Prox1 in Mammalian Lymphangiogenesis

描述(申请人提供)：淋巴系统对保持良好的健康和疾病的预防和治疗至关重要。先天性发育不良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)，或者更常见的是在青春期之后(Meige病)。虽然淋巴水肿最早是在一个多世纪前被描述的，但在理解导致淋巴水肿的机制方面进展甚微。此外，在确定参与淋巴管系统正常发育的参与者方面进展甚微。淋巴系统正常发育的研究由于缺乏已知的淋巴特异性标记物而受到阻碍。因此，关于淋巴管起源的假说仍然存在争议。由F.Sabin于1902年提出的最被广泛接受的观点是，在发育早期，孤立的原始淋巴囊从静脉内皮细胞萌发；从这些初级淋巴囊，外周淋巴系统通过内皮萌芽传播到局部毛细血管形成的组织中。这项拨款建议是基于我们将同源异型盒基因Prox1确定为淋巴管内皮细胞的第一个特异性标记。在小鼠中，Proxl的功能失活会导致淋巴管系统的表型变化，并最终导致胚胎死亡。对Proxl缺失和Prox1杂合子小鼠的详细分析表明，淋巴管生成需要胚胎静脉内皮细胞亚群中Prox1的活性。Proxl基因缺失的小鼠缺乏淋巴管系统。Proxl的活性也决定了萌芽内皮细胞的最终淋巴管命运。阐明Prox1参与淋巴管形成的分子机制，并寻找其他参与此过程的新分子，将加深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.