Key Dates

Related Announcements

• May 05, 2020 - Research Project Grant (Parent R01 Basic Experimental Studies with Humans Required). See NOFO PA-20-184.
• May 05, 2020 - NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed). See NOFO PA-20-185.
• May 10, 2022 - Dissemination and Implementation Research in Health (R01 Clinical Trial Optional). See NOFO PAR-22-105.

Issued by

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

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

• Develop studies for early diagnosis of LD as well as epidemiologic studies to determine the prevalence of lymphedema and other LDs. Investigate the impact on women and minorities, in addition to health and gender disparities.
• Develop studies for early diagnosis that focus on reducing disparities and increasing access to diagnostic instruments/measures.
• Develop studies for early diagnosis that include community and system-level data reflective of social determinants of health including, for example, the built environment, health insurance access, food deserts, to reveal targets for multilevel preventive interventions.
• Discovery of lymphatic-specific pharmacotherapies and novel treatments with low off-target effects for best clinical translation.
• Develop studies that surface patient preferences for and ability to engage in various promising treatment types to increase implementability and uptake of novel treatments
• Develop targeted treatments to modulate lymphatic function, profile lymphatic cell heterogeneity, and characterize the role of the lymphatic vasculature in immune activation during cardiovascular and pulmonary diseases. For example, targeted modulation of lymphatic function to increase lymphatic contractility, decrease lymphatic leakiness, or otherwise improve lymphatic transport capacity.
• Develop bio-behavioral markers to measure the relationship between health-related quality of life (HRQOL) and LD, including markers to measure the impact of therapeutic interventions, especially long term outcomes.Consideration of the development of disseminable markers or testing proxies of markers that are salable, particularly in under-resourced settings, is of interest.
• Foster research on quality of life, including analyses of LD comorbidities using retrospective data to better understand LD burden, which may surface novel treatments that are efficient for patients in aligning whole-person care.
• Develop studies to explore functional roles of the lymphatic system (lymphatic vasculature and factors) in organogenesis and tissue repair (e.g., cardiac growth and post-MI repair). For example, studies to better understand the cellular and molecular changes in LS due to injuries that can be harnessed in combination with targeted therapies.
• Compile the current knowledge of lymphatic anatomy using current imaging technology to provide updates to the existing anatomy, and leveraging HuBMAP consortium data. Develop studies to determine how anatomic differences may contribute to LD, including lower-extremity lymphedema.
• Develop new animal models, including lymphatic muscle cell- and endothelial cell-specific Cre drivers, and novel methods to specifically study lymphatic muscle cell function, contractility, and valvular function. Using technologies like CRISPR/Cas9 to develop large animal models of lymphatic dysfunction to better represent the clinical scenario are of interest.
• Elucidate the process of lymphangiogenesis, including lymphatic valve formation, during the formation of functional lymphatic vessels. Explore the beneficial and adverse effects of lymphangiogenesis in LD development.
• Identify new genes controlling the earliest steps of lymphatic endothelial cells (LEC) specification, causative mutations in novel genes, molecular information and cell-type markers to specifically perturb the relevant cell population.
• Profile LEC and lymphatic muscle cell heterogeneity; analyze gene expression signatures and their function; mechanisms that maintain lymphatic vessel homeostasis, and plasticity of LEC phenotype and its regulation by metabolic factors using advanced omics and spatial mapping techniques.
• Explore lymphatic response to aging, chronic inflammation, and other environmental cues using technologies such as spatial transcriptomics to identify novel lymphatic endothelial cell markers.
• Explore the link between lymphatic vessels and stem cell activity during health and disease development to identify new axes that can be targeted to enhance tissue repair and regeneration.
• Understand effects and mechanisms of lymphatic dysfunction in risk and progression of cardiovascular diseases (e.g., lipoprotein-cholesterol removal from atherosclerotic plaques, lymphatic smooth muscle contractility associated pathophysiology of hypertension, pathophysiology of tissue- and organ-specific congestion in heart failure) and pulmonary diseases (e.g., pathogenesis of sepsis, COPD, asthma, IPF, pulmonary fibrosis, and lung transplantation).
• Investigate disparities in the effects of lymphatic dysfunction in risk and progression of cardiovascular and pulmonary diseases.

NIAMS

• Skeletal muscle lymphatics and muscle function in health and disease
• Synovial lymphatics in osteoarthritis and rheumatoid arthritis
• Lymphatics in systemic sclerosis
• Skin lymphatics: development, interaction with skin vasculature and other skin components
• Role of lymphatics in skin repair and regeneration
• Lymphedema and its impact on skin function

NIDCR

• Identify mechanisms of crosstalk between lymphangiogenesis and immunity that modulate the tissue microenvironment to maintain oral/craniofacial health towards resolution of wound healing following infection, chronic inflammation, and cancer.
• Explore cellular and molecular mechanisms and biomarkers of head and neck cancer metastasis through cervical lymph nodes, and relative risk measurements of developing secondary lymphedema in head and neck cancer survivors caused by surgery, radiation, and other treatments.
• Study immune modulation in peripheral lymphoid system (including tonsils, peripheral lymph nodes, and mucosal lymphoid tissues) and tissue-resident immune cells and stem cells.
• Clarify the role of lymphatics in oral infections (submandibular lymph nodes in viral infections), inflammation (pulpitis, edema) and temporomandibular joint disorders.

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.

• PA-20-184 Research Project Grant (Parent R01 Basic Experimental Studies with Humans Required)
• PA-20-185 Research Project Grant (Parent R01 Clinical Trial Not Allowed)
• PAR-22-105 Dissemination and Implementation Research in Health (R01 Clinical Trial Optional)

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:

• For funding consideration, applicants must include NOT-HL-23-099 (without quotation marks) in the Agency Routing Identifier field (box 4B) of the SF424 R&R form. Applications without this information in box 4B will not be considered for this initiative.

Applications nonresponsive to terms of this NOSI will not be considered for the NOSI initiative.

Inquiries

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