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）。尽管淋巴水肿早在一个多世纪前就被描述出来了，但直到最近才在理解引起淋巴水肿的机制以及识别参与淋巴血管正常发育的因素方面取得了一些进展。由于缺乏已知的淋巴特异性标记物，在发育性淋巴管生成领域的研究一直受到阻碍。因此，关于淋巴内皮细胞前体的起源以及调节淋巴血管形成的细胞和分子机制的假设仍然存在争议。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完全缺失。对肥胖Proxl杂合小鼠的详细分析表明，在这些小鼠中观察到的脂肪异常堆积是淋巴血管渗漏的结果，这表明淋巴管生成需要恒定的Proxl活性。更好地了解发育和出生后淋巴管生成过程中淋巴内皮细胞的来源，并阐明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.