The long-term goal of our laboratory is to define the molecular mediators and signaling intermediates of human melanocyte (HM) dendricity &melanosome (MS) transfer. Prostaglandins (PG) are lipid signaling molecules released by keratinocytes in response to UVR. Our global hypothesis is that PG stimulate HM pigmentation through the action of specific PG receptors that are increased by UVR. We propose that these receptors (EP1, EP3 and FP) activate Rac/Cdc42 and or inhibit Rho, which we have shown in the first funding period mediate HM dendricity and MS transfer. Since submission of this revised proposal we have defined the profile of PGE2 &PGF2_ receptors in HM, have identified which PG receptors that mediate HM dendricity &have shown a particularly important role for the PGF2_ receptor (FP) in HM dendricity and pigmentation. New data indicate that secretory phospholipase (sPLA2) -X modulates HM dendricity and pigmentation through the release of the lysophospholipid (LPL) lysophosphatidylcholine. The first two aims will define signaling intermediates that mediate PG-dependent dendricity, and MS transfer and will analyze PG receptor regulation by UVR and paracrine/autocrine factors. Receptor expression in HM in skin in vivo and regulation by UVR will be examined &identification of PG produced by HM will be analyzed. Based on new preliminary data, we hypothesize that effects of sPLA2(s) on HM are not mediated primarily by arachidonic acid-dependent PG production but rather through receptor or non-receptor dependent action of LPL on HM. In the third aim we will define effects of sPLA2 &LPL &fatty acids resulting from secretory phospholipase activity on HM dendricity and MS transfer, and will identify potential receptors that mediate this effect. Finally, we will examine the function of cytosolic PLA2 (cPLA2) on HM and its potential regulation by UVR. We hypothesize that PG and phospholipases stimulate HM dendricity, MS transfer &pigmentation through different mechanisms that act synergistically to modulate cutaneous pigmentation following UVR.
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