Cerebral palsy affects 8,000-12,000 children born in the United States each year. The etiology of cerebral palsy remains poorly understood and despite improvements in perinatal medicine, the prevalence of cerebral palsy has not diminished in recent decades. Although existing studies of cerebral palsy often focus on preterm infants, half of children with cerebral palsy are born at term. The overall hypothesis of this proposal is that perinatal inflammation in the term fetus is associated with injury to the developing nervous system that later leads to cerebral palsy. Inflammation is a final common pathway following diverse insults including infection and hypoxia-ischemia. Inflammatory mediators are known to promote neuronal and oligodendrocyte cell death, and to mediate brain injury resulting from hypoxia-ischemia and excitotoxicity. The inflammatory pathways are susceptible to genetic modulation, and specific polymorphisms of pro-inflammatory cytokines may increase the risk of cerebral palsy. We propose to test the following hypotheses in term infants: 1) elevated neonatal serum levels of pro inflammatory cytokines (IL-1, IL-6, TNF-alpha) predict the development of cerebral palsy, and 2) specific polymorphisms in the IL-6 gene and in other genes involved in the inflammatory pathway increase the risk of cerebral palsy. We propose the following three Specific Aims. In a case-control study of cerebral palsy nested within a large cohort of term and near term infants born at Kaiser Northern California between the years 1991-2001, we will 1) measure protein markers of inflammation in stored newborn blood from children with idiopathic cerebral palsy and from control children; 2) determine the rate of specific genetic polymorphisms related to inflammation in children with cerebral palsy and in control children; and 3) correlate markers of inflammation with specific subtypes of cerebral palsy defined by neuroradiologic features. The long-term goal of this research program is to develop new strategies to prevent cerebral palsy. A better understanding of the role of inflammation underlying perinatal brain injury will pave the way towards new preventative and therapeutic approaches. The research plan will also foster the candidate's development as an independent researcher in neuroepidemiology.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Scientist Development Award - Research (K02)
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NST-2 Subcommittee (NST)
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Hirtz, Deborah G
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University of California San Francisco
Schools of Medicine
San Francisco
United States
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