NIAID is collaborating with the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) to establish a new research consortium within the Human Islet Research Network that will develop and optimize in vitro and in vivo disease models that enable the study of human islet and immune interactions in type 1 diabetes (T1D). Apply through the notice of funding opportunity (NOFO) Human Islet Research Network–Consortium on Modeling Autoimmune Diabetes (HIRN-CMAD) (UG3/UH3, Clinical Trial Not Allowed) if you’re capable of implementing exploratory studies to establish the initial concept of such model systems, and subsequently refining and validating the utility of the models for mechanistic studies of islet-immune interactions.
Research Priorities
This initiative prioritizes T1D models to study early islet dysfunction, autoimmunity initiation, and other metabolic perturbations present during the early stages of disease for which there are still few clinical interventions. Further, we encourage you to include both in vivo and in vitro models in your research plan as complementary approaches to interrogate T1D biology.
Examples of relevant study topics include:
- Fully isogenic modeling of islet cells and immune cells
- Modeling the islet niche
- Changes in islet function and behavior
- Recapitulating autoimmune pathogenesis
- Identification of therapeutic targets and testing
Read the NOFO linked above for full descriptions of these research areas.
Phases and Milestones
The CMAD initiative uses the exploratory/developmental cooperative agreement (UG3/UH3) activity code. Awardees will begin with a UG3 phase of preparatory studies including activities like readying the differentiation of induced pluripotent stem cells (iPSCs) to all required cell components; designing and constructing novel tools and reagents; and successful assembly of the models.
Example objectives for this first phase include:
- Generating human iPSC derived islet organoids from individuals with T1D and pre-T1D, or iPSC-derived organoids from non-diabetic individuals that have been engineered to contain T1D-associated genetic risk variants.
- Incorporating other supportive cells to establish vascularized islet tissue with intra-islet capillaries or innervation, lymphatic drainage, and lymph nodes in vitro and in vivo.
- Developing and validating the tools needed to interrogate how islet dysfunction or destruction of human pancreatic beta cells is initiated.
Following a successful UG3 phase, awardees will transition to a UH3 phase to refine and validate the model designs to demonstrate translational utility. Describe in your application which features of T1D clinical pathophysiology are meant to be replicated, and which translational aspects are to be tested.
Example objectives for the second phase include:
- Demonstrating reproducibility of the models with iPSC lines from non-diabetic and T1D sources; as well as assembly of a fully isogenic human T1D model.
- Cross-validating T1D model endpoints with clinical measures in humans or physiologically relevant human tissues.
- Identifying therapeutic targets and conducting preclinical efficacy testing of candidate therapeutics to prevent, halt, or reverse T1D.
To determine whether each CMAD recipient may progress to the UH3 phase, NIH staff will assess whether the project met its UG3 phase milestones. You will define the milestones for your project when you apply, and if selected for award then NIH staff will negotiate and agree to a final set of UG3 milestones to be listed in your Notice of Award.
Other Project Priorities
If you propose any of the following studies in your application, NIDDK and NIAID will consider your application nonresponsive and not review it:
- Developing 3D tissues specifically for transplantation as a therapeutic modality
- Engineering nonhuman tissue models
- Developing simple cell mixtures and clusters in static incubation formats
- Developing systems for which an informative animal model already exists
- Clinical trials
Additionally, ensure that your project will not use transformed or immortalized cell lines except for preliminary, proof-of-concept studies. In choosing a source of human cells and tissues, you should use high-quality repositories, biobanks, and procurement networks.
Administrative Details
The maximum project period is 5 years, which includes a maximum of a 2-year UG3 phase and a maximum of a 3-year UH3 phase. Your budget cannot exceed $750,000 in annual direct costs for both the UG3 and UH3 phases.
If you plan to apply, promptly send a letter of intent to allow peer review staff to estimate the potential review workload and plan the review; specifically, NIDDK’s Dr. Elena Sanovich at Elena.sanovich@mail.nih.gov or 301-594-8886.
The deadline to apply is March 20, 2024, by 5 p.m. local time of the applicant organization.
Direct questions to Dr. Maggie Morris Fears, NIAID’s scientific/research contact for this NOFO, at maggie.morrisfears@nih.gov or 301-761-5444.