Prox1 in Mammalian Lymphangiogenesis

产品描述（由申请人提供）：淋巴系统对于保持身体健康以及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水肿。原发性水肿出现在出生时（米尔罗伊病），或更常见的是，青春期后（梅杰病）。尽管水肿是在世纪前首次描述的，但直到最近才在理解引起水肿的机制和识别参与淋巴管系统正常发育的参与者方面取得了一些进展。由于缺乏已知的淋巴管特异性标记物，发育性淋巴管生成领域的研究受到阻碍。因此，关于淋巴管内皮细胞前体的起源以及调节淋巴管形成的细胞和分子机制的假说仍然存在争议。这项拨款建议是基于我们的同源异型盒基因Proxl作为淋巴管内皮细胞的第一个特异性标志物的鉴定。在小鼠中Proxl的功能失活导致淋巴管系统的完全缺失。对肥胖的Proxl杂合小鼠的详细分析表明，在这些小鼠中观察到的脂肪的异常积累是淋巴管渗漏的结果，该结果表明淋巴管生成需要恒定的Proxl活性。更好地理解在发育和出生后淋巴管生成过程中淋巴管内皮细胞的来源，以及阐明Proxl参与淋巴管形成的细胞和分子机制，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, only recently some progress has been made in understanding the mechanisms that cause it and in the identification of the players that participate in the normal development of the lymphatic vasculature. Research in the area of developmental lymphangiogenesis has been hindered by the lack of known lymphatic-specific markers. Consequently, hypotheses about the origin of lymphatic endothelial cell precursors, and the cellular and molecular mechanisms regulating the formation of the lymphatic vasculature are still controversial. 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 results in the complete absence of the lymphatic vasculature. Detailed analyses of obese Proxl heterozygous mice demonstrated that the abnormal accumulation of fat observed in these mice is the consequence of lymphatic vascular leakage, a result indicating that lymphangiogenesis requires constant Proxl activity. A better understanding of sources of lymphatic endothelial cells during developmental and postnatal lymphangiogenesis and the elucidation of the cellular and molecular mechanisms by which Proxl participates in the formation of the lymphatic vasculature will increase our understanding of normal lymphangiogenesis, and therefore, advance the treatment and prevention of disorders of the lymphatic system.