Organ-specific Mechanisms of Vascular Development

描述(由申请人提供)：本项目的目标是以发育中的小鼠睾丸为模型系统，了解血管发育和器官发生之间的相互作用。血管系统高度专业化，以满足不同器官的功能需求，但组织和血管如何相互作用以实现这种整合尚不清楚。传统上，血管系统被认为扮演着被动的角色，仅仅是作为发育中的器官的氧气和营养来源。相反，我们假设血管系统在器官发育中扮演着交互作用：不仅器官塑造其血管系统，而且来自血管系统的信号积极影响器官的模式、组织和分化。许多关于血管信号的工作都是在细胞培养系统中完成的，很少有模型可以在一个完整的器官的背景下研究血管系统的发育。双潜能性腺是实现这一目标的一个很好的模型系统。由于睾丸或卵巢的发育不同于相同的原基，比较研究可以用来确定相关的信号通路。此外，我们开发了一种器官培养系统，在这种系统中，控制血管发育的信号可以被阻断或诱导，而不会产生与整个动物的这一关键系统中断相关的正常致命性。在这笔赠款的头几年，我们描述了睾丸动脉系统的早期形成，并确定了几条与男性和女性血管系统分化有关的信号通路。在接下来的五年里，我们计划调查非传统的观点，即血管系统在睾丸的发育中发挥积极作用。我们将使用基因突变和体外技术来确定血管发育在睾丸索图案形成和睾丸细胞类型分化中的作用。此外，我们计划表征候选信号通路(成纤维细胞生长因子、PDGF、Wnt、Fst、BMP)在睾丸中诱导或在卵巢中阻断这一过程中的作用。利用基因突变和微阵列技术，我们将识别控制男性特有体腔血管形成的新基因。在器官发生、内分泌学和血管生物学等更广泛的领域，研究血管特化如何调节和整合器官发育具有超越卵巢和睾丸形成领域的意义。此外，控制或抑制组织中血管生长的分子信号对于创伤愈合和肿瘤生物学领域的治疗设计至关重要。

DESCRIPTION (provided by applicant): The goal of this project is to understand the interplay between vascular development and organogenesis, using the developing mouse testis as a model system. Vascular systems are highly specialized for the functional needs of different organs, but precisely how the tissue and blood vessels interact to achieve this integration is not known. Traditionally, the vasculature has been considered to play a passive role, simply as a source of oxygen and nutrients for developing organs. In contrast, we hypothesize that the vasculature plays an interactive role in organ development: Not only does an organ shape its vasculature, but signals from the vasculature actively influence the pattern, organization, and differentiation of an organ. Much of the work on vascular signaling has been done in cell culture systems and few models exist to study the development of the vasculature in the context of an intact organ. The bipotential gonad is an excellent model system to achieve this goal. Because development of the testis or ovary diverges from an identical primordium, comparative studies can be used to identify relevant signaling pathways. In addition, we have developed an organ culture system in which signals that control vascular development can be blocked or induced without the normal lethality associated with disruption of this critical system in the whole animal. In the first years of this grant, we characterized the early formation of the arterial system in the testis, and identified several signaling pathways involved in the divergence of male and female vascular systems. In the next five years, we plan to investigate the unconventional idea that the vasculature plays an active role in the development of the testis. We will use both genetic mutants and in vitro techniques to determine the function of vascular development in the patterning of testis cords and the differentiation of testis cell types. In addition, we plan to characterize the role of candidate signaling pathways (Fgf, Pdgf, Wnt, Fst, Bmp) in inducing this process in the testis, or blocking it in the ovary. Using genetic mutants and microarray technology, we will identify new genes that control the formation of the male-specific coelomic vessel. The study of how vascular specialization is regulated and integrated with organ development has significance beyond the fields of ovary and testis formation, in broader fields of organogenesis, endocrinology, and vascular biology. In addition, the molecular signals that control or repress the growth of vasculature into a tissue are of critical concern for the design of therapies in the fields of wound healing and tumor biology.