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Regenerative Medicine aims to replace or regenerate human cells, tissues or organs to restore or establish normal function lost due to injury, toxicological/metabolic damage, congenital pathologies or ageing. Regenerative medicine has the potential to overcome the shortage of organs available for human transplants by replacing or stimulating the body's own repair mechanisms to heal or regrow damaged tissues or organs. The recent discovery of the reprogramming of adult cells to a pluripotent state provides opportunities to address a major problem of regenerative medicine, immune rejection of transplanted tissue. The ability to generate differentiated cells and tissues using cells from specific patients will facilitate individualized medicine and eventually will lead to specialized therapies. The field is moving toward translation to clinical practice and is becoming increasingly dependent on animal models. Generating the correct type and quantity of the specific cell types required for replacement therapy is a significant challenge, as are the problems associated with introducing these cells into the proper environment in vivo and overcoming immune reactions. Finding solutions to these problems will require extensive testing in experimental animal models.
Major advances have been made in the past several years in deriving pluripotent cells, such as embryonic stem cells (ESCs) and induced pluripotent cells (iPSCs) from both humans and animals. In parallel, other investigations have isolated and characterized multipotent “somatic” or “adult” stem cells from various tissues, including Mesenchymal Stem Cells (MSCs) and Germinal Stem Cells (GSCs).
The discovery of mouse ESCs in 1981 revolutionized the field of developmental biology and provided new capability for genome manipulation and investigations of gene function. Isolation of human ESCs created new possibilities for the field of regenerative medicine. ES-like cells have been derived from a number of animal species, including rats, fish, cows, pigs and non-human primates. Many characteristics of animal ES-like cells, including surface markers, growth factor requirements, ability to differentiate and others can be quite different from human ESCs.
The field of stem cell research experienced a dramatic new direction with the isolation of iPSCs, derived by reprogramming human or mouse somatic cells to a pluripotent state. Several studies on various animal systems suggest that the basic pluripotency network appears to be conserved among different species, allowing derivation of iPSCs from a variety of animals.
MSCs, a type of somatic stem cell, were originally identified as a subpopulation of bone marrow cells with osteogenic potential. The properties of MSCs have been examined extensively over the past decade. Studies using animal models have shown promising results following MSC therapy for induced injury in the musculoskeletal, cardiovascular, digestive and nervous systems. In addition, many clinical trials have demonstrated the efficacy of MSC infusion for treating various human diseases. Given the wide range of tissue sources, the recognition of subpopulations with specific properties, and the frequent production of genomic alterations upon expansion in cell culture, extensive characterization of MSCs and development of improved techniques are required. Most importantly, there is relatively limited understanding of the normal biological functions of MSCs and the mechanisms by which they participate in tissue repair.
Along with rodents, several other animal species are being developed as models for various studies in the field of regenerative medicine. Understanding the properties and capabilities of stem cells derived from animals such as rabbits, pigs, sheep, goats and monkeys will increase the potential for the use of the most appropriate systems for modeling particular human disease conditions or for other medical applications. Non-rodent mammalian species (often referred to as “large animal models”) provide important advantages for transplantation studies, including large size, similarity to human physiology and pathology and longer life span, thus facilitating translation to studies in humans. The use of animal stem cells as a model for human cells in procedures related to regenerative medicine requires in-depth understanding of common regulatory pathways as well as species-specific properties and their impact on potential therapeutic applications.
Animal experiments have historically made a significant contribution to understanding human disease. However, animal studies need to be improved in order to better predict the efficacy of treatment strategies in clinical trials. Several possible causes of the disparity between the results of animal studies and clinical trials have been identified, including failure to acknowledge the limitations of animal models, inadequate animal data and conclusions from them, less than optimal disease models and overestimation of treatment efficacy due to the preferred publishing of positive results. These problems should be addressed in the design and execution of preclinical, animal-based studies involving stem-cell based therapies.
The potential results of investigations must be applicable to the research interests of two or more of the categorical NIH Institutes and Centers. In addition, projects that predominantly address the research interests of one NIH Institute or Center, but that are peripherally related to the research interests of other Institutes and Centers, will not be considered appropriate for this FOA. An example of an inappropriate request is one exclusively involving an animal model of cancer or some other specific disease.
Research activities that are being sought to be supported under this FOA are intended to improve existing or create new animal models for regenerative medicine applications. Highly innovative projects are encouraged and can include, but are not limited to: