LRP mediated cellular signaling events

低密度脂蛋白受体相关蛋白（LRP）是存在于大多数细胞类型的表面上的大的内吞受体，在那里它结合细胞外配体并将它们靶向到溶酶体以进行降解。大多数LRP配体在炎症和/或伤口修复过程中产生的事实使我们推测LRP的功能可能超出分解代谢的功能，并且这些配体中的某些与LRP的结合可产生细胞应答。在这方面，我们已经观察到，LRP基因重建为本申请的中心假设是，在炎症和LRP的伤口修复期间产生的分子的结合可以触发炎性细胞因子和趋化因子治疗的产生，从而改变炎性疾病如动脉粥样硬化的进展。待检验的具体假设为：1）某些配体与LRP相互作用以刺激炎症反应的介质的产生，所述介质是特异性胞质分子，（例如蛋白激酶Calpha）与LRP的胞质结构域相互作用并参与LRP介导的信号传导活性，和3）LRP可以调节巨噬细胞的细胞因子产生，从而改变炎性疾病如动脉粥样硬化的进展。这些假设将在以下目的进行检验：1.确定LRP是否作为导致炎症细胞因子和趋化因子分泌的信号受体发挥作用，并鉴定触发这种反应的配体。2.在小鼠模型中使用组织特异性LRP敲除确定PKCalpha与LRP对巨噬细胞功能的贡献是否相关。

The low density lipoprotein receptor-related protein (LRP) is a large endocytic receptor present on the surface of most cell types, where it binds extracellular ligands and targets them to lysosomes for degradation The fact that most LRP ligands are generated during inflammation and/or wound repair processes led us to speculate that the function of LRP may extend beyond that of a catabolic one, and that association of certain of these ligands with LRP may generate a cellular response. In this regard, we have observed that reconstitution of the LRP gene into central hypothesis of this application is that binding of molecules generated during inflammation and wound repair of LRP can trigger the production of inflammatory cytokines and chemokines therapy altering the progression of inflammatory diseases such as atherosclerosis. The specific hypotheses to be tested are: 1) that the certain ligands interact with LRP to stimulate production of mediators of the inflammatory response, that specific cytosolic molecules, (e.g. protein kinase Calpha) interact with the cytoplasmic domain of LRP and participate in LRP- mediated signaling activities, and 3) that LRP can modulate cytokine production by macrophages, and thereby alter the progression of inflammatory diseases such as atherosclerosis. These hypothesis will be tested in the following aims: 1. Determine if LRP functions as a signaling receptor leading to secretion of inflammatory cytokines and chemokines, and identify ligands that trigger this response. 2. Determine if association of PKCalpha with LRP's contribution to macrophage function using tissue specific LRP knockouts in a mouse model.