Development of the Renal Arterioles

肾小动脉的发育

• 批准号: 8682811
• 负责人: MARIA LUISA Soledad SEQUEIRA-LOPEZ
• 金额: $ 33.5万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-20 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8682811
• 关键词: Adult; Biological Process; Blood Vessels; Brachyury protein; Cell Lineage; Cells; Child; Chronic Kidney Failure; Data; Development; Embryo; Endothelial Cells; Endothelium; Endowment; Erythroid Cells; Event; Failure; Family; Fibroblasts; G-Protein-Coupled Receptors; Glycocalyx; Health; In Situ; In Vitro; Kidney; Kidney Diseases; Knowledge; Lead; Lesion; Morphogenesis; Mus; Natural regeneration; Pericytes; Play; Prevalence; Renal function; Renin; Role; Smooth Muscle Myocytes; Sphingolipids; Sphingosine-1-Phosphate Receptor; Stem cells; Stromal Cells; Testing; Trees; Vascular Diseases; Work; angiogenesis; arteriole; cell behavior; cell type; design; edg-1 Protein; edg-3 Protein; in vivo Model; kidney cell; kidney vascular structure; mesangial cell; precursor cell; progenitor; receptor; research study; sphingosine 1-phosphate

DESCRIPTION (provided by applicant): The origin, lineage relationships and morphogenesis of the kidney vasculature are not well understood. We hypothesize that the embryonic renal stromal compartment has at least two distinct early progenitor cells that give rise to all other cells of the kidney arterioles and their perivascular compartment: 1) A precursor of hemogenic endothelium (Scl+, hemangioblast) capable of giving rise to erythroid and endothelial cells (ECs) of the renal arteriole and 2) A Foxd1+ cell from which all other vascular and perivascular/adventitial cells originate. Further, renal hemangioblasts may give rise to Flk1+ precursors that in turn may contribute not only hemogenic ECs but also vascular SMCs. The lineage relationship among all these cell types has not been clarified and the mechanisms underlying the differentiation and assembly of the kidney arterioles are unclear. Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid metabolite crucial in many biological processes, including angiogenesis. S1P1 and S1P3 are highly expressed in precursors and definitive cells of the kidney arteriole and may play an important role in the differentiation and assembly of arteriolar cells. The proposed studies will test two interrelated hypotheses: 1) The renal arterial tree originates from hemogenic and non-hemogenic- stromal cell precursors 2) Locally generated S1P (by hemogenic endothelium) interacting with S1P1 and S1P3 receptors is crucial for the maturation and assembly of the renal arterioles There is currently very limited information regarding the crucial events that govern the morphogenesis of the renal arterial tree. The proposed work will fill this important gap in our knowledge by defining the precise cellular origin and mechanisms whereby those early and intermediate precursors lead to the successful formation of the renal arterial tree, without which there is no functioning kidney. As designed, the proposed experiments will solve an existing challenge and generate new and exciting information of relevance to the fields of regeneration and hemo-vascular development with the potential to benefit children and adults with kidney and vascular diseases.

描述（由申请方提供）：对肾脏血管系统的起源、谱系关系和形态发生尚不清楚。我们假设胚胎肾间质隔室至少有两种不同的早期祖细胞，它们产生肾小动脉及其血管周围隔室的所有其他细胞：1）生血内皮的前体（Scl+，成血管细胞），能够产生肾小动脉的红细胞和内皮细胞（EC），和2）Foxd 1+细胞，所有其他血管和血管周围/外膜细胞起源。此外，肾成血管细胞可能产生Flk 1+前体，进而不仅可以促进生血EC，还可以促进血管SMC。所有这些细胞类型之间的谱系关系尚未澄清，肾小动脉分化和组装的机制也不清楚。 1-磷酸鞘氨醇（S1 P）是一种具有生物活性的鞘脂代谢产物，在包括血管生成在内的许多生物学过程中至关重要。S1 P1和S1 P3在肾小动脉的前体细胞和定形细胞中高表达，可能在小动脉细胞的分化和组装中起重要作用。拟议的研究将检验两个相互关联的假设：1）肾动脉树起源于生血和非生血基质细胞前体2）局部产生的S1 P（通过生血内皮）与S1 P1和S1 P3受体的相互作用对于肾小动脉的成熟和组装至关重要。目前关于控制肾动脉形态发生的关键事件的信息非常有限。树拟议的工作将填补我们知识中的这一重要空白，通过定义精确的细胞起源和机制，使这些早期和中期前体导致肾动脉树的成功形成，没有肾动脉树就没有功能性肾脏。按照设计，拟议的实验将解决现有的挑战，并产生与再生和血管发育领域相关的新的令人兴奋的信息，有可能使患有肾脏和血管疾病的儿童和成人受益。