Intrauterine inflammation is known to be one of the risk factors for periventricular leukomalacia (PVL) that subsequently leads to the development of cerebral palsy. In recent years, microglial cell activation has been implicated in the development of PVL. The long term goal of this study is to understand the cellular and metabolic derangements leading to brain injury during development and use this information to design specific, targeted therapy to prevent the brain injury. The central hypothesis is that endotoxin induced intrauterine inflammation leads to activation of microglial cells in the fetal brain that progresses over time leading to oligodendrocyte damage and white matter injury, and that decreasing the time course of microglial activation will arrest this injury. This hypothesis will be tested in a rabbit model of intrauterine inflammation, by pursuing the following specific aims: (1) Determine the microglial response and white matter injury in the newborn rabbit brain in pups exposed to intrauterine inflammation by assessing changes in uptake of the PET tracer [C-11] PK11195, by microglial numbers and oligodendrocyte loss on histology, by diffusion tensor imaging, and by neurobehavioral changes. (2) Determine whether postnatal anti- inflammatory treatment with minocycline can decrease the time course of microglial cell activation, diminish brain injury and improve neurobehavioral outcome in the neonatal rabbit exposed to intrauterine inflammation as assessed by longitudinal measurements of [C-11] PK11195 uptake, diffusion tensor imaging and neurobehavioral scores in the newborn rabbit brain in pups exposed to endotoxin in utero. We expect that this research will lead to better understanding of the temporal and spatial progression of microglial activation and its relationship to white matter injury in the developing brain using novel non- invasive neuroimaging techniques that can be translated to the clinical setting and can be used to follow the injury and response to therapy. The training objective of this proposal is to achieve investigative independence as a pediatric neurointensivist with expertise in the application of neuroimaging for assessing novel drug therapies in perinatal brain injury. The educational aspect involves supervised research and analyses in the area of neuroimaging with Positron Emission Tomography (PET), in developing the animal model, immunohistochemistry and identification of inflammatory markers and formal, structured training in biostatistics and the ethical conduct of research. ? ? ?

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HD050652-02
Application #
7497440
Study Section
Pediatrics Subcommittee (CHHD)
Program Officer
Zajicek, Anne
Project Start
2007-09-18
Project End
2011-08-31
Budget Start
2008-09-01
Budget End
2009-08-31
Support Year
2
Fiscal Year
2008
Total Cost
$127,521
Indirect Cost
Name
Wayne State University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
001962224
City
Detroit
State
MI
Country
United States
Zip Code
48202
Anglewicz, Philip; VanLandingham, Mark; Manda-Taylor, Lucinda et al. (2018) Health Selection, Migration, and HIV Infection in Malawi. Demography 55:979-1007
Kendall, Jacob; Anglewicz, Philip (2018) Migration and health at older age in rural Malawi. Glob Public Health 13:1520-1532
Anglewicz, Philip; VanLandingham, Mark; Manda-Taylor, Lucinda et al. (2017) Cohort profile: internal migration in sub-Saharan Africa-The Migration and Health in Malawi (MHM) study. BMJ Open 7:e014799
Frye, Margaret; Chae, Sophia (2017) Physical attractiveness and women's HIV risk in rural Malawi. Demogr Res 37:251-294
Myroniuk, Tyler W; Prell, Christina; Kohler, Hans-Peter (2017) Why rely on friends instead of family? The role of exchanges and civic engagement in a rural sub-Saharan African context. Afr Stud 76:579-596
Anglewicz, Philip; VanLandingham, Mark; Manda-Taylor, Lucinda et al. (2016) Migration and HIV infection in Malawi. AIDS 30:2099-105
Fedor, Theresa M; Kohler, Hans-Peter; McMahon, James M (2016) Changing attitudes and beliefs towards a woman's right to protect against HIV risk in Malawi. Cult Health Sex 18:435-52
Myroniuk, Tyler W; Anglewicz, Philip (2015) Does Social Participation Predict Better Health? A Longitudinal Study in Rural Malawi. J Health Soc Behav 56:552-73
Baranov, Victoria; Bennett, Daniel; Kohler, Hans-Peter (2015) The indirect impact of antiretroviral therapy: Mortality risk, mental health, and HIV-negative labor supply. J Health Econ 44:195-211
Fedor, Theresa M; Kohler, Hans-Peter; Behrman, Jere R (2015) The Impact of Married Individuals Learning HIV Status in Malawi: Divorce, Number of Sexual Partners, and Condom Use With Spouses. Demography 52:259-80

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