Causes and Consequences of Digestive Tract Lymphangiectasia

描述（由申请人提供）：在过去的十几年中，已经阐明了参与淋巴管系统发育的基因和分子途径的扩展库。然而，考虑到淋巴管在肠道脂质吸收中的重要作用以及肠道炎性疾病的患病率增加，目前关于淋巴管是否和/或如何导致（或可能导致）成人病理生理学疾病的问题比答案更多，这是相当值得注意的-正如最近NIDDK申办的PAR-12- 259中所强调的那样。我们建议直接解决许多这些问题的基础上，我们令人兴奋的发现信号的重要作用，在神经网络。我们的实验室是第一个提供体内遗传 AM信号通路在胚胎发育中的重要性的证据，因为AM-/-、RAMP-/-和RAMP 2-/-小鼠在妊娠中期死亡，具有由淋巴管生成停滞引起的严重间质水肿组成的保守表型。此外，我们最近的研究已经使用了一个可诱导的基因敲除等位基因，以表明成年动物中的lymphocyte丢失完全概括了与淋巴管扩张相关的临床后遗症，包括扩张性淋巴管扩张、肠道脂质吸收减少、蛋白质丢失性肠病和肢体水肿。在这项资助申请中提出的研究将建立在这些令人兴奋的发现的基础上，并致力于阐明肠道药物在i）肠道疾病的启动和进展，ii）各种不同挑战条件下的正常肠道脂质吸收和iii）粘膜损伤，炎症和修复的启动和进展中发挥的生理和分子过程。通过完成这些目标，我们希望为肠道中淋巴管和AM信号的作用提供新的见解。这些分子途径的阐明可能最终形成用于肠淋巴管的治疗性调节的GPCR靶向方法的基础，特别是在淋巴管扩张和与消化道炎症相关的疾病状况期间。

DESCRIPTION (provided by applicant): In the past dozen years, an expanded repertoire of genes and molecular pathways involved in the development of the lymphatic vascular system has been elucidated. However, considering the essential role of lymphatic vessels in intestinal lipid absorption and the increased prevalence of inflammatory diseases of the intestine, it is rather remarkable that there are currently more questions than answers regarding whether and/or how lymphatic vessels contribute to (or may be causative of) pathophysiological diseases in adults-as recently highlighted in the NIDDK-sponsored PAR-12- 259. We propose to directly address many of these questions by building upon our exciting discoveries on the essential roles of signaling in lymphatics. Our laboratory was the first to provide genetic in vivo evidence for the importance of the AM signaling pathway in embryonic development since AM-/-, CLR-/- and RAMP2-/- mice die at midgestation with a conserved phenotype that consists of profound interstitial edema caused by arrested lymphangiogenesis. In addition, our most recent studies have used an inducible knockout allele to show that loss of CLR in adult animals fully recapitulates the clinical sequelae related to lymphangiectasia, including dilated lymphatics, reduced intestinal lipid absorption, protein losing enteropathy and limb edema. Studies proposed in this grant application will build upon these exciting findings and strive to elucidate the physiological and molecular processes that lymphatics play in i) intestinal disease initiation and progression, ii) normal intestinal lipid absorption under a variety of different challenge conditions and iii) the initiation and progression of mucosal injury, inflammation and repair. By completing these aims we hope to provide novel insights into the role of lymphatic vessels and AM signaling in the intestinal tract. The elucidation of these molecular pathways may ultimately form the basis of GPCR- targeted approaches for the therapeutic modulation of intestinal lymphatic vessels, particularly during lymphangiectasia and disease conditions associated with digestive tract inflammation.