July 24, 2023
National Heart, Lung, and Blood Institute (NHLBI)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
National Institute of Dental and Craniofacial Research (NIDCR)
National Center for Complementary and Integrative Health (NCCIH)
Purpose
This NOSI aims to promote research on the normal biology of the lymphatic system (LS) and ascertain factors that account for individual differences in the LS impacting resilience. Also of interest is research to identify factors that account for individual differences in pathobiology and response to treatments, and understand the mechanisms and potential novel therapeutics for lymphatic diseases (LDs) and secondary heart, lung, blood, and sleep (HLBS) disorders related to lymphatic dysfunction. Further, this notice intends to stimulate lymphatic research at molecular, cellular, tissue, organ, and whole-body levels, and aims to facilitate research on innovations for identifying and intervening in LDs across the lifespan and disease states. The NOSI may also reach a broader community and facilitate multidisciplinary research needed to determine the function and role LS in health, disease prevention, and to identify biomarkers and test prevention and treatment strategies with specific attention to social determinants of health, and both treatment and health inequities.
Background
The LS is composed of lymphoid organs and a network of vessels that transport interstitial fluid, antigens, lipids, cholesterol, immune cells, and other materials in the body. Abnormal development or malfunction of the lymphatic system has been shown to play a key role in the pathophysiology of many disease states. Failure of lymphatic function through inherited or acquired disease causes a broad array of pathological conditions, such as primary and secondary lymphedema, lymphatic and complex vascular malformations, cancer growth and metastases, acute and chronic inflammation and infection, and various metabolic derangements.
The vast network of vessels in all tissues of the body, together with lymphoid organs converge to transport lymph away from tissues back to the blood in order to maintain extracellular fluid homeostasis and provide critical immune trafficking. This traditional paradigm of passive transport of lymph fluid has been updated by cellular and molecular characterization of lymphatic vascular development. Our improved understanding of the function of the lymphatic vasculature has revealed new roles in health and disease in addition to the critical role of lymph production and flow for removal of interstitial fluid from tissues to prevent tissue edema. In addition to the previously known rare lymphatic diseases, recent investigations of the lymphatic system anatomy have led to observations that lymphatic anatomy variations may be involved in highly prevalent and morbid disease states such as congestive heart failure which affects more than six million Americans annually. Inadequate lymph flow caused by variants in lymphatic anatomy may contribute to abnormal patterns of lymph flow in certain vital organs including the heart, lungs, and other organs, further contributing to the overall pathophysiology of tissue- and organ-specific congestion in heart failure. Similarly, recent studies suggested that lymphatics are critical for lipoprotein-cholesterol removal from atherosclerotic plaques and lymph capillary controls interstitial electrolyte and volume balance, which may blunt increased blood pressure. Furthermore, lymphatic vessels are critical to the mobilization of cholesterol for excretion and enhancing lymphatic function might also be therapeutic in atherosclerosis. Additionally, dysregulation of lymphatic smooth muscle contractility may be associated with the pathophysiology of hypertension through decreased lymphatic compliance as a novel mechanism in addition to lymphatic endothelial dysfunction. Acute and chronic lymphatic dysfunction causes abnormal immune cell trafficking and increases lung inflammation, thus likely contributes to the pathogenesis of multiple lung diseases, including sepsis, COPD, asthma, IPF, pulmonary fibrosis, and lung transplantation. The recent discovery of LS in the CNS, showed the link between the primary function of the tissue lymphatic vasculature and neurological disorders like vascular dementia. Taken together, recent studies suggest that manipulation of the lymphatic system may improve cardiac and lung function and outcomes following cardiac injury, decrease atherosclerosis, manage hypertension and improve cognition.
Additionally, secondary lymphedema, a disease with no known cure, is considered one of the most significant cancer survivorship morbidities in the United States. Breast cancer-related lymphedema (BCRL) results from disruption of the lymphatic system associated with cancer treatment. Black women are more likely to experience common adverse effects of cancer treatment, including BCRL. Variations in peripheral lymphatic anatomy of the upper arm may explain why certain women undergoing breast cancer treatment develop BCRL and others do not. This highlights the need for fundamental understanding of LS structure and function in preventing lymphedema in cancer survivors in general, but especially in women and particularly African-American women.
The knowledge of molecular aspects of the lymphatic network is fundamental to understand the mechanisms of disease progression and prevention. Therefore, there is growing interest in studying the LS in development and disease in diverse areas, including lymphatic malformations, lymphedema, acute and chronic lung diseases, cancer biology, metabolism, obesity, and degenerative diseases of the central nervous system. Thus, improved knowledge of the anatomical and molecular characteristics of the lymphatic system may provide novel approaches for disease prevention or treatments.
Selected research topics include, but are not limited to:
NHLBI
NIAMS
NIDCR
NCCIH
The National Center for Complementary and Integrative Health (NCCIH) will accept applications investigating the mechanisms by which complementary and integrative health approaches modulate lymphatic system, including glymphatics and brain lymphatic systems, for therapeutic purposes such as pain relief, improvement of other symptoms (e.g., anxiety, stress, sleep disturbance), enhancement of the resilience, and/or whole person health. The proposed research may include basic and mechanistic studies in cellular systems or model organisms, as well as clinical mechanistic studies to develop complementary intervention strategies for lymphatics improvement. NCCIH will not fund trials of efficacy or effectiveness of an intervention.
Complementary health approaches include a broad range of practices and interventions that are not typically part of conventional medical care. They can be classified by their primary therapeutic input, including nutritional (e.g., special diets, dietary supplements, herbs, probiotics, and microbial-based therapies); psychological (e.g., meditation, hypnosis, music-based interventions, relaxation therapies); physical (e.g., acupuncture, massage, chiropractic manipulation, other force-based manipulations, or devices related to these approaches); or a combination of psychological and physical (e.g., yoga, tai chi, dance therapies, some forms of art therapy such as music-based interventions). Of particular interest for this NOFO is the role of multisensory therapeutics and whole person approach in the regulation of the lymphatic system.
Application and Submission Information
This notice applies to due dates on or after October 5, 2023, and subsequent receipt dates through September 7, 2026.
Submit applications for this NOSI using one of the following notices of funding opportunity (NOFOs) or any reissues of these announcements through the expiration date of this notice. This NOSI expires on September 8, 2026; thus no applications will be accepted on or after September 8, 2026.
All instructions in the SF424 (R&R) Application Guide and the notice of funding opportunity used for submission must be followed, with the following additions:
Applications nonresponsive to terms of this NOSI will not be considered for the NOSI initiative.
Please direct all inquiries to the contacts in Section VII of the listed notice of funding opportunity with the following additions/substitutions:
Scientific/Research Contact(s)
Selen Catania, Ph.D.
Division of Cardiovascular Sciences
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-480-8353
Email: selen.catania@nih.gov
Alexey Belkin, Ph.D.
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Telephone: 301-827-6475
Email: alexey.belkin@nih.gov
Zhong Chen, MD, Ph.D.
National Institute of Dental and Craniofacial Research (NIDCR)
Telephone: ?301-529-7083
Email: zhong.chen@nih.gov
Inna Belfer, MD, Ph.D.
National Center for Complementary and Integrative Health (NCCIH)
Phone: 301-435-1573
Email: inna.belfer@nih.gov
Peer Review Contact(s)
Examine your eRA Commons account for review assignment and contact information (information appears two weeks after the submission due date).
Financial/Grants Management Contact(s)
John Diggs
National Heart, Lung, and Blood Institute(NHLBI)
Telephone: 301-827-8028
Email: diggsjw@nhlbi.nih.gov
Erik Edgerton
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Phone: 301-594-7760
E-mail: erik.edgerton@nih.gov
Gabriel Hidalgo, MBA
National Institute of Dental and Craniofacial Research (NIDCR)
Telephone: 301-827-4630
Email: hidalgoge@mail.nih.gov
Debbie Chen
National Center for Complementary and Integrative Health (NCCIH)
Phone: 301-594-3788
Email: debbie.chen@nih.gov