The proposed development award focuses on the role of neurosteriods in Niemann-Pick type C disease as well as the developing rodent nervous system. The candidate's research background is in biochemical genetics and molecular biology with long term interest in molecular developmental neurobiology. Immediate goals during the period of this research award include the accumulation of experience in basic neurobiological research techniques as well as a greater understanding of neural systems and steroid biology as a whole, serving as an outstanding complement for the candidate's previous research training in molecular genetics. Long term goals are to apply both of these areas of experience to a research and clinical career in molecular and developmental neurobiology. It has recently been shown that specific types of steroid hormones, called neurosteriods, are synthesized de novo in the brain using the same steroid synthesizing enzymes found in the adrenal and gonads. These neurosteroids, have profound effects on the modulation of ion influx through the GABAA and NMDA receptors and have been also shown to affect embryonal neuronal and glial survival and differentiation in culture. The role of these neurosteriods in the development of the normal nervous system are unknown. This proposal seeks to investigate the alterations in neurosteriods in the nervous system of the murine model of Niemann Pick type C (NP- C) through analysis of endogenous neurosteroids in neural cell culture and in the developing rodent. The role of neurosteroids in neuronal demise will be examined through analysis of dendritic growth and regression. The factors that influence expression of the steroidogenic enzymes and the effects of neurosteriods on cortical growth and differentiation will be determined. This information will be used to create mouse models with abnormal neurosteriod synthesis to determine specific effects on behavior, neuronal excitation, and neuronal network formation. These experiments will provide vital information about the role of neurosteriods in the generation of the NP-C phenotype.
| Mellon, Synthia H; Griffin, Lisa D (2002) Neurosteroids: biochemistry and clinical significance. Trends Endocrinol Metab 13:35-43 |
| Griffin, L D; Conrad, S C; Mellon, S H (2001) Current perspectives on the role of neurosteroids in PMS and depression. Int Rev Neurobiol 46:479-92 |
| Griffin, L D; Mellon, S H (2001) Biosynthesis of the neurosteroid 3 alpha-hydroxy-4-pregnen-20-one (3 alpha hp), a specific inhibitor of FSH release. Endocrinology 142:4617-22 |
| Mellon, S H; Griffin, L D; Compagnone, N A (2001) Biosynthesis and action of neurosteroids. Brain Res Brain Res Rev 37:3-12 |
| Griffin, L D; Mellon, S H (1999) Selective serotonin reuptake inhibitors directly alter activity of neurosteroidogenic enzymes. Proc Natl Acad Sci U S A 96:13512-7 |
