Understanding the development of the brain and the extracellular signals used by forming neurons has clear relevance to mental and neurological diseases. This proposal focuses on a new simple phospholipid called """"""""sphingosine 1 -phosphate"""""""" or """"""""S1P,"""""""" that is known to function through a set of 5 cognate G-protein coupled receptors S1P1-5. Four of these receptors are expressed to varying degrees in embryonic brain. Determining the role of receptor-mediated S1P signaling in central nervous system (CNS) development is the focus of the proposed studies. In this proposal, we will test the hypothesis that a sphingolipid, S1P, can alter CNS development through activation of cognate G-protein coupled receptors. This hypothesis will be tested by 3 aims: 1) Determine roles for S1P on embryonic brain development using ex vivo models, 2) Determine roles for S1P on embryonic brain development using in vivo models, and 3) Determine the receptor selectivity of S1P effects in ex vivo and in vivo models. Gain-of-function (GOF) analyses will utilize a) a new cell culture system in which intact embryonic brain or cortex can be grown ex vivo while maintaining normal anatomical landmarks and b) embryonic intraventricular injections of ligands. Both GOF analyses permit receptor over activation by exogenous exposure to S1P or S1P agonists. Receptor selectivity of SIP effects will be determined using S1P receptor mutant & wild type animals combined with GOF experiments. Loss-of-function phenotypes during in vivo embryonic development will also be characterized for relevant S1P receptors. It is notable that the small size of these lipid molecules makes them attractive targets for drug design, and results from this proposal could serve as a foundation for new therapies based upon lysophospholipid-mimetic drugs. ? ?
Showing the most recent 10 out of 39 publications
