Key Dates

Related Announcements

PA-20-185 - NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed)

PA-20-195 - NIH Exploratory/Developmental Research Grant Program (Parent R21 Clinical Trial Not Allowed)

Issued by

National Institute of Neurological Disorders and Stroke (NINDS)

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Purpose

Gastrointestinal (GI) complications in children and adults with neurodevelopmental disorders have drawn attention to gaps in understanding their causes and treatment. GI dysfunction is particularly common in individuals with neurodevelopmental disorders such as autism, Fragile X syndrome, and Rett syndrome, as well as chromosomal disorders such as Down syndrome. GI disorders in these conditions can include gut malformations present at birth (such as pyloric stenosis or Hirschsprung disease) but also functional issues such as feeding problems, gastro-esophageal reflux disease (GERD), cyclic vomiting, delayed gastric emptying, diarrhea, bloating, celiac disease, irritable bowel symptoms, and constipation leading to encopresis, incontinence, and stool impaction. These GI issues may be associated with severe nutritional deficiencies, weight loss, and failure to thrive. GI symptoms are reported in between 23-70% of individuals with autism, a rate ~ 8 times higher than in the general population, with similar rates in individuals with other less common forms of intellectual and developmental disabilities (IDD) (Holingue et al., Autism Res 2018:11:24-36). Unfortunately, mechanisms to accurately diagnose GI conditions in this population are limited, and tailored treatments to address them are almost nonexistent, particularly since clinical trials for IDD populations are rare.

Symptom management is often only partially effective with currently available treatments, and people with neurodevelopmental disabilities may not perceive pain and discomfort in a typical way or they might have impaired communication about the gastrointestinal symptoms they experience, making diagnosis a challenge for some. Their inability to articulate these symptoms may result in irritability, behavioral outbursts, and worsening of symptoms. Many families report that GI issues significantly negatively impact quality of life for these individuals and their family members, and that these symptoms can be a major cause of family distress. Thus, effective treatments for GI issues may address some of the observed behavioral issues in this population.

However, there is increasing evidence pointing to a correlation between the gut and the brain, and it stands to reason that disorders that affect the function of the brain would impact the function of the “brain” in the gut—the enteric nervous system. There has also been recent interest in the function of the gut microbiome in human health and disease, particularly the role of gut microbes in this gut-brain connection. Current research findings suggest that gut microbes affect neuronal circuits involved in motor control and anxiety behavior through signaling mechanisms. Recent research has also begun to focus on potential immunological and inflammatory factors affecting gastrointestinal function and complications related to feeding tubes. Moreover, the microbiome may play a role in pathogenesis, disease modification, and potentially, as a therapeutic target. The underlying role of enteric nervous system development and function in these disorders has not been fully characterized.

The National Institute of Neurological Disorders and Stroke is issuing this Notice to highlight interest in receiving grant applications focused in the following area(s) to support basic, translational, and/or clinical research on the causes, diagnosis, prevention, or treatment of gastrointestinal dysfunction in people with neurodevelopmental disorders. Areas of programmatic interest include, but are not limited to:

• Identifying the etiology of these conditions, including mechanisms involving central, peripheral, and enteric nervous systems; brain/gut interactions; immunological or neuroimmunological factors; or other genetic or environmental susceptibility factors
• Understanding disease mechanisms (in the gastrointestinal system) as they are influenced by the underlying neurodevelopmental disorder
• Developing model systems (e.g. animal, cell or organ culture) to study pathogenesis and serve as screening platforms for more reliable diagnosis, prevention, or therapy development
• Accurately diagnosing these conditions, including imaging- or electrophysiology-based techniques

• Developing biomarkers (diagnostic, prognostic, predictive and pharmacodynamic/response) for use in clinical studies/trials for these conditions or developing pharmacodynamic biomarkers for use in preclinical therapy development for the same conditions.
• Developing and validating clinical outcome assessment measures (including patient-reported outcomes) for use in clinical trials.

• Developing treatments, including potential novel therapies or drug/biologic repurposing

The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) is interested in receiving grant applications focused in the following area(s) to support basic, translational, and/or clinical research on the causes, diagnosis, prevention, management, or treatment of gastrointestinal dysfunction in people with neurodevelopmental disorders, in particular, in children. Areas of programmatic interest include, but are not limited to:

• Identifying the etiology of these conditions, including mechanisms involving central, peripheral, and enteric nervous systems; brain/gut interactions; impact of congenital GI anomalies and later functional intestinal disorders; gut motility and function; neuroendocrine function; immunological or neuroimmunological factors; or other genetic or environmental susceptibility factors (such as socioeconomically disadvantaged populations)
• Understanding disease mechanisms (in the gastrointestinal system) as they are influenced by the underlying neurodevelopmental disorder, including the correlation of GI symptoms with observed behavioral problems and/or other co-morbidities
• Understanding the role of the gut microbiome on GI function and motility
• Developing technologies and devices (such as smart pills) to noninvasively measure GI motility, peristalsis and function, including imaging- or electrophysiology-based techniques and noninvasive approaches, in order to accurately diagnose these conditions in pediatric populations and those that are nonverbal and/or have limited cognitive function
• Developing biomarkers (diagnostic, prognostic, predictive, or pharmacodynamic/response) and outcome measures for use in preclinical therapy development or clinical studies of these conditions
• Understanding the role of dietary interventions, behavioral therapy,0 and/or physical activity in these GI disorders
• Developing treatments, including potential novel therapies or drug/biologic repurposing

Application and Submission Information

This notice applies to due dates on or after October 5, 2021 and subsequent receipt dates through July 16, 2024.

Submit applications for this initiative using one of the following funding opportunity announcements (FOAs) or any reissues of these announcements through the expiration date of this notice.

• PA-20-185 - NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed)
• PA-20-195 - NIH Exploratory/Developmental Research Grant Program (Parent R21 Clinical Trial Not Allowed)

All instructions in the SF424 (R&R) Application Guide and funding opportunity announcement used for submission must be followed, with the following additions:

• For funding consideration, applicants must include “NOT-NS-22-003” (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.

To ensure application assignment to either NINDS or NICHD, please use the NIH Assignment request form to indicate to which institute your applications should be directed. (https://grants.nih.gov/grants/how-to-apply-application-guide/forms-e/general/g.600-phs-assignment-request-form.htm)

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

Inquiries

Scientific/Research Contact(s)

Adam L. Hartman, MD
National Institute of Neurological Disorders and Stroke
Telephone: 301-496-9135
Email: adam.hartman@nih.gov

Melissa Parisi, MD, PhD
Eunice Kennedy Shriver National Institute of Child Health and Human Development
Telephone: 301-435-6880
Email: parisima@mail.nih.gov