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

肾脏是一个高度血管化的器官，在正常成人中接收约20%的心输出量。 每个肾单位的肾小动脉的独特空间排列对于调节肾功能至关重要。 肾血流量、肾小球滤过率和其他维持体内平衡的专门肾功能。 因此，小动脉与其相应的肾单位的适当和及时的组装是至关重要的。 形态发生事件，导致形成独立的子宫外所必需的功能性肾脏 生活对支配肾血管发育的机制知之甚少。 Foxdl +细胞和它们的后代，Ren+前体，是所有人的最早的后肾祖细胞。 肾小动脉的壁细胞包括JG细胞、周细胞、小动脉平滑肌细胞（SMC）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子）的缺失是 这是维持肾素表达细胞数量所必需的，并且在血管的可塑性中至关重要。 平滑肌细胞恢复肾素表型以应对稳态的威胁。初步谱系追踪 体内研究还表明来自携带RBP-J -/-突变的肾素谱系的细胞不会死亡， 而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可能发生在肾素上游， 前体，如Foxdl +祖细胞，将显著影响细胞的分化， 利用体内谱系追踪、时间特异性和细胞特异性条件缺失 方法，全基因组表观遗传和基因表达谱分析和细胞鉴定， 我们将检验RBP-J是分化所必需的这一总体假设。 Foxdl +和Renin+祖细胞以及细胞身份特异性表观遗传标记的建立， 基因表达模式随着肾细胞分化壁细胞的出现而达到顶峰， 小动脉 相关性（参见说明）： 阐明RBP-J如何调节肾动脉发育和系膜细胞分化可能会导致一种新的肾动脉疾病。 对血管发育和疾病的新认识，以及最终的治疗应用。的 拟议的实验将产生新的i和令人兴奋的信息有关的领域的再生 和血管发育和可塑性，有可能使儿童和成人肾脏和 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 .