Internal Deadline: Contact RII.
LOI: October 16, 2023
External Deadline: November 15, 2023
Award Type: Cooperative Agreement
Estimated Number of Awards: 5
Anticipated Award Amount: Application budgets are limited to $300,000 in direct costs in FY 2024, and to $450,000 in direct costs per year in FYs 2025-2029. Budgets need to reflect the actual needs of the proposed project.
Who May Serve as PI: Standard NIH requirements.
Process for Limited Submissions
PIs must submit their application as a Limited Submission through the Research Initiatives and Infrastructure (RII) Application Portal: https://rii.usc.edu/oor-portal/. Use the template provided here: RII Limited Submission Applicant Template
Materials to submit include:
- (1) Two-Page Proposal Summary (1” margins; single-spaced; standard font type, e.g. Arial, Helvetica, Times New Roman, or Georgia typeface; font size: 11 pt). Page limit includes references and illustrations. Pages that exceed the 2-page limit will be excluded from review. You must use the template linked above.
- (2) CV – (5 pages maximum)
Note: The portal requires information about the PIs in addition to department and contact information, including the 10-digit USC ID#, Gender, and Ethnicity. Please have this material prepared before beginning this application.
The goal of this Notice of Funding Opportunity (NOFO) is to enhance our understanding of the temporal onset of GI symptoms in PD and changes in gut-brain communication that can be used to leverage the potential role of the GI tract in the pathogenesis and progress of PD and to improve patient diagnosis, care, and outcomes. To achieve this objective, two different types of centers will form a consortium. This NOFO invites cooperative agreement applications for multiple Gastroenterology Neurology Research Centers (GNRC) that would work together with a biospecimen repository and Coordinating and Data Management Center (CDMC) described in the companion NOFO, RFA-DK-23-001. Although a CDMC and GNRC may exist at the same institution, the two types of centers require separate applications, and these will be evaluated independently by the criteria outlined below. The CDMC and GNRCs will work together cooperatively as a Consortium (GBPDC) to address these research objectives: 1) to collect prospective cross-sectional and longitudinal participant biospecimens with temporally coordinated evaluations of GI and neurological functions to better characterize the phenotype of PD patients with, versus those without, GI symptoms; 2) to elucidate the biological processes and pathways relevant to the role of the GI tract in pathogenesis and progress of PD with regard to disease heterogeneity or severity; 3) to characterize GI symptoms, pathology, and gut-brain communication in PD to detect early and longitudinal changes in gut function and activity that correspond to the development or progression of PD motor symptoms; 4) to identify possible novel gut-based functional/ molecular/other biomarkers, diagnostic tools, and therapeutic targets; and 5) to investigate the impact of neuroimmune interactions in the GI tract on gut-brain communication and PD risk. Studies should focus on PD patients with and without overt GI symptoms and may include patients with GI pathologies (e.g., genetic markers, like LRRK2, associated with PD and chronic GI inflammation) who may be at higher risk for PD. Studies must have age-matched healthy controls. Participant enrollment targets should be supported by documentation of institutional availability, include recruitment and retention strategies that may be specific to the target population, and be sufficient to power the proposed functional and molecular analyses. While participant enrollment and sample collection and analyses are critical components of the consortium, applications should also include pathobiological mechanism-based objectives. Projects submitted to this NOFO should include expertise in both areas of clinical gastroenterology and clinical neurology with documented accomplishments in their field. A previous or ongoing collaboration or record of collaboration is not required.
Specific Areas of Research Interest
Areas of research interest include, but are not limited to:
- Prospective recruitment and phenotypic evaluation of PD patients that consider the heterogeneity of the disease with regard to occurrence of prodromal GI dysfunction, symptom onset, and disease progression to generate a multi-sample repository of participant biosamples and clinical data. Analyses may include environmental exposure data collection for the identification of known (e.g., alpha-synuclein) or putative GI-based or circulating biomarkers; changes in specific populations of enteric neurons, particularly as they relate to autonomic function or CNS neuronal function; alterations in the GI microbiome or microbial metabolites; or other molecular mechanisms that predict or contraindicate patient stratification, correlate with specific symptoms of prodromal GI dysfunction, or associate with disease severity in PD.
- Prospective participant recruitment and evaluation for longitudinal studies of temporal, region-specific, cellular, molecular, or other changes in the GI tract in PD that correspond to onset or progression of GI symptoms, altered gut-brain communication, evolution and/or progression of motor symptoms. These studies should have multipoint time sampling (e.g., blood, stool, biopsy tissue) and protocols will be harmonized across the GBPDC. The timing and number of samples collected each year should be consistent with the proposed GI- and neurology-based objectives.
- Participant analyses should be complemented by focused mechanistic studies using participant biospecimens that may be designed in parallel with animal models of PD, in-vitro, or other experimental (e.g., induced pluripotent stem cells) systems. These studies should provide clinically relevant mechanistic insights by leveraging state-of-the-art technologies to perform functional, imaging, molecular, or multi-omic assessments including multi-modal single-cell analyses, Cite-seq for cell immunotyping, or other specialized techniques as required by specific projects.
- Multi-omic analyses of the composition and activities of the intestinal microbiome in participants to identify relationships between microbiome composition and the phenotype, onset, duration, risk and severity of GI dysfunction in PD.
- Pilot analyses of pre-existing clinical data and biological samples from within and beyond the GNRC, either by request or through collaboration, to determine changes in GI function, gut-brain molecular pathways, gut biomarkers, or other factors that predict the course of PD. This could involve integration of multi-level datasets and/or use of novel molecular or multi-omic approaches to identify and characterize differences in the GI tract of PD patients that predict onset or existence of GI symptoms, disease progression or severity, sensory or motor function in gut-brain communication and would be leveraged to inform longitudinal studies.
- Application of novel technologies such as scalable multi-omic tools for data analyses and integration; assessment of gut brain bidirectional communication in PD patients through advanced neuroimaging of brain and gut or tests of autonomic function; studies that integrate enteric nervous system function, epithelial cell biology, and mucosal immunology in PD patients. If neuroimaging is proposed as part of the study, imaging protocols should match those followed by the Alzheimer’s Disease Neuroimaging Initiative (https://adni.loni.usc.edu/methods/) as closely as possible and also meet the requirements set by NIDDK Central Repository (NIDDK-CR).
- Connections or interactions between dopaminergic or other relevant neurotransmitter circuitry in the brain and the corresponding circuitry in the gut and the initiation or progression of motor or non-motor symptoms.
Organization and Management of the Gastroenterology Neurology Research Centers (GNRC) of the Gut-Brain Communication in Parkinson’s Disease Consortium (GBPDC)
The NIDDK IBDGC will consist of up to five Gastroenterology Neurology Research Centers (GNRC) and one Coordinating and Data Management Center (CDMC). This NOFO invites applications for the GNRC components of the GBPDC. The CDMC is fully described in the companion NOFO, RFA-DK-23-001. Applicants are strongly encouraged to form a multidisciplinary team of investigators (e.g., clinical and research gastroenterologists, clinical and research neurologists, enteric neurobiologist, neuroscientists, computational scientists, etc. as appropriate) and additional necessary personnel, such as a research coordinator and staff research associates. Applicants may also establish additional collaborations to ensure inclusion of appropriate expertise in the use of the proposed clinical and experimental techniques and analytical methods.
This program also encourages applications that would support diverse teams of investigators, including team members that are underrepresented in the biomedical, behavioral, or clinical research workforce. Such individuals include but are not limited to those from underrepresented racial and ethnic groups, those with disabilities, and those from disadvantaged backgrounds. Research shows that diverse teams working together and capitalizing on innovative ideas and distinct perspectives outperform homogenous teams. Scientists from diverse backgrounds and life experiences bring different perspectives, creativity, and individual enterprise to address complex scientific problems. There are many benefits that flow from a diverse NIH-supported scientific workforce, including: fostering scientific innovation, enhancing global competitiveness, contributing to robust learning environments, improving the quality of the research, advancing the likelihood that underserved or health disparity populations participate in, and benefit from health research, and enhancing public trust. Please see NOT-OD-20-031 for details.
Each GNRC will be actively involved in the recruitment and evaluation of PD patients and age-matched controls. GNRC may include one or more institutions in order to conduct center-specific studies that take advantage of the experience and expertise in the diagnosis, management, and care of PD patients. The GNRCs will recruit participants into the study and conduct phenotypic evaluations, cross-sectional, and longitudinal follow-up of these subjects. Inclusion and exclusion criteria for PD subject enrollment must be clearly defined, and the applicant must describe how many follow-up visits are expected. All applicants are encouraged to consider strategies that include recruitment and inclusion of individuals from diverse populations. .
The GNRCs may collect a variety of biological samples from participants (e.g., cerebrospinal fluid (CSF), saliva, stool, blood, plasma, serum, intestinal biopsies). Collection of biological specimens should conform to the specimen collection protocols of the NIDDK-CR (https://repository.niddk.nih.gov/pages/for_submitters/) and NINDS BioSEND Repository (https://biosend.org/expertise.html). Applicants are required to collect blood for DNA at the initial visit, and to collect blood for RNA, serum, and plasma annually. Where applicable, applicants will be expected to collect CSF and GI biopsies at least once and are strongly encouraged to collect these samples annually. Costs for biospecimen kits, processing, and storage must be included in the application budget, and applicants are advised to contact the NIDDK (NIDDK-CRadmin@niddk.nih.gov or NIDDK-CRsupport@niddk.nih.gov) Repository staff for a quote. As an alternative, the GBPDC may subcontract biospecimen processing to a commercial provider of these services if needed. Applicants will be required to collect standard GBPDC clinical assessments for PD subjects (e.g., https://pdbp.ninds.nih.gov/researcher/clinical-assessments#lewy-body-dementia-forms) and should budget for any assessments they may need to purchase. Additional clinical, imaging, and/or biospecimen measures may be proposed if needed and justified, and the applicant should provide details on collection methods, protocols and whether these additional assessments will be shareable through the GBPDC or through other repositories. Applicants proposing to use induced pluripotent stem cells (IPSC) line derivation should include an appropriate budget for these studies.
The GNRCs will be expected to conduct independent analyses (enlisting support from the CDMC, as appropriate), to participate in collaborative projects with other GNRCs, and to allocate resources and personnel for the performance of both independent and collaborative studies. GNRCs will be expected to share data and participant specimens with other GBPDC centers, as appropriate and consistent with program goals. In addition, all applications must follow GBPDC protocols for data and biospecimen collection in subjects with PD and controls. NIDDK-CR requires Limited Data Sets devoid of direct identifiers and not considered fully de-identified (https://privacyruleandresearch.nih.gov/pr_08.asp). GNRCs must work in concert with the CDMC to implement procedures for uniform data collection, handling and transmittal, as well as data audits and other data quality control procedures, as determined by the study protocol to include establishment of a single IRB and Global Unique Identifier (GUID) solution for participant data management. GUIDs are required for each GNRC participant and the NIDDK has joined the NIH-centralized GUID server for participant data management across institutes and studies. The GUID allows data to be associated with a research participant without exposing or transferring personally identifiable information (PII) and/or protected health information (PHI). GNRCs will transmit phenotypic, genetic, microbiome, and other data to databases maintained by the CDMC (described in the companion NOFO, RFA-DK-23-001).
Annual milestones should be included in the application. Milestones are goals that create go/no-go decision points in the project and must include clear and quantitative criteria for success. Milestones should address timely subject recruitment and complete/accurate data and biospecimen submission. These awards will be managed as cooperative agreements and funding of non-competing award years will depend on milestone accomplishment. Projects that do not comply with terms, conditions, and established milestones of the award and of this program may be terminated early.
GNRC members will staff the operational committees of the GBPDC (e.g., Steering Recruitment, Phenotyping, Analysis, etc.), thereby collaborating on the design of joint projects and the establishment of uniform procedures and policies.
Visit our Institutionally Limited Submission webpage for more updates and other announcements.