The candidate is an MD/PhD trained clinical neurologist whose career goal is to investigate genetic causes of susceptibility to traumatic brain injury (TBI), with emphasis in dementia and Alzheimer's disease (AD). The proposed period of mentored scientific training in the laboratory of Dr. David Holtzman at Washington University will allow the candidate develop the scientific skills to become an independent investigator. The central hypotheses that will be tested during the proposed project are as follows: 1) TBI causes increased production and/or decreased clearance of the amyloid-beta peptide (A-beta) in the brain. 2) The resulting increase in A-beta concentration contributes significantly to both acute cognitive impairment and the chronic pathology of AD in humans and in transgenic mice. 3) Blocking A-beta production or enhancing its clearance will reduce cognitive and pathological sequelae of TBI. 4) The increased vulnerability to TBI and increased risk of AD conferred by the apolipoprotein E e4 genotype (APOE4) occurs largely via apoE's effects on A-beta handling and metabolism. 5) Preventing TBI related changes in A-beta will lessen the adverse outcomes conferred by APOE4 after TBI. The candidate proposes to test these hypotheses using double transgenic mice that produce both apoE and a mutant amyloid precursor protein, and hence deposit A-beta in Alzheimer's disease-like pathological patterns. Experimental TBI will be performed on these mice in collaboration with Drs. Tracy McIntosh and Phil Bayly. Cognitive outcomes will be assessed using the Morris water maze and other behavioral tasks, and histological analysis of TBl-induced lesions and AD-like pathological changes will be made. Interventions will include administration of an anti-A-beta antibody that enhances A-beta clearance from the brain and a gamma secretase inhibitor that blocks A-beta production. Mechanistic studies of A-beta concentrations measured in brain homogenates and in vivo using microdialysis will be performed to gain insight into the underlying mechanisms involved. This work may lead to improved therapeutic options for patients with TBI in the future. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08NS049237-03
Application #
7118581
Study Section
NST-2 Subcommittee (NST)
Program Officer
Hicks, Ramona R
Project Start
2004-07-01
Project End
2009-06-30
Budget Start
2006-07-01
Budget End
2007-06-30
Support Year
3
Fiscal Year
2006
Total Cost
$152,823
Indirect Cost
Name
Washington University
Department
Neurology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Magnoni, Sandra; Mac Donald, Christine L; Esparza, Thomas J et al. (2015) Quantitative assessments of traumatic axonal injury in human brain: concordance of microdialysis and advanced MRI. Brain 138:2263-77
MacDonald, Christine L; Johnson, Ann M; Nelson, Elliot C et al. (2014) Functional status after blast-plus-impact complex concussive traumatic brain injury in evacuated United States military personnel. J Neurotrauma 31:889-98
Bennett, Rachel E; Esparza, Thomas J; Lewis, Hal A et al. (2013) Human apolipoprotein E4 worsens acute axonal pathology but not amyloid-? immunoreactivity after traumatic brain injury in 3xTG-AD mice. J Neuropathol Exp Neurol 72:396-403
Esparza, Thomas J; Zhao, Hanzhi; Cirrito, John R et al. (2013) Amyloid-? oligomerization in Alzheimer dementia versus high-pathology controls. Ann Neurol 73:104-19
Mac Donald, Christine; Johnson, Ann; Cooper, Dana et al. (2013) Cerebellar white matter abnormalities following primary blast injury in US military personnel. PLoS One 8:e55823
Magnoni, Sandra; Esparza, Thomas J; Conte, Valeria et al. (2012) Tau elevations in the brain extracellular space correlate with reduced amyloid-ýý levels and predict adverse clinical outcomes after severe traumatic brain injury. Brain 135:1268-80
Tran, Hien T; Sanchez, Laura; Brody, David L (2012) Inhibition of JNK by a peptide inhibitor reduces traumatic brain injury-induced tauopathy in transgenic mice. J Neuropathol Exp Neurol 71:116-29
Shitaka, Yoshitsugu; Tran, Hien T; Bennett, Rachel E et al. (2011) Repetitive closed-skull traumatic brain injury in mice causes persistent multifocal axonal injury and microglial reactivity. J Neuropathol Exp Neurol 70:551-67
Tran, Hien T; Sanchez, Laura; Esparza, Thomas J et al. (2011) Distinct temporal and anatomical distributions of amyloid-* and tau abnormalities following controlled cortical impact in transgenic mice. PLoS One 6:e25475
Tran, Hien T; LaFerla, Frank M; Holtzman, David M et al. (2011) Controlled cortical impact traumatic brain injury in 3xTg-AD mice causes acute intra-axonal amyloid-ýý accumulation and independently accelerates the development of tau abnormalities. J Neurosci 31:9513-25

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