Genes in X-linked Ectodermal Dysplasia Receptor

描述（由申请人提供）：XEDAR、EDAR和TAJ是TNFR家族的三种最近分离的受体，主要在胚胎发育期间的外胚层衍生物中表达。我们已经表征了XEDAR激活的信号通路，并发现它以配体依赖性方式与TRAF 3和TRAF 6结合，并激活NF-κ B和JNK通路。虽然XEDAR不具有死亡结构域，但它也通过半胱天冬酶依赖性和非依赖性机制诱导细胞凋亡。该提案的总体目标是确定参与XEDAR激活NF-κ B、JNK和细胞死亡途径的下游基因，并将其信号传导活性与EDAR和TAJ的信号传导活性进行比较。我们计划通过以下具体目标实现这一目标。在具体的目标1中，我们将尝试通过XEDAR及其同源物来鉴定参与NF-κ B和JNK通路激活的基因。具体目标2将集中于描绘参与通过XEDAR诱导半胱天冬酶依赖性和非依赖性细胞死亡的蛋白质。在具体目标3中，我们将鉴定通过XEDAR及其同源物参与信号传导的新蛋白质。我们相信，上述研究不仅将导致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，这些研究可能会导致更好的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.