Genes in X-linked Ectodermal Dysplasia Receptor

描述(申请人提供)：XEDAR、EDAR和TAJ是最近分离的三个TNFR家族的受体，主要在胚胎发育期间的外胚层衍生物中表达。我们已经鉴定了XEDAR激活的信号通路，发现它以配体依赖的方式与TRAF3和TRAF6结合，并激活NF-kappaB和JNK通路。虽然XEDAR不具有死亡结构域，但它也通过caspase依赖和独立的机制诱导细胞凋亡。该方案的总体目标是确定参与XEDAR激活NF-kappaB、JNK和细胞死亡途径的下游基因，并将其信号活性与EDAR和TAJ的信号活性进行比较。我们计划通过以下具体目标实现这一目标。在特定的目标1中，我们将试图通过XEDAR及其同源物来鉴定参与激活NF-kappaB和JNK通路的基因。具体目标2将重点描述通过XEDAR诱导caspase依赖和独立的细胞死亡所涉及的蛋白质。在特定的目标3中，我们将通过XEDAR及其同源物鉴定参与信号转导的新蛋白质。我们相信，上述研究不仅有助于更好地了解外胚层分化和颅面发育的过程，而且有助于阐明外胚层发育不良的临床异质性。从长远来看，这些研究可能导致更好地诊断和治疗外胚层发育不良和颅面畸形。

DESCRIPTION (provided by applicant): XEDAR, EDAR and TAJ are three recently isolated receptors of the TNFR family that are mainly expressed in ectodermal derivatives during embryonic development. We have characterized the signaling pathways activated by XEDAR and discovered that it binds to TRAF3 and TRAF6 in a ligand-dependent fashion and activates the NF-kappaB and JNK pathways. Although XEDAR does not possess a death domain, it also induces apoptosis via both caspase-dependent and independent mechanisms. The overall aim of this proposal is to identify the downstream genes involved in the activation of NF-kappaB, JNK and cell death pathways by XEDAR and to compare its signaling activities with those of EDAR and TAJ. We plan to achieve this goal through the following specific aims. In specific aims 1 we will try to identify the genes involved in the activation of NF-kappaB and JNK pathways by XEDAR and its homologs. Specific aim 2 will focus on delineating the proteins involved in induction of caspase-dependent and independent cell death via XEDAR. In specific aim 3, we will identify novel proteins which are involved in signaling via XEDAR and its homologs. We believe that the above studies will not only lead to a better understanding of the process of ectodermal differentiation and craniofacial development but also help to clarify the clinical heterogeneity of ectodermal dysplasias. In the long-term these studies may lead to better diagnosis and treatment of ectodermal dysplasias and craniofacial abnormalities.