sara A. McEwan; undergrad RISE Fellow
- Paul J. Lascuna; undergrad RISE Fellow
- Cary Mundell; undergrad RISE Fellow
- Justin Branch; undergrad RISE Fellow
Butler D, Hwang J, Estick C, Nishiyama A, Kumar SS, Baveghems C, Young-Oxendine HB, Wisniewski ML, Charalambides A, and Bahr BA (2011) Protective effects of positive lysosomal modulation in Alzheimer’s disease transgenic mouse models. PLoS One 6: e20501 (pp 1-16).
Wisniewski ML, Hwang J, and Bahr BA (2011) Submicromolar Aβ42 reduces hippocampal glutamate receptors and presynaptic markers in an aggregation-dependent manner. Biochim Biophys Acta (Mol. Basis of Disease) 1812:1664-1674.
Zheng X, Gessel MM, Wisniewski ML, Viswanathan K, Wright DL, Bahr BA, and Bowers MT (2012) Z-Phe-Ala-diazomethylketone (PADK) disrupts and remodels early oligomer states of the Alzheimer disease Aβ42 protein. J Biol Chem 287:6084-6088.
Naidoo V, Karanian DA, Vadivel SK, Locklear JR, Wood JT, Nasr M, Quizon PMP, Graves EE, Shukla V, Makriyannis A, and Bahr BA (2012) Equipotent inhibition of fatty acid amide hydrolase and monoacylglycerol lipase – dual targets of the endocannabinoid system to protect against seizure pathology. Neurotherapeutics 9:801-813.
Bahr BA, Wisniewski ML, and Butler D (2012) Positive lysosomal modulation as a unique strategy to treat age-related protein accumulation diseases. Rejuvenation Res 15:189-197.
Viswanathan K, Hoover DJ, Hwang J, Wisniewski ML, Ikonne US, Bahr BA, and Wright DL (2012) Nonpeptidic lysosomal modulators derived from Z-Phe-Ala-diazomethylketone for treating protein accumulation diseases. ACS Med Chem Lett 3:920-924.
Melo CV, Okumoto S, Gomes JR, Baptista MS, Bahr BA, Frommer WB, and Duarte CB (2013) Spatiotemporal resolution of BDNF neuroprotection against glutamate excitotoxicity in cultured hippocampal neurons. Neuroscience 237:66-86.
Hoffmann DB, Williams SK, Bojcevski J, Müller A, Stadelmann C, Naidoo V, Bahr BA, Diem R, and Fairless R (2013) Calcium influx and calpain activation mediate preclinical retinal neurodegeneration in autoimmune optic neuritis. J Neuropathol Exp Neurol 72:745-757.
Filipovic R, Kumar SS, Bahr BA, and Loturco J (2014) Slice culture method for studying migration of neuronal progenitor cells derived from human embryonic stem cells (hESC). Curr Protoc Stem Cell Biol 29:1H.7.1-1H.7.14.
Bahr BA (2014) A single pathway targets several health challenges of the elderly. Rejuvenation Res 17:382-384.
Previous Undergraduate Researchers (RISE Fellows*):
- Joanna Cooper* (NCBC Fellow)
- Hollie Young* (Gordon Conference Carl Storm Fellow)
- David Blake
- Emily Graves*
- Christopher Visser
- Rebecca Howell* (NCBC Fellow)
- Daisy Irra*
- Jasmine Robinson*
- Sarah Gambrel*
- Josie Torrence*
- Vivian Anunobi*
- Arieana Van Allen
- Tyler Loehr*
- Katharine Willoughby (Hawk Fellow)
- Jody Long
- Jasmine Rowlett*
- Ginny Holland
- Thomas Romine (Research & Engineering Apprenticeship)
- John Locklear*
- Pamela Marie Quizon (Research Assistant)
- Davita Brockington
- Ye Lin (undergrad research assistant)
- Elizabeth Metzger (NC Space Grant/NASA Scholar)
- Robert Baldi
- Kassie Conway*
- Jordon Smink*
- Louis Leonard
- M. Tyler Bullock (Research Engineering Apprenticeship)
- Sarah Ruiz* (NC Space Grant/NASA Scholar)
- Olivia Bullard* (Glaxo Scholar Women in Science)
- Marsalis Smith*
- Armando Corona*
- Julia McGee*
- Samantha Suggs
- Paul Freeman*
- Rebecca Jackson
- Veronica Robles
- Kassie Conway*
- Emily Suzanne Pope
- Kayla J. Oxendine
- Sonny Ruiz
- Chaterria Perry*
- Darian Duval
- Joshua Ellerbe
- Benson Mbugua
- Kathlyn Stephens (PURC Research Fellow)
- Justin Showers
- Matt MacDougall
- Dalton Brooks