Organ-specific Mechanisms of Vascular Development

描述（由申请人提供）：该项目的目标是利用发育中的小鼠睾丸作为模型系统，了解血管发育与器官发生之间的相互作用。血管系统是高度专门化的，以满足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尚不清楚。传统上，脉管系统被认为是一个被动的角色，仅仅是发育器官的氧气和营养来源。相反，我们假设脉管系统在器官发育中起着相互作用：不仅器官塑造其脉管系统，而且来自脉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的研究都是在细胞培养系统中完成的，很少有模型能够研究完整器官中血管系统的发育。双势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，因此可以通过比较研究来确定相关的信号通路。此外，我们已经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，而不会导致整个动物因这一关键系统的破坏而导致正常的致命性。在这项资助的头几年，我们描述了睾丸动脉系统的早期形成，并确定了几个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，我们计划研究脉管系统在睾丸发育中起积极作用的非传统观点。我们将使用基因突变体和体外技术来确定睾丸索模式和睾丸细胞类型分化中血管发育的功能。此外，我们计划描述候选信号通路（Fgf, Pdgf, Wnt, Fst, Bmp）在睾丸中诱导这一过程或在卵巢中阻断这一过程中的作用。利用基因突变体和微阵列技术，我们将识别控制雄性特异性体腔血管形成的新基因。研究血管特化是如何调控并与器官发育结合的，其意义不仅限于卵巢和睾丸的形成，还涉及器官发生、内分泌学和血管生物学等更广泛的领域。此外，控制或抑制血管生长进入组织的分子信号对于伤口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.