Research conducted by the BCBC
The BCBC will work collaboratively to facilitate research in the following areas and will be responsible for collaboratively generating the necessary reagents, mouse strains, antibodies, assays, protocols, technologies and validation assays that are beyond the scope of any single research effort proposed by the investigators:
- Use cues from pancreatic development to directly differentiate pancreatic beta cells and islets from stem/progenitor cells for use in cell-replacement therapies for diabetes,
- Determine how to stimulate beta cell regeneration in the adult pancreas as a basis for improving beta cell mass in diabetic patients,
- Determine how to reprogram progenitor/adult cells into pancreatic beta-cells both in-vitro and in-vivo as a mean for developing cell-replacement therapies for diabetes, and
- Investigate the progression of human type-1 diabetes using patient-derived cells and tissues transplanted in humanized mouse models.
Discover late developmental pro-beta cell signals and efficiently produce of human beta cells:
A goal of this FOA and the BCBC is to discover signals (developmental, epigenetic, chemical) that can lead to the production of a fully functioning pancreatic beta cell. Tremendous progress has been achieved in programming mouse and human embryonic stem cells (ESCs) to a stage mimicking that of multipotent pancreatic progenitor cells (e.g. Pdx1- and Ptf1a-positive cells). However, the specific signals that induce the formation of late pancreatic progenitors (e.g. Ngn3-positive cells), or the partitioning of such late progenitors into the different pancreatic islet types, remain largely unknown. A focus of the consortium in the next five years should be the discovery of pro-beta cell signals that function beyond the Pdx1 induction step, as well as the description of the epigenetic controls that could allow one to prospectively program stem cells into functional beta cells. Areas of emphasis may include but are not restricted to:
- Identify secreted factors, small molecules, extracellular matrices, genes, epigenetic regulators and/or protein transduction strategies that could allow the prospective programming of human ESC- or induced human pluripotent stem cell (iPSC)-derived Pdx1-positive progenitors to mature beta cells in-vitro.
- Assess the chromatin/epigenomic state of mature beta cells and their progenitors, and use this knowledge to devise differentiation strategies and help determine a mature "beta cell" signature.
- Develop techniques that would allow for the isolation, purification and the scale-up in producing defined progenitor populations and their endocrine pancreas progeny.
Enhancement of beta cell mass
A goal of this FOA and the BCBC is to understand the mechanisms of beta cell regeneration in the adult animal as well as in human islet. Areas of emphasis may include but are not restricted to:
- Better understand the cell types, signaling pathways and genes that control islet cell mass and beta cell replication/regeneration, that are relevant to the regenerative capacity of the human islet.
- Identify small molecules and secreted factors that promote expansion of human beta cell mass.
- Determine the regenerative capacity of human islets in a variety of pathophysiological settings (hyperglycemia, inflammation, etc) following transplantation in immunodeficient mouse models.
- Identify immunosuppressive drugs that do not inhibit beta cell regeneration and test the effects of drugs often used by diabetic patients for their compatibility with beta cell regeneration and beta cell proliferation/survival.
- Develop new strategies to assess beta cell mass in-vivo.
Transdifferentiation or reprogramming of progenitor or adult cells to beta cells
Recent evidence has demonstrated that it is possible to directly reprogram a fully committed, differentiated cell, from one lineage into another, thereby bypassing steps of either de-differentiation or reversion to a pluripotent state. A goal of this FOA and the BCBC is to find strategies to generate large quantities of fully functional beta cells through the transdifferentiation or direct reprogramming of other progenitor or adult cell types in-vitro and/or in-vivo. Areas of emphasis may include but are not restricted to:
- Understand the mechanisms (epigenetic, developmental, etc) of how the process of transdifferentiation or reprogramming to beta cell takes place.
- Identify and use small molecules rather than viral reprogramming inducers to achieve reprogramming and the safe generation of beta cells for replacement therapies.
- Generate human pancreatic beta cells beginning with other cell types that could readily be obtained from patients with T1D.
- Explore strategies for the in vivo reprogramming of non-beta cells into regulated insulin-producing cells.
Reconstructing human T1D in a mouse using patient-derived iPSCs
Patient-derived iPSCs have the potential to help us understand the pathogenesis of diseases resulting from complex genetic predispositions such as T1D, become an expandable and personalized source of transplantable cells, and test future T1D treatments. Thus, the BCBC will consider projects leading to the generation and use of T1D patient-derived iPSCs. Areas of emphasis may include but are not restricted to:
- Derive clinical-grade iPSCs from T1D patients using small molecules rather than viral reprogramming inducers.
- Recapitulate both normal and pathologic human tissue formation in vitro.
- Develop humanized mouse pancreata from non-diabetic subjects and T1D patients
- Use human iPSC technology to create murine models of T1D that would include the generation of functional beta cells as one of the key components.
- Use T1D patient-derived iPSCs to test whether a patient's own immune system will target his/her islet-like cells generated in vitro.
- Engineer T1D patient-derived iPSCs in order to produce beta-cells that are protected from autoimmune destruction following transplantation.
The BCBC includes investigators from various funding sources:
The ARRA Signature Project Program provides research support for a limited time (up to 24 months) to enable eligible investigators to develop novel human islet cell replacement therapies for diabetes. While insulin replacement therapy has transformed type 1 diabetes (T1D) from a fatal disease to a chronic one, it is still associated with significant morbidity. Complications of diabetes lead to kidney failure, blindness, amputations, and urologic complications, while diabetes increases the risk of macrovascular disease by 2-4 fold. Intensive therapy is associated with significant adverse events related to hypoglycemia. Thus, a restoration of pancreatic function through transplantation or regeneration would be a vast improvement over current practice.
The NIDDK, through the BCBC Cooperative Agreement (U01 Grants) funding mechanisms, supports a wide range of research projects focused on understanding the underlying mechanisms of beta cell development, stem cell biology, and beta cell regeneration, with the overarching goal of developing cellular therapies for Type 1 diabetes.
The Collaborative Bridging Project (CBP) program is a funding mechanism designed to encourage synergy via collaboration amongst BCBC investigators, as well as with scientists outside the BCBC. It is expected that these collaborative efforts will generate new reagents and resources or apply cutting-edge technology that has the potential to accelerate research relevant to the BCBC.
The Pilot and Feasibility Program will provide research support for a limited time (1-2 years) to enable eligible investigators to explore the feasibility of concepts related to the mission of the BCBC.
The SCRBCB program provides research support for a limited time (18 months) to enable eligible investigators to explore the feasibility of a concept related to the mission of the BCBC and generate sufficient data to pursue it through future funding mechanisms. The SCRBCB program provides funding for specific types of research activities that will help the consortium to get closer to its ultimate goal of providing cell-based therapeutic solutions to the chronic depletion of beta-cell mass observed in type-1 and severe type-2 diabetes.
The BCBC CC will support the travel of trainees/trainers between BCBC laboratories by awarding short term training travel awards. In general, the training taking place should directly benefit BCBC funded projects, complement existing research activities, and provide knowledge/techniques not available in the laboratory receiving the training.
The Transformative Collaborative Project Award (TCPA) provides research support for a limited time (up to 24 months) to enable eligible investigators to acquire key pieces of knowledge and/or to develop new technologies and tools that will help the consortium reach its ultimate goal of providing cell-based therapeutic solutions to the chronic depletion of beta cell mass observed in type-1 and severe type-2 diabetes.