Role of Prostaglandins & Phospholipase A in melanocytes

描述（由申请人提供）：我们实验室的长期目标是确定人类黑素细胞（HM）树突和黑素小体（MS）转移的分子介质和信号中间体。前列腺素（PG）是角质形成细胞在紫外线照射下释放的脂质信号分子。我们的总体假设是，PG通过特定的PG受体的作用刺激HM色素沉着，这些受体被UVR增加。我们提出这些受体（EP1， EP3和FP）激活Rac/Cdc42和或抑制Rho，我们已经在第一个资助期证明了它们介导HM树突和MS转移。自提交此修订提案以来，我们定义了HM中PGE2和PGF2_受体的谱，确定了介导HM树突的PG受体，并显示了PGF2_受体（FP）在HM树突和色素沉着中的特别重要作用。新的数据表明，分泌磷脂酶(sPLA2) -X通过释放溶血磷脂（LPL）溶血磷脂酰胆碱来调节HM的树突和色素沉着。前两个目标将定义介导PG依赖性树突和质谱转移的信号中间体，并将分析UVR和旁分泌/自分泌因子对PG受体的调节。我们将研究HM在体内皮肤中的受体表达和UVR的调控，并分析HM产生的PG的鉴定。基于新的初步数据，我们假设sPLA2(s)对HM的影响主要不是通过花生四烯酸依赖的PG产生介导的，而是通过LPL对HM的受体或非受体依赖作用介导的。在第三个目标中，我们将定义sPLA2和LPL以及由分泌磷脂酶活性引起的脂肪酸对HM树形和质转移的影响，并将确定介导这种影响的潜在受体。最后，我们将研究细胞质PLA2 （cPLA2）在HM中的功能及其在UVR中的潜在调控作用。我们假设PG和磷脂酶通过不同的机制刺激HM树突、MS转移和色素沉着，这些机制协同作用来调节紫外线照射后的皮肤色素沉着。

DESCRIPTION (provided by applicant): 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.