Prox1 in Mammalian Lymphangiogenesis

描述（由申请人提供）：淋巴系统对保持身体健康和预防和治疗疾病至关重要。先天性发育不全和淋巴组织再生失败导致淋巴水肿。原发性淋巴水肿出现在出生时（Milroy病）或更常见的出现在青春期后（Meige病）。尽管淋巴水肿在一个多世纪前被首次描述，但在了解导致它的机制方面进展甚微。此外，在确定参与淋巴脉管系统正常发育的参与者方面进展甚微。由于缺乏已知的淋巴特异性标记物，对淋巴系统正常发育的研究一直受到阻碍。因此，关于淋巴管起源的假说仍然存在争议。1902年由F. Sabin提出的最被广泛接受的观点是，在发育早期，从静脉内皮中分离出原始淋巴袋芽；外周淋巴系统通过内皮发芽从这些原发性淋巴囊扩散到局部毛细血管形成的组织。这项拨款提案是基于我们鉴定同源盒基因Proxl作为淋巴内皮细胞的第一个特异性标记物。Proxl在小鼠体内的功能失活导致淋巴血管的表型改变，最终导致胚胎死亡。对Proxl-null和Proxl杂合小鼠的详细分析表明，在胚胎静脉内皮细胞亚群中，淋巴管生成需要Proxl的活性。Proxl-null小鼠缺乏淋巴血管。Proxl活性也决定出芽内皮细胞的最终淋巴命运。Proxl参与淋巴血管形成的分子机制的阐明以及参与这一过程的其他新分子的鉴定将增加我们对正常淋巴管生成的理解，从而促进淋巴系统疾病的治疗和预防。

DESCRIPTION (provided by applicant): The lymphatic system is crucial for the maintainance of good health and for the prevention and cure of disease. Congenital hypoplasia and failed regeneration of lymphatic tissue result in lymphedema. Primary lymphedema appears at birth (Milroy disease) or, more commonly, after puberty (Meige disease). Although lymphedema was first described more than a century ago, little progress has been made in understanding the mechanisms that cause it. Furthermore, little progress has been made in identifying the players that participate in the normal development of the lymphatic vasculature. Investigation of the normal development of the lymphatic system has been hindered by the lack of known lymphatic-specific markers. Consequently, hypotheses about the origin of the lymphatic vessels are still controversial. The most widely accepted view, which was proposed by F. Sabin in 1902, is that isolated primitive lymph sacs bud from the endothelium of veins during early development; from these primary lymph sacs, the peripheral lymphatic system spreads by endothelial sprouting into tissues where local capillaries form. This grant proposal is based in our identification of the homeobox gene Proxl as the first specific marker of lymphatic endothelial cells. Functional inactivation of Proxl in mice leads to phenotypic alterations in lymphatic vasculature and, ultimately, to embryo death. Detailed analyses of Proxl-null and Proxl heterozygous mice have indicated that lymphangiogenesis requires activity of Proxl in a subpopulation of endothelial cells in embryonic veins. Proxl-null mice are devoid of lymphatic vasculature. Proxl activity also determines the final lymphatic fate of budding endothelial cells. The elucidation of the molecular mechanisms by which Proxl participates in the formation of the lymphatic vasculature and the identification of other novel molecules that participates in this process will increase our understanding of normal lymphangiogenesis, and therefore, advance the treatment and prevention of disorders of the lymphatic system.