ELUCIDATING THE FUNCTION OF PROGESTERONE RECEPTORS IN PERINATAL SUBSTANTIA NIGRA

University Of Delaware, Newark DE

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Abstract

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Parkinson's disease (PD) is a progressive neurodegenerative disease. It results from the gradual loss of dopaminergic cells in the substantia nigra, pars compacta (SNc), which produces gradual deterioration of voluntary movement. Common treatment options serve to boost dopamine function in some way. Few treatment options prevent the loss or replace lost SNc cells (for review see Thomas and Beal, 2007). Two treatments that aim to replace cells include fetal tissue transplantation and stem cell therapy. However, neither technique has had much success due to the low rate of survival of grafted tissue/cells (Kim and deVellis, 2009). The adult brain lacks many of the developmental factors required for the maturation and survival of dopamine neurons. Perhaps, if we were to provide the replacement tissue/cells with these essential factors, it would result in better retention of the graft. One of these factors may be the steroid hormone, progesterone. Receptors for progesterone (progesterone receptors (PRs)) are present exclusively during development in the rat SNc;it is absent in adulthood (Quadros et al., 2008;Lonstein and Blaustein, 2004). Additionally, progesterone provided to murine neural stem cells increases their differentiation into dopamine neurons (Diaz et al., 2009). These two findings suggest that progesterone may have potent effects on the development of SNc dopamine system and could potentially serve as a therapeutic agent for treating PD with stem cells. The present proposal will test the hypothesis that progesterone, acting via its receptors, is essential for SNc dopamine development. The first aim will characterize PR expression in the mouse SNc. The aim will address questions such as (1) when and for how long is PR expressed in the SNc?;(2) do PR expressing cells in the SNc also express dopamine? The second aim will utilize the powerful genetic tool of knockout mice to ask questions about PR function in SNc development. By comparing mice lacking functional PRs (PR knockout;PRKO) to controls (wild type;WT), we will ask questions such as (1) do PRKO mice have fewer dopamine producing neurons in adulthood compared to WT mice?;(2) are there fewer dopamine fibers (connections) from SNc dopamine neurons in PRKOs compared to controls? Results from these aims will establish a role for progesterone and PRs in SNc dopamine development. Future experiments will ascertain the mechanisms by which progesterone may be influencing SNc development. By identifying the factors that control normal dopamine development, we may be able to use them to ensure or increase survival rate of grafted tissue or stem cells for the treatment of PD