Lymphatic vessels perform critical roles in organ functions, yet their roles in health and disease are poorly understood and understudied. This funding opportunity announcement (FOA) invites applications that investigate aspects of lymphatic vessel physiology development and pathophysiology related to health and diseases of the digestive system. Studies to understand the factors that control local lymphatic vessel functional anatomy and physiology and development during health or disease in this system and its organs, and the mechanisms by which alterations of lymphatic vessel function affect organ function, are of interest.
The lymphatic system is a crucial component of nutrient and hormone absorption, fluid homeostasis and immunity. In the digestive system, lymphatic vessel function is interwoven with organ function, both anatomically and physiologically and these vessels lie at the nexus of critical hormonal, digestive and immune functions. The lymphatic system plays an important role in uptake of dietary fat and clearance of cholesterol from peripheral tissues and has been implicated in several disease states such as obesity, metabolic syndrome and inflammatory bowel disease (IBD). Lymphatic vessels within different organs and in different physiological and pathological processes show a remarkable plasticity and heterogeneity, reflecting their functional specialization. In addition, lymphatic endothelial cells of different organs have been recently shown to have alternative developmental origins, which may contribute to the development of the diverse lymphatic vessel and endothelial functions seen in the adult. The gastrointestinal tract is a system with multiple functions. Many of these functions include key roles of lymphatic vessels, yet the roles of lymphatics, the character of the vessels in the intestinal environment and key regulators of lymphatic function in intestinal health and disease remain understudied. Anatomically, the intestinal lymph vessels are found as a network in the wall of the organ and, in the small intestine as lacteals extending into each of the villi. Their general functions as lymph and immune cell transporters are magnified and adapted to critical gut nutrient and barrier functions. Lymphatics are essential conduits for absorption and transport of nutrients, hormones, some drugs, and other extracellular components from the digestive tract to the blood. Lymph contains chylomicrons from digestion, as well as hormones secreted by enteroendocrine cells. In addition, there is evidence that innervation of intestinal lacteals forms part of a neurolymphocrine system stimulated by interstitial fluid. There are many open questions regarding these roles of lymphatics, particularly with regard to the importance of the lymph system in distribution of gastrointestinal-derived hormones, and how the signals lymphatics are receiving may affect their function and, thus, overall intestinal function. Lymphatic vessels potentially play active roles in the relationship of gut health to the microbiome and in inflammatory disease, however the factors that affect these roles, and the resultant effects on the local tissue, are not well understood. Even less is known about lymphatics in other organs of the digestive system, such as liver and pancreas. Under conditions of inflammation, and in diseases such as IBD and liver fibrosis, the lymphatic network is altered. The relationship of these alterations to disease is currently not well understood, but may present new therapeutic opportunities. Whether, and how, lymphatic drainage affects transplanted digestive organs is also unclear. Furthermore, as a transportation system that intersects with the blood circulatory system, the lymphatic vessels and lymph from the gut and liver have the potential to affect distant organs. Research on lymphatic vessels of the digestive system holds the potential for greater understanding of not only lymphatic system function and local organ function, but whole-body health, as well.
For many years now, NIDDK has participated in several activities to encourage the study of lymphatics in health and disease. In 2009 NIDDK sponsored a workshop entitled “Lymphatics in the Digestive System”. This workshop was followed by funding announcements in 2012 where NIDDK partnered with NHLBI to support research on lymphatics in health and disease in the digestive, urinary, cardiovascular and pulmonary systems. In 2015 NIDDK reissued the solicitation to support research in lymphatics in health and disease in the digestive, kidney and urinary tract systems. In September 2015, a symposium was organized by the Trans-NIH Lymphatics Research Committee entitled “The Third Circulation: Lymphatics as Regulators in Health and Disease”. In addition to reviewing current relevant research, major questions for future research were also identified through participant discussions. This announcement is a continued effort to stimulate research in response to these needed research areas and important questions in the digestive system.
However, studies with the major focus on immune mechanisms, role of lymphatics in cancer metastasis and study of lymphatic vessels in organs other than those from the digestive system will be considered nonresponsive. Clinical research and clinical trials will not be supported under this FOA.
Examples of research areas of interest under this FOA include, but are not limited to the following:
- How is the process of lymphangiogenesis regulated in the organs of the digestive system in health and disease states? What are the key molecular and regulatory determinants that provide and functionally distinguish lymphatics in the organs of the digestive system from other organs? How do environmental factors such as diet and dietary constituents change the structure and function of local lymphatic vessels as they relate to the health and disease of digestive system organs?
- Are the lymphatics in the organs of the digestive system selective to passage of cells and substances? If so, how does this organ-specific character influence function, and how might it be altered in disease? What is the role of lymphatics in the transport of hormones, drugs and xenobiotics? What are the mechanisms by which impaired lymph pumping or transport affect nutrient, hormonal and/or water transport from digestive organs?
- Does altered lymph composition originating from diseased digestive tract impact health? Can lymph composition be actively modulated? What are the metabolomics and proteomics profiles of lymph in health and disease states?
- What is the interplay of gut microbiome and dietary constituents on the structure and function of lymphatic vessels? How do the microbiota influence lymphatic function, and what are the pathways by which this takes place? What is the role of the lymphatic system in the interaction between the microbiome and the host?
- Are there specific interactions between organ cells and lymphatics, and are these important to organ function and protection from inflammation?
- How are lymphatics involved in formation of adipose tissue? How defective lymphatics vessels lead to adipose tissue accumulation and obesity? How obesity affects lymphatic function in the digestive system?
- How does the milieu of the digestive system lymphatic smooth muscle influence pumping in health and disease, and do changes in the resultant lymph flow exacerbate or ameliorate inflammation? What is the role of lymphedema in diseases of the digestive system? Can we learn how to regulate the digestive system lymphatic function to ameliorate edema, inflammation, and disease?
- What is the role of the autonomic nervous system in digestive system lymphatic vessels contraction in health and disease states? What are the mechanisms involved?
Deadline: January 21, 2019 (letters of intent); February 21, 2019 (full proposals)
Filed Under: Funding Opportunities