Project 1 Lineage relationships in the kidney vasculature: role of RBP-J

肾脏是一个高度血运丰富的器官，在正常成年人中，它接受大约20%的心输出量。 肾小动脉与每个肾单位的独特空间排列对肾功能的调节至关重要。 肾脏血流量、肾小球滤过率和其他维持动态平衡的特殊肾脏功能。 因此，适当和及时地将小动脉与其各自的肾单位组装在一起是至关重要的 形态发生事件导致形成独立宫外所必需的有功能的肾脏 生活。控制肾血管发育的机制还知之甚少。 Foxdl+细胞及其后代，Ren+前体，是所有 肾小动脉的壁细胞包括JG细胞、周细胞、小动脉平滑肌细胞(SMCs)和 系膜细胞。 我们最近发现RBP-J(所有Notch受体的最终转录效应因子)的缺失是 维持肾素表达细胞的数量，对血管的可塑性至关重要 在动态平衡受到威胁时，SMC重新获得肾素表型。初步血统溯源 体内研究还表明，含有RBP-J-/-突变的肾素谱系的细胞不会死亡， 取而代之的是采用不同的肌成纤维细胞表型。这些实验表明，RBP-J调节 肾素细胞的命运和维持。我们预计类似的突变在肾素的上游 前体，如在Foxdl+祖细胞中，将显著影响 组成肾小动脉树。使用活体谱系追踪，特定时间和细胞的条件删除 方法，全基因组表观遗传学和基因表达谱以及适当的细胞鉴定 分化标记物，我们将检验RBP-J对于分化是必要的总体假设 Foxdl+和Renin+祖细胞及其细胞特异性表观遗传标记的建立 随着肾脏分化壁细胞的出现而达到顶峰的基因表达模式 小动脉。 相关性(请参阅说明)： 阐明RBP-J如何调节肾动脉发育和系膜细胞分化可能导致 对血管发育和疾病的新认识以及最终的治疗应用。这个 拟议的实验将产生与再生领域相关的新的和令人兴奋的信息 以及血管发育和可塑性，有可能造福于患有肾脏和 血管疾病。

The kidney is a highly vascularized organ that in the normal adult receives about 20% of the cardiac output. The unique spatial arrangement of the kidney arterioles with each nephron is crucial for the regulation of renal blood flow, glomerular filtration rate and other specialized kidney functions that maintain homeostasis. Thus, the proper and timely assembly ofthe arterioles with their respective nephrons is a crucial morphogenetic event leading to the formation of a functioning kidney necessary for independent extrauterine life. The mechanisms that govern the development ofthe kidney vasculature are poorly understood. Foxdl + cells and their descendants, the Ren+ precursors, are the earliest metanephric progenitors for all the mural cells ofthe kidney arterioles including JG cells, pericytes, arteriolar smooth muscle cells (SMCs) and mesangial cells. We recently showed that deletion of RBP-J (the final transcriptional effector for all Notch receptors) is required to maintain the number of renin-expressing cells, and that it is crucial in the plasticity of vascular SMCs to regain the renin phenotype in response to a threat to homeostasis. Preliminary lineage tracing studies in vivo also suggest that cells from the renin lineage harboring the RBP-J -/- mutation do not die, adopting instead a distinct myofibroblast phenotype. Those experiments suggest that RBP-J regulates the fate and maintenance of renin cells. We anticipate that similar mutation further upstream from the renin precursor, such as in the Foxdl + progenitors, will significantly affect the differentiation ofthe cells that compose the renal arteriolar tree.Using in vivo lineage tracing, time- and cell-specific conditional deletion approaches, genome wide epigenetic and gene-expression profiling and cell identification with appropriate differentiation markers we will test the he overall hypothesis that RBP-J is necessary for the differentiation of Foxdl + and Renin+ progenitor cells and the establishment of cell identity-specific epigenetic marks and gene-expression patterns that culminate with the emergence of the differentiated mural cells of the renal arterioles. RELEVANCE (See instructions): Elucidating how RBP-J regulates renal arterial development and mesangial cell differentiation could lead to a new understanding of vascular development and disease with eventual therapeutic applications. The proposed experiments will generate new iand exciting information of relevance to the fields of regeneration and vascular development and plasticity with the potential to benefit children and adults with kidney and vascular diseases .