This FOA invites new applications to participate in the Human Islet Research Network-Consortium on Human Islet Biomimetics (HIRN-CHIB). NIDDK will support the development of a microphysiological system (MPS) that allows the study of interactions between primary human islets or assembled islet spheroids (organoids made up of human beta/alpha/delta/other cells) and immune cells within a 3D microenvironment to mimic aspects of the autoimmune process and its regulation. The ultimate goal will be to create an in vitro human disease model(s) that could recapitulate some aspects of the complex pathophysiology of Type 1 diabetes (T1D), by using T1D patient-derived islets [created using induced pluripotent stem cells (iPSCs)] combined with autologous immune components. CHIB is already part of HIRN, whose overall mission is to support innovative and collaborative translational research to understand how human beta cells are lost in T1D, and to find innovative strategies to protect and replace functional beta cell mass in humans.
The need for high quality, well-characterized isogenic/patient-derived iPSC lines and standardized differentiation procedures for achieving maturation of beta cells and other pancreatic islet subtypes is a critical step for HIRN-CHIB. Expansion of islet chip capabilities such as multiplexed hormone sensing, instrumentation and systems engineering for robust control of fluidic and biochemical cellular microenvironments, the integration of bioanalytical systems, and incorporation of novel microfluidic systems that permit the controlled introduction of both stimuli and cells, coupled with the assessment of their impact on islet stress and function will be needed. CHIB will lay the groundwork for establishing reproducible and translatable MPS platforms that are capable of modeling key aspects of T1D pathophysiology. An essential feature of HIRN-CHIB will be a multidisciplinary approach that brings together basic science experts and physician scientists in stem cell biology, bioengineering, immunology, islet biology and T1D.
Funds from the NIDDK will be made available through the UG3/UH3 cooperative agreement award mechanism. The UG3 phase should include sensitive on-chip assays that measure normal islet function. The UG3/UH3 phase should use primary human tissues to help characterize both the maturity and adult function of iPSC-derived tissues, and by the end of the UH3 phase, assembly of an iPSC-based MPS model of T1D should be well-underway.
CHIB has focused on deriving engineered platforms that support the survival, maintenance and function of cadaveric human islets for periods of time up to 4 weeks. Interdisciplinary teams have combined technological advances and knowledge in islet biology, stem cell biology, and microengineering to accelerate progress in creating a human islet biomimetic or MPS. CHIB has generated a network of blood vessels around human islets in microdevices to deliver oxygen, nutrients and promote islet health, developed extracellular matrices that support islet function and survival, and continues to integrate robust, reproducible, and sensitive assays to monitor islet function (such as dynamic insulin secretion). These platforms will enable future investigations focused on how human islets and immune components interact, and provide insight as to how beta cells are lost in T1D. The Consortium on Modeling Autoimmune Interactions (CMAI), also part of HIRN, has been working on the development of “in vivo” humanized models of T1D, thus, the establishment of the in vitro platforms proposed here may support and complement research that is being advanced.
Research Objectives and Scope
UG3 Phase Objectives (up to 2 years)
The UG3 Phase should develop platform technology that allows the study of interactions between primary human islets/re-aggregated islet spheroids (organoids) and immune cells involved in the T1D inflammatory/autoimmune process, and its regulation within a 3D environment.
- Devices should include the addition of flow for dynamic perifusion, with controlled inputs and outputs;
- Incorporation of 3D technology to enable the controlled and targeted temporal and spatial introduction and removal of soluble factors or cellular components;
- Incorporation of other supportive cells (endothelial cells, non-endocrine cells within the islet and/or tissues);
- Introduction of reporter systems that will provide information in real-time to monitor beta cell function and health, as well as immune cell activation and effector/regulatory function;
- Inclusion of primary human beta/alpha/other islet subtypes and immune populations involved in promoting islet inflammation and antigen-specific interactions;
- Integration of sensitive and robust assays for insulin and glucagon secretion, as well as assays capable of measuring the health and function of other cells operating within the islet microenvironment;
- Inclusion of a well-conceived plan to develop a human iPSC-based MPS consisting of human beta, alpha, and other islet subtypes, CD8/CD4/DC/other relevant immune components, and supportive cells such as endothelial cells, mesenchyme, and neural components, etc. This plan should include a strategy to achieve maturation and glucose-responsiveness of human iPSC-derived beta cells in a vascularized organoid platform.
UH3 phase Objectives (up to 3 years)
HIRN-CHIB’s long-term goal is to develop personalized chips for studying T1D. To work towards this goal, an MPS to study islet/immune interactions using an autologous T1D patient based platform will require:
- Generation of human iPSC derived islet organoids from individuals with T1D and pre-T1D, or iPSC-derived organoids from normal individuals that have been engineered to contain T1D-associated genetic risk variants;
- Integration of human iPSC components into the platforms;
- Cross-validation of T1D model endpoints with clinical measures in humans.
All projects will be milestone-driven with clear go/no-go criteria that are quantifiable and milestones with a timeline, must be included in the application. Prior to funding an application, the Program Official will contact the applicant to discuss the proposed UG3 and UH3 milestones and any changes supported by NIH staff or the NIH review panel. The Program Official and the applicant will negotiate and agree on a final set of approved UG3 milestones which will be specified in the Notice of Award. These milestones will be the basis for judging the successful completion of the work proposed in the UG3 stage and progress toward interim milestones in the UH3 stage. Only UG3 projects that meet their milestones will have an opportunity to move to the UH3 phase. UH3 milestones will be the basis for judging progress towards and completion of interim milestones in the UH3 phase.
Studies of interest for both the UG3 and UH3 phases will examine key cellular and environmental factors controlling autoimmune killing of human cadaveric islets/iPSC-generated islet cell populations. These studies could include the following but are not limited to:
- Identify potentially novel therapeutic targets to prevent beta cell killing or modulate Cytotoxic T Lymphocyte (CTL) effector mechanisms;
- Examine the influence of HLA expression in beta cells on immune mediated responses in the MPS and develop strategies to monitor expression/production of autoimmune targets by islet cells, including altered antigens such as hybrid peptides;
- Evaluate the impact of combining subsets of immune effector/regulatory cells in the MPS on islet/beta cell health and function, and quantify the magnitude of any resulting beta cell dysfunction or death;?
- Directly compare the susceptibility of various bioengineered islets/cells to immune-mediated killing relative to primary human beta cells recovered from juvenile and adult donors;
- Address mechanistic questions about immunomodulatory agents tested in clinical trials that have shown some clinical response (e.g. Abatacept, Teplizumab, ATG, Rituximab, etc.);
- Study the role of stromal/support cells as promoting of beta cell preservation and function in the MPS environment;
- Evaluate the impact of perifusion on soluble pathways of beta cell killing (cytokine storm);
- Examine conditions that control islet/beta cell stress in the MPS and identify intrinsic factors that contribute to beta cell dysfunction/death in the context of an immune attack;
- Define the role of human endothelial cells as modulators of islet cell health, and as contributors to the autoimmune process;
- Characterize the impact of islet metabolic byproducts or glucose on immune cell function in the local MPS environment;
- Study basic processes of immune cell attachment, integrin binding, chemokine gradient trafficking, degradation of extracellular matrix, etc. within and around beta cell/islets in the MPS platform to measure key features of human immune cell trafficking with the islet microenvironment;
- Compare alloreactive versus autoreactive models of beta cell killing and their differential components;
- Apply novel single cell technologies (RNA, chromatin, protein) to define cell heterogeneity and signatures of immune cells, islet cells and endothelial cells in the T1D islet niche within the MPS.
All methods, reagents, resources, biomaterials (including cell lines), protocols, data and models developed by HIRN-CHIB are expected to be made available to the research community. Because individual UG3/UH3 projects will be coordinated through HIRN-CHIB, the timeline and processes for sharing within HIRN-CHIB, and with the community at-large will be established by the HIRN-CHIB NIDDK Project Scientist and the HIRN-CHIB PD(s)/PI(s). All participants are expected to adhere to these policies as a term of the award, consistent with achieving the goals of the program. Policy documents for HIRN-CHIB will be accessible in the HIRN website.
Meetings of HIRN-CHIB
Program Director(s)Principal Investigators(s) of HIRN-CHIB must participate in an initial in-person meeting soon after awards are made, in the annual HIRN Investigator’s Scientific Retreat held in the spring, in CHIB teleconference meetings to be held at least tri-annually thereafter, and in the in-person HIRN-CHIB Scientific Fall Retreat, to be held annually. All participants must be obligated to abide by the policies adopted by the majority vote of the HIRN-CHIB Steering Committee. In the application, research project budget requests should include costs for the PD/PI and up to two other members of the individual project to attend the annual HIRN Investigator’s Scientific Retreat and the annual in-person HIRN-CHIB meeting.
Cells: The use of transformed or immortalized cell lines is discouraged, except for preliminary, proof-of-concept studies. The use of primary cells and organ explants in initial studies, progressing to pluripotent stem cells, e.g. iPSCs is encouraged. The current NIH guidance on stem cell usage can be found at http://stemcells.nih.gov/policy/pages/2009guidelines.aspx
Collaborations: Collaborative interactions are a critical aspect of this FOA. The development of MPS(s) for modeling T1D will require extensive collaboration among tissue engineers, stem cell biologists, diabetes experts and clinicians. Additional funds may be made available at a later time to support collaborative studies with HIRN-Consortium on Beta Cell Death and Survival (CBDS), to validate or test new therapeutics/biomarkers for T1D, or with HIRN-CMAI, to facilitate complementary studies investigating islet cell/immune interactions in humanized animal models, and the cross-validation of T1D model endpoints with clinical measures in humans.
Applications that include the following types of studies will be considered non-responsive and will not be reviewed:
- Development of 3D tissues for transplantation
- Engineering of non-human tissue models
- Development of simple organoid models that do not go significantly beyond those currently available and in use
- Development of systems for which an informative animal model already exists
- Clinical trials?
Deadline: November 11, 2018 (letters of intent); December 11, 2018 (full proposals)
Filed Under: Funding Opportunities