Elderly patients who suffer traumatic brain injury (TBI) have increased mortality and survivors have a poorer prognosis than young or middle aged adults who suffer comparable injuries. We have demonstrated that the aging brain is in a hyperinflammatory state before any injury, that the inflammatory response after brain injury is exaggerated, and that both edema and blood brain barrier disruption are increased after TBI in the aged brain. The proposed experiments test the specific hypothesis that increased matrix metalloproteinase (MMP) activity worsens blood brain barrier disruption and causes increased edema after TBI in the aged brain, leading to increased death of neurons and poor behavioral recovery. An interdisciplinary research team including a neuroscientist with expertise in molecular and behavioral neuroscience and neuroanatomy, an MRI physicist, and an expert in pharmacokinetics will test this hypothesis using the controlled cortical impact (CCI) model of TBI in mice.
The specific aims are 1) to determine whether CCI results in increased MMP-2 and MMP-9 activity in aged mice, 2) to determine whether blood brain barrier disruption, edema, and neuron death are greater after CCI in aged mice leading to poor behavioral recovery, and 3) to determine whether reducing MMP activity improves outcomes. The overall goal of these studies is to provide a rationale for specific treatments to improve outcomes of TBI in the elderly and to test effectiveness of treatments based on this rationale.

Public Health Relevance

Elderly patients who suffer traumatic brain injury have increased mortality, and survivors have a poorer prognosis, than younger adults who suffer comparable injuries. The goal of this research program is to understand the reason for these poor outcomes and to provide new treatment strategies using an animal model.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
1R01AG031140-01A2
Application #
7730659
Study Section
Acute Neural Injury and Epilepsy Study Section (ANIE)
Program Officer
Wise, Bradley C
Project Start
2009-08-15
Project End
2011-07-31
Budget Start
2009-08-15
Budget End
2010-07-31
Support Year
1
Fiscal Year
2009
Total Cost
$371,500
Indirect Cost
Name
University of Kansas
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
016060860
City
Kansas City
State
KS
Country
United States
Zip Code
66160
Taylor, Jordan M; Montgomery, Mitchell H; Gregory, Eugene J et al. (2015) Exercise preconditioning improves traumatic brain injury outcomes. Brain Res 1622:414-29
Sandhir, Rajat; Gregory, Eugene; Berman, Nancy E J (2014) Differential response of miRNA-21 and its targets after traumatic brain injury in aging mice. Neurochem Int 78:117-21
Harris, Janna L; Yeh, Hung-Wen; Choi, In-Young et al. (2012) Altered neurochemical profile after traumatic brain injury: (1)H-MRS biomarkers of pathological mechanisms. J Cereb Blood Flow Metab 32:2122-34
Lee, Phil; Kim, Jieun; Williams, Rachel et al. (2012) Effects of aging on blood brain barrier and matrix metalloproteases following controlled cortical impact in mice. Exp Neurol 234:50-61
Sandhir, Rajat; Berman, Nancy E J (2010) Age-dependent response of CCAAT/enhancer binding proteins following traumatic brain injury in mice. Neurochem Int 56:188-93
Onyszchuk, Gregory; LeVine, Steven M; Brooks, William M et al. (2009) Post-acute pathological changes in the thalamus and internal capsule in aged mice following controlled cortical impact injury: a magnetic resonance imaging, iron histochemical, and glial immunohistochemical study. Neurosci Lett 452:204-8