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.
Our laboratory has had a long-standing interest in using genetically engineered mouse models to elucidate the physiological functions of adrenomedullin peptide and its receptors in normal and disease physiology. Our most recent studies in which we have used inducible knockout models to delete genes during adulthood has provided us with extremely exciting and unexpected results that have broad implications for the field of lymphatic biology and intestinal biology. Briefly, mice which lack the adrenomedullin receptor during adulthood develop intestinal lymphangiectasia resulting in poor lipid absorption though intestinal lacteals, protein-losing enteropathy and failure to thrive. Therefore, with this new model in hand, we are in a very unique position to begin to elucidate the many complex functions of lymphatic vessels within the intestinal tract, as they relate to normal lipid absorption and under basal conditions, high-fat diet conditions and conditions of mucosal injury and inflammation. We emphasize that our proposed experiments will expand our current mechanistic understanding of genetic and molecular factors that regulate intestinal lipid absorption and simultaneously provide potentially new therapeutic opportunities for the specific targeting of the lymphatic vasculature during digestive disease conditions.
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