The objective of this K01 proposal is to establish an innovative research strategy and sound career development plan for Dr. Candice Brown to successfully transition to an independent investigator in neuroscience. The research plan implements a novel, multidisciplinary approach to test the hypothesis that the ovarian estrogen, 17?-estradiol (E2), modifies sepsis-induced brain dysfunction by altering the inflammatory mechanisms at the brain-micro vascular interface. The experimental approach uses a cecal ligation and puncture model of sepsis-induced brain dysfunction, commonly referred to sepsis-associated encephalopathy (SAE). SAE results in neurological impairment in ~70% of sepsis patients, and therapeutic options for treatment are limited.
Aim 1 will employ intravital microscopy combined with molecular biology to determine whether E2 attenuates vascular inflammation at the brain-micro vascular interface.
Aim 2 will use magnetic resonance imaging combined with immunocytochemistry to determine whether E2 attenuates cerebral edema and metabolic dysfunction in the early and late stages of sepsis. The career development plan has four specific aims designed to achieve short and long term career goals. These include: 1) Mastering surgical techniques and microscopy imaging tools; 2) Acquiring competency in MRI and its capabilities to use as tool to study acute brain dysfunction; 3) Improving presentation, publication, and craftsmanship skills, and 4) Gaining faculty development skills to become a productive science-citizen in academia. Completion of Research and Career Aims will provide broad competencies and a valuable set of tools to establish a productive independent research program and enhance the diversity of the neuroscience community at Wake Forest School of Medicine.

Public Health Relevance

Brain damage from inflammation occurs in approximately 70% of patients with sepsis; the 10th leading cause of death in the United States. Ovarian estrogens exert powerful anti-inflammatory activity on the brain's vascular system and determining whether estrogen decreases brain inflammation in sepsis can guide future therapies designed to protect brain function and diminish loss of life.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
7K01NS081014-04
Application #
9035982
Study Section
NST-2 Subcommittee (NST)
Program Officer
Wong, May
Project Start
2012-09-30
Project End
2017-08-31
Budget Start
2015-03-16
Budget End
2015-08-31
Support Year
4
Fiscal Year
2014
Total Cost
$142,793
Indirect Cost
$10,577
Name
West Virginia University
Department
Biology
Type
Schools of Medicine
DUNS #
191510239
City
Morgantown
State
WV
Country
United States
Zip Code
26505
Brichacek, Allison L; Brown, Candice M (2018) Alkaline phosphatase: a potential biomarker for stroke and implications for treatment. Metab Brain Dis :
Geldenhuys, Werner J; Benkovic, Stanley A; Lin, Li et al. (2017) MitoNEET (CISD1) Knockout Mice Show Signs of Striatal Mitochondrial Dysfunction and a Parkinson's Disease Phenotype. ACS Chem Neurosci 8:2759-2765
Engler-Chiurazzi, E B; Brown, C M; Povroznik, J M et al. (2017) Estrogens as neuroprotectants: Estrogenic actions in the context of cognitive aging and brain injury. Prog Neurobiol 157:188-211
Hall, Jennifer L; Ryan, John J; Bray, Bruce E et al. (2016) Merging Electronic Health Record Data and Genomics for Cardiovascular Research: A Science Advisory From the American Heart Association. Circ Cardiovasc Genet 9:193-202
Kan, Matthew J; Lee, Jennifer E; Wilson, Joan G et al. (2015) Arginine deprivation and immune suppression in a mouse model of Alzheimer's disease. J Neurosci 35:5969-82
Brown, Candice M; Bushnell, Cheryl D; Samsa, Gregory P et al. (2015) Chronic Systemic Immune Dysfunction in African-Americans with Small Vessel-Type Ischemic Stroke. Transl Stroke Res 6:430-6
Vachharajani, Vidula T; Liu, Tiefu; Brown, Candice M et al. (2014) SIRT1 inhibition during the hypoinflammatory phenotype of sepsis enhances immunity and improves outcome. J Leukoc Biol 96:785-96