Basic Biology V
The objective of this proposal is to understand how immune aging diminishes the ability of stem cells to make new brain cells. We found that when a certain type of immune cell (T cell) was missing, stem cells in aged brains produced more new nerve cells, and this depended on certain T cell molecules and surface receptors. This could help us promote new nerve cell production in the aged, if we knew it that just aged T cells and not other things in aging brain were responsible for decreasing neuron production, exactly how aged T cells might keep neurons from forming from stem cells, and . Aim #1 will determine if just aged T cells are responsible for decreasing neuron production, by seeing how well neurons are made in young and old animals bearing T cells aged outside their bodies. Aim #2 will determine how well neurons form from stem cells, in the presence of aged or normal T cells, and with and without drugs that block certain T cell functions. Aim #3 will determine if aged T cells prevent transplanted stem cells meant to treat diseases from making new nerve cells in the brain, and will use information gained from the previous Aims to determine how nerve cell production can be enhanced with T cells. Our studies take advantage of a unique way we developed to age T cells outside the body, and previous studies of T cell plus stem cells in culture together. They thus promise to best determine how to promote new nerve cell production in the aged, and in diseases of the elderly.
Statement of Benefit to California:
Central nervous system disorders of aging that could potentially benefit from enhanced neurogenesis (i.e., through engraftment of iPS-derived neural stem cells) include neurodegenerative conditions such as Amyotrophic Lateral Sclerosis, Alzheimer’s, Parkinson’s, and Huntington’s diseases; vascular conditions such as stroke and cerebral amyloid angiopathy; and increased risk of neurotrauma secondary to falls. In aggregate, these conditions place a very large burden on state resources through lost work, caregiver time, and hospital equipment. It is estimated that the cost of caring for a single Alzheimer’s (AD) patient, for example, is $56,800 per year. Multiplied by the over 588,000 patients in the state currently living with AD, plus costs of other conditions, and the burden is truly staggering. Engrafting iPS-derived neural stem cells into patients promises to improve such conditions, but this technology needs to be more efficient and reliable in the elderly in particular. This project aims to exploit aspects of immune cell aging to enhance neurogenesis and iPS-derived graft function in the aged. As the first study to examine the effects of the most common form of immune aging on neurogenesis it will make California a center of excellence for aging and Regenerative Medicine research. It will also attract scientists and companies interested in this area of medicine to California thus increasing state revenue and state prestige in these rapidly growing fields.
This Exploratory Concepts Award application is based on the hypothesis that a specific type of T cell is resident in the brain and that when these cells are aged, they become dysfunctional and negatively affect neurogenesis. The overall goal of the application is to investigate whether immune cell aging diminishes the ability of stem cells to make new brain cells (neurogenesis) and gain mechanistic insight into the process by which this occurs. The applicant suggests that age-related dysfunctional immune cells produce cytokines that inhibit neurogenesis; contrasting with the normal immune regulatory cells that promote neurogenesis through cell signaling. To test this hypothesis, the applicant proposes a series of in vivo transplant and in vitro experiments. Initially, the investigators propose to evaluate levels of cytokines and receptor signaling in both young and old recipients in a nonhuman vertebrate model. The applicant will then confirm and extend these studies using in vitro models, including the nonhuman and human neural stem cells (NSCs). Finally, the applicant proposes to combine in vitro and in vivo models by implanting induced pluripotent stem cell (iPSC)-derived human NSCs into the nonhuman vertebrate recipients with normal or dysfunctional immune regulatory cells in order to examine engraftment and survival of the transplanted cells in different environments and gain insight into the mechanism by which the immune cells affect neurogenesis. Novelty and Transformative Potential - The hypothesis is novel and, if supported by the experimental findings, has the potential to impact the understanding of the relationship between the aging immune system and neurogenesis and NSC transplantation. - The application does not directly address some other publications on the topic, particularly those that have reported negative results. For example, previously published data indicated that ablation of these specific immune cells does not affect neurogenesis, a finding that reduces the novelty of Aim 1. Other previous studies demonstrate similar findings using an athymic pre-clinical model. Feasibility and Experimental Design - The rationale was not completely supported by the preliminary data as the interpretation of some of the preliminary data is not conclusive. There are confounding issues related to maintenance of the aged immune cell phenotype upon expansion, the potential for migration of cell transplants, and the specificity of neurogenic markers to the region of the brain to be studied. - While the experimental design of Aim 1 was particularly elegant and the overall experimental design was clearly stated and sound, reviewers felt it unlikely the applicant would be able to complete all the proposed experiments in the 2-year timeframe. - The applicants appear to have all the necessary tools and resources available to complete the planned experiments. The tools available are interesting and novel resources. - Reviewers also noted that the applicant intends to study hippocampal neurogenesis but the preliminary data does not sufficiently support the hypothesis that the T cell population of study affects this particular region of the brain. Principal Investigator (PI) and Research Team - While the PI has an overall strong publication record and is an accomplished immunologist, the PI has limited expertise in adult neurogenesis, which was reflected in the application. However, the PI has recruited appropriate collaborators in this area. - The research team has appropriate expertise to conduct the proposed research and the collaborations are critical for success of the proposal. Responsiveness to the RFA - The application was regarded as generally responsive to the RFA. Certainly the use of nonhuman vertebrate recipients, human cells and humanized vertebrate recipients are appropriately justified.
- Sean Palecek