July 18, 2022
PA 20-185 - NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed)
National Heart, Lung, and Blood Institute (NHLBI)
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
National Institute of Neurological Disorders and Stroke (NINDS)
The purpose of this NOSI is to encourage research grant applications focused on respiratory complications of the muscular dystrophies. This includes further elucidation of respiratory phenotypes in humans; research to optimize pulmonary function testing and existing respiratory therapies in humans; and mechanistic and translational research, including in vitro and in animal models, that examines respiratory muscle response to gene therapies and other therapeutic strategies in the muscular dystrophies.
Muscular dystrophies are a heterogenous group of inherited muscular diseases that include Duchenne muscular dystrophy (DMD), facioscapulohumeral muscular dystrophy, myotonic dystrophy, limb-girdle muscular dystrophies, congenital muscular dystrophies and other types of muscular dystrophy, all of which invariably lead to progressive weakness and respiratory decline. Advances in clinical pulmonary care have delayed the onset of respiratory failure and increased the life span in some of these conditions like DMD. However, acute respiratory failure from pneumonia, aspiration events, Acute Respiratory Distress Syndrome (ARDS) with prolonged stays in the intensive care unit, and chronic respiratory insufficiency with need for invasive and non-invasive support remain some of the leading causes of mortality and morbidity in affected individuals. Cardiopulmonary interactions in the context of the progressive obstructive and/or restrictive respiratory disorders in these conditions also need elucidation.
The devastating respiratory consequences of the muscular dystrophies lead to progressive functional impairment, posing a significant burden on individuals with these conditions that greatly impairs the duration and quality of their lives. While significant advances in mitigating heart failure and conduction abnormalities associated with the dystrophies have contributed to increased longevity in these patients, disordered mechanisms of central ventilatory control, mechanisms and early diagnosis of pulmonary decline, optimization of respiratory protocols for anticipating and mitigating deterioration in respiratory function in humans, and effects of gene therapy and other therapeutic strategies on respiratory function in animal models still need elucidation. This NOSI is aimed at enhancing research on the respiratory complications of the muscular dystrophies, including understanding the mechanisms, natural history and causes of heterogeneity and optimizing treatment and prevention of respiratory complications in these conditions. This NOSI invites studies in animal models of muscular dystrophy and observational studies in patients with muscular dystrophies; however, clinical trials are excluded.
This NOSI calls for detailed respiratory phenotyping to elucidate the trajectory, early biomarkers, and outcome measures of decline in respiratory function to facilitate early intervention, which has been shown to delay mortality and significantly improve Health Related Quality of Life (HRQOL). Additionally, research on optimizing prediction and quantification metrics of the impact of existing interventions on pulmonary function is considered responsive to this NOSI. Also encouraged are studies that are aimed at optimizing pulmonary function testing to better address physiological variations in the different dystrophies related to upper airway obstruction due to weakness (both when awake and during sleep); research on early diagnosis of obstructive and restrictive lung disease in the setting of increased thoracic compliance and decreased elastic recoil; and investigations to understand inspiratory strength training and its role in improving pulmonary function.
Individuals with muscular dystrophies exhibit sleep-disordered breathing, underscoring the need to better understand mechanistic and clinical issues of upper airway obstruction and central ventilatory control such as obstructive sleep apnea, and the relatively blunted response to hypoxemia and hypercarbia observed in patients with Myotonic Dystrophy and other dystrophies. The observed heterogeneity in pulmonary decline in the different dystrophies and in different individuals with the same condition need to be better understood through studies of pulmonary disease trajectory in longitudinal cohorts. Race, ethnicity, socioeconomic status and access to appropriate and timely health care have been shown to result in differential outcomes, demonstrating a need for concerted efforts to enhance equity by encouraging the participation of understudied racial and ethnic minority groups and NIH-designated populations that experience health disparities and those living in rural areas.
This NOSI is a call for research that will address barriers to participation in research in NIH-designated populations that experience health disparities and/or other understudied populations in the muscular dystrophies by employing strategies and resources to reduce obstacles and encourage outreach to these populations living with muscular dystrophies, as described in the website, https://www.mdcc.nih.gov/strategies-promote-diversity-muscular-dystrophy-research-participation. To enhance awareness and participation in research among understudied population, resources built by NIH-wide Community Engagement Alliance (CEAL) against COVID-19 disparities could also be leveraged by investigators in the muscular dystrophy space, building upon proven strategies.
This NOSI also encourages research to better characterize respiratory consequences of targeted experimental gene therapy to respiratory muscles in animal models. A better understanding of respiratory implications would guide appropriate targeting of therapies when gene therapy becomes available for humans with these conditions. The NHLBI Gene Therapy Resource Program (GTRP) could be leveraged during the application phase and post-award to accelerate research in studying the effects of gene therapy targeted to the respiratory muscles in animal models.
In summary, this NOSI encourages scientists in the space of muscular dystrophies to investigate respiratory function, and scientists in sleep-disordered breathing, ventilatory control and respiratory pathobiology and physiology to bring their expertise to research in the respiratory implications of these neuromuscular diseases. There is a possibility of cross-collaboration between disciplines that will bring synergy to research in diseases that are primarily neuromusculoskeletal with a profound and debilitating impact on the patient’s quality of life, largely due to pulmonary limitation. This is an opportunity to understand ways to effectively help patients remain in optimal pulmonary health for responding to currently available therapies, and potentially to future innovative therapies that are in the pipeline.
Suggested Examples of Research Areas under this NOSI:
Factors contributing to heterogeneity of outcome in humans
- Research on better implementation and adherence to current guidelines for respiratory evaluation and care
- Understanding the impact of racial disparities, including disparities in access to health care (e.g., poverty, rural areas, racial and ethnic minorities), on pulmonary outcomes and quality of life
Current testing and therapies in humans
- Development of biomarkers and/or outcome measures to predict and monitor pulmonary decline
- Biomarkers of the neural control of respiration
- Optimization of pulmonary function testing and devices in humans with muscular dystrophies
- Upper airway obstruction and sleep apnea in adults and children
- Optimization of home ventilation strategies
- Adherence to inspiratory and expiratory muscle strength training
- Longitudinal studies to assess the impact of timely respiratory care, including treatments for sleep- disordered breathing associated with the dystrophies
- Research on effective training for caregivers
Mechanistic and translational science
- Markers and metrics of respiratory decline in animal models and humans
- Cardiopulmonary interactions in animal models and humans
- Central control of respiratory systems
- Mechanisms and treatments for sleep-disordered breathing
- Mechanisms of diaphragmatic dysfunction in the muscular dystrophies
- Targeted delivery of gene therapies to the diaphragm in animal models and their effect on respiratory function
Application and Submission Information
This notice applies to due dates on or after September 25, 2022 and subsequent receipt dates through January 7, 2025.
Submit applications for this initiative using one of the following funding opportunity announcements (FOAs) or any reissues of these announcement through the expiration date of this notice.
- PA-20-185 - NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed)
All instructions in the SF424 (R&R) Application Guide and the funding opportunity announcement used for submission must be followed, with the following additions:
- For funding consideration, applicants must include NOT-HL-22-025" (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.
Scientific/Research Contact(s)
Aruna Natarajan, MD, PhD
National Heart Lung and Blood Institute (NHLBI)
Telephone: 301-827-0180
Email: [email protected]
Bettina Buhring, PhD
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Telephone: 301-827-8626
Email: [email protected]
Glen H. Nuckolls, Ph.D.
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-5745
Email: [email protected]
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)
Kimberley Stanton
National Heart Lung and Blood Institute (NHLBI)
Telephone: 301-827-8054
Email: [email protected]
Margaret Young
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Telephone: 301-642-4552
Email: [email protected]
Chief Grants Management Officer
National Institute of Neurological Disorders and Stroke (NINDS)
Email: [email protected]
and Human Services (HHS)
