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Life In Discovery
Granting Agency: National Institute on Aging Project Title: Stem Cells for Brain Repair Principal Investigator: Daniel A. Peterson, Ph.D.
Many neurological deficits result from the loss of neurons through neurodegenerative disease, traumatic injury, or stroke. The adult central nervous system (CNS) demonstrates little endogenous capacity for repair and lost neurons are not replaced. However, the generation of new neurons persists in two specific brain regions. Recent progress in understanding the signals regulating the proliferation and differentiation of new neurons in these two neurogenic regions opens the possibility to use these neural stem cells, as they are collectively called, to repopulate other non-neurogenic areas of the brain that have been injured. The major goal of this study is to repopulate the injured entorhinal cortex, a region with severe cell loss in Alzheimer's disease, with neural stem cells. To achieve this goal, post-injury changes in entorhinal cortex trophic factor expression will be evaluated and neural stem cells will be grafted into the intact or injured entorhinal cortex. To determine if trophic factor expression is a limiting component of successful stem cell neuronal differentiation, ex vivo and in vivo gene therapy will be used to augment expression. These objectives will be accomplished using a combination of molecular and protein analysis, gene therapy, quantitative stereology, and modern microscopic analysis to evaluate stem cell differentiation and connectivity. By increasing our understanding of the signals required for neuronal differentiation of stem cells, this study will provide a rationale for clinical cell replacement strategies for the treatment of various neurodegenerative diseases and traumatic injuries where neuron loss is experienced.
Granting Agency: National Institute on Aging Project Title: Neurogenesis in the Aging Brain Principal Investigator: Daniel A. Peterson, Ph.D.
Stem cells hold great promise for treating many age-related disorders through cell replacement therapy, yet little is known about the ability of aged tissue to support critical events in the survival, spatial targeting, or differentiation of grafted stem cells or primitive progenitor cells. In the central nervous system, an age-related decline in neurogenesis in the dentate gyrus has been reported. We have recently found a massive decline in neurogenesis in the aged olfactory bulb, the other region supporting neurogenesis in the adult brain. Therefore, the environment of the aging brain may be impaired for supporting differentiation and integration of either endogenous or grafted stem cells. In this regard, comparison of aging brain with young brain may provide a useful model to discriminate between critical environmental factors regulating neurogenesis and supporting neuronal differentiation. Identifying such age-related deficits and restoring their expression in the aged brain would be necessary to extend the possible use of cell replacement strategies for treating age-related neurodegeneration, stroke, or cognitive decline. Alternatively, the environment of the aging brain may retain adequate neuronal differentiation signals in these neurogenic regions, but the endogenous stem cells may exhibit age-related impairment in their ability to differentiate. This project will test these two possibilities by 1) evaluating differences in expression of identified stem cell proliferation and differentiation signals between young and aged adult brain and 2) restoring expression of deficient signals by gene delivery to enhance neurogenesis in the aged brain. The subsequent grafting of rodent stem cells derived from embryonic, young adult and aged adult tissue sources will reveal the extent to which environmental modification of aged tissue can facilitate effective cell replacement therapy.
Granting Agency: American Diabetes Association Project Title: The Contribution of Bone Marrow-Derived Mesenchymal Stem Cells to Diabetic Wound Healing Trainee: Laura Shin, Supervisor: Daniel A. Peterson, Ph.D.
Diabetic ulcers and chronic wounds in the legs and feet are difficult to heal and closure is often temporary. Diabetic patients have a much higher risk of amputation. Many therapies have been developed over the years but the severity and frequency of these lesions continues to plague patients physically and financially. A new approach to wound healing uses the regenerative properties of bone marrow derived mesenchymal stem cells (MSCs). MSCs in the bone marrow are able to turn into cartilage, adipose tissue, and bone which makes it an important factor in the study of wound healing. Early clinical work has suggested that applying a person's own bone marrow stem cells topically to the site of injury shortens closure time and reduces the number of recurring wounds as well (Rogers, et al. 2007). Using the patient's own cells will reduce the immune response to transplantation and may be more cost effective. However, this is dependent on whether cells from patients that are diabetic can enhance wound healing. Diabetes may negatively impact the MSCs in bone marrow. If cells from these patients are not as effective at wound healing, it is necessary to develop ways to amplify these cells in cell culture before using them for therapy. This project will determine how best to culture MSCs from diabetic patients and how much they help wounds heal.