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，但直到最近才在了解其发生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，发育淋巴管生成领域的研究一直受到阻碍。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的功能失活导致淋巴管系统的完全缺失。对肥胖的Proxl杂合子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管泄漏的结果，这一结果表明淋巴管生成需要持续的Proxl活性。更好地了解淋巴管生成过程中淋巴管内皮细胞的来源，阐明Prox1参与淋巴管生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.