The (pro)renin receptor and cardiovascular disease

原肾素受体（PRR）最初被认为通过参与肾素-血管紧张素系统（RAS）而参与心血管疾病的发病机制。然而，最近的范式转变表明PRR的新作用，独立于RAS，有助于细胞内稳态。具体而言，PRR被认为是液泡H +-ATP酶（V-ATP酶）活性所必需的，并作为V-ATP酶和Wnt信号通路之间的衔接子。最近的PRR条件性敲除研究已经证实了V-ATP酶和PRR之间的联系，缺失导致自噬空泡的积累和动物致死。此外，弗林蛋白酶在全长PRR内的单个位点切割导致产生可溶形式的受体（sPRR），其在血浆中可检测到。可溶性PRR被假设为与特异性配体和受体结合并介导信号转导途径。全长PRR参与V-ATP酶活性和信号转导的机制以及sPRR在信号转导中的作用尚不清楚。我们将结合生物化学、细胞生物学和转基因动物方法，确定PRR对V-ATP酶活性、信号转导和膜受体运输的分子细节。总的来说，该项目产生的信息将揭示PRR在细胞生物学和疾病中的作用。

The (pro)renin receptor (PRR) was initially believed to be a contributor to the pathogenesis of cardiovascular diseases via its involvement in the renin-angiotensin system (RAS). However, a recent paradigm shift suggests a new role for PRR, separate from the RAS, in contributing to cellular homeostasis. Specifically, PRR is thought to be essential for vacuolar H+-ATPase (V-ATPase) activity, and to act as an adaptor between the V-ATPase and the Wnt signalling pathway. Recent PRR conditional knockout studies have confirmed the link between V-ATPase and PRR, with deletion resulting in the accumulation of autophagic vacuoles and animal lethality. Additionally, cleavage by furin at a single site within full-length PRR results in the production of a soluble form of the receptor (sPRR), which is detectable in plasma. Soluble PRR is hypothesised to bind to specific ligands and receptors and mediate signal transduction pathways. The mechanism by which full-length PRR contributes to V-ATPase activity and signal transduction, and the role of sPRR in signal transduction remains unclear. We will determine the molecular details by which PRR contributes to V-ATPase activity, signal transduction and membrane receptor trafficking with a combination of biochemical, cell biology and transgenic animal approaches. Overall, the information generated from this project will reveal the role of PRR in cellular biology and disease.