Causes and Consequences of Digestive Tract Lymphangiectasia

消化道淋巴管扩张的原因和后果

• 批准号: 8723187
• 负责人: Kathleen M Caron
• 金额: $ 32.56万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8723187
• 关键词: Acute; Address; Adult; Affect; Alleles; Amino Acids; Applications Grants; Attenuated; Biochemical; Biology; Chronic; Clinical; Complex; Development; Diet; Digestive System Disorders; Disease; Edema; Embryonic Development; Enterocytes; Failure to Thrive; Fatty acid glycerol esters; Financial compensation; G-Protein-Coupled Receptors; Gastrointestinal tract structure; Genes; Genetic; Genetic Models; Genetically Engineered Mouse; Genomics; Hand; Health; Indomethacin; Inflammation; Inflammatory disease of the intestine; Injury; Intestinal Absorption; Intestinal Diseases; Intestines; Ischemia; Knock-out; Knockout Mice; Laboratories; Limb structure; Lipids; Lymphangiogenesis; Lymphatic; Lymphatic Endothelial Cells; Lymphatic vessel; Modeling; Molecular; Molecular Genetics; Mus; National Institute of Diabetes and Digestive and Kidney Diseases; Pathway interactions; Peptides; Permeability; Phenotype; Physiological; Physiology; Play; Positioning Attribute; Prevalence; Process; Protein-Losing Enteropathies; RAMP2; Recovery; Reperfusion Therapy; Role; Signal Pathway; Signal Transduction; Small Intestines; Structure; Testing; Therapeutic; Tissues; Vascular System; absorption; adrenomedullin; adrenomedullin receptor; base; calcitonin receptor-like receptor; feeding; in vivo; insight; interest; interstitial; lipid transport; mature animal; mouse model; novel; novel therapeutics; public health relevance; receptor; receptor-activity-modifying protein; regenerative; repaired; research study; response

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.

描述（由申请人提供）：在过去的十几年中，涉及淋巴血管系统发育的一系列基因和分子途径已被阐明。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症性疾病患病率的增加，值得注意的是，目前关于淋巴管是否和/或如何促进（或可能导致）成人病理生理疾病的问题多于答案——正如最近在 NIDDK 赞助的 PAR-12-259 中强调的那样。我们建议直接 通过我们关于淋巴信号传导的重要作用的令人兴奋的发现，解决了其中许多问题。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重要性的证据，因为AM-/-、CLR-/-和RAMP2-/-小鼠在妊娠中期死亡，并具有保守的表型，该表型由淋巴管生成停滞引起的严重间质水肿组成。此外，我们最近的研究使用诱导型敲除等位基因表明，成年动物中CLR的丧失完全重现了与淋巴管扩张相关的临床后遗症，包括淋巴管扩张、肠道脂质吸收减少、蛋白质丢失性肠病和肢体水肿。本拨款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，并努力阐明淋巴管在 i）肠道疾病的发生和进展，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、炎症和修复的发生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 信号传导的作用提供新的见解。这些分子途径的阐明可能最终构成用于治疗性调节肠道淋巴管的 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期间。