Organ-specific Mechanisms of Vascular Development

描述（由申请人提供）：本项目的目的是了解血管发育和器官发生之间的相互作用，使用发育中的小鼠睾丸作为模型系统。血管系统是高度专业化的不同器官的功能需求，但确切地说，组织和血管如何相互作用，以实现这种整合是未知的。传统上，脉管系统被认为扮演着被动的角色，只是作为发育器官的氧气和营养物质的来源。相反，我们假设血管系统在器官发育中起着相互作用：器官不仅塑造其血管系统，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。大部分关于血管信号传导的工作已经在细胞培养系统中完成，并且存在很少的模型来研究在完整器官的背景下脉管系统的发育。双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是从相同的原基分化而来的，因此可以通过比较研究来确定相关的信号通路。此外，我们还开发了一种器官培养系统，在该系统中，控制血管发育的信号可以被阻断或诱导，而不会导致与整个动物中这一关键系统的破坏相关的正常致死性。在这项资助的第一年，我们描述了睾丸动脉系统的早期形成，并确定了几个参与男性和女性血管系统分歧的信号通路。在接下来的五年里，我们计划研究血管在睾丸发育中起积极作用的非传统观点。我们将使用遗传突变体和体外技术来确定睾丸索图案和睾丸细胞类型的分化中血管发育的功能。此外，我们计划表征候选信号通路（FGF，Pdgf，Wnt，Fst，Bmp）在睾丸中诱导此过程或在卵巢中阻断此过程中的作用。利用基因突变体和微阵列技术，我们将确定新的基因，控制男性特定的体腔血管的形成。研究血管特化是如何被调节并与器官发育整合的，其意义超出了卵巢和睾丸形成的领域，在器官发生、内分泌学和血管生物学的更广泛领域。此外，控制或抑制脉管系统生长到组织中的分子信号对于伤口愈合和肿瘤生物学领域中的治疗设计是至关重要的。

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.