Basic Biology V
$1 317 381
Neurodegenerative diseases comprise a broad spectrum of acute and chronic conditions in which the structure or functions of neurons are progressively lost, leading to their death. Acute neurodegenerative diseases include ischemic stroke and traumatic brain and spinal cord injury. Chronic neurodegenerative diseases include Parkinson’s disease, amyotrophic lateral sclerosis “Lou Gehrig's disease”, and Alzheimer’s disease among many others. Stem cell-based approaches hold tremendous hope to restore neuronal function in neurodegenerative disease. Transplantation of stem cells in animal models of neurodegenerative disease has been proven to restore neuronal function to some extent. However, significant barriers still exist to responsively translate stem cell-based approaches into treatments for human neurodegenerative diseases. We need to further investigate the action of stem cells after transplantation. In particular, one of the underrepresented areas in this research field is the effect of inflammation on transplanted stem cells. Notably, neurodegenerative diseases are accompanied by inflammation. Inflammation damages neurons as well as transplanted stem cells. This proposal attempts to find a way to reduce the damage to stem cells by inflammation to enhance the ability of stem cells to regenerate neuronal functions after transplantation. This project will help to discover new approaches to improve stem cell-based therapies for various neurodegenerative diseases.
Statement of Benefit to California:
Human stem cells hold great potential for regenerative medicine to treat many progressive neurodegenerative diseases such as Parkinson’s disease, amyotrophic lateral sclerosis, Alzheimer’s disease, stroke, and spinal cord injuries, to name just a few. These devastating neurodegenerative diseases are the leading causes of death and disability in the State of California. The progressive nature of these diseases with increasing disability is a burden on the patients, their families, and the State of California in both human suffering and healthcare costs. The goal of this project is to study the molecular changes within human neural stem cells (hNSCs) transplanted in neurodegenerative diseases in order to discover means to increase the regenerative capacity of transplanted hNSCs. This mechanistic and translational approach to characterize transplanted hNSCs will provide possible therapeutic strategies and clinical applications for neurodegenerative diseases, providing hope for the development of stem cell based therapies. Therefore, successful completion of this research will greatly benefit Californians suffering from neurodegenerative diseases and in need of such treatments, and have a tremendous impact on quality of life for the patient, his or her family, and for the economic and emotional burden on the State of California and its citizens.
It is well-recognized that the success of stem cell transplantation is highly dependent on how the donor cells proliferate, survive, differentiate, and integrate into host tissues in a neurodegenerative microenvironment. This pathological environment has a significant inflammatory component. In fact, inflammation has a major impact on neural recovery after injury and during the disease process and is detrimental to therapeutic stem cell efforts and, therefore, meaningful recovery. Inflammation may also limit the potential for neuronal plasticity. The goal of this Fundamental Mechanisms Award proposal is to improve the outcome of human neural stem cell (hNSC) transplantation in rodent models of stroke by manipulating signaling that depends on an understudied transcription factor. In previous works, the PI and collaborators have demonstrated that the transcription factor of study is linked to other regulators that suppress signaling of the inflammatory response. The application proposes experiments that will chart the pathway from this transcription factor to the specific regulators and further to the suppression of downstream inflammatory molecules. It will also investigate whether the attenuation of this response influences the regenerative capacity of hNSCs. Significance and Innovation - This study represents a worthy, but incremental, step rather than being truly innovative. A concern was expressed that the potential findings were too evident from the preliminary results and not likely to move the field forward significantly. It is already known that the signaling pathway of study has direct negative effects on NSCs, thus it is not surprising that interfering with that signaling would improve survival. -There was concern that the experimental design does not effectively interrogate the mechanism by which inflammation affects engraftment and how inflammatory signaling in the NSC affects the inflammatory milieu, thus lessening the potential impact of the research. - Dissection of this neuroinflammatory signaling cascade could lead to the development of strategies to improve hNSC-based therapies for neurodegenerative diseases. An exploitation of the molecular cascade of study is a novel approach to tackle the inflammatory niche. - The use of innovative technologies is a plus. Feasibility and Experimental Design - The preliminary data was not sufficiently strong. There was a lot of preliminary data showing the importance of the transcription factor of study in neurogenesis, but the link between other regulators and the inflammatory signaling cascade is not convincing. - There was a concern regarding the necessity for repeating the ChIP-seq experiments. Repeating the same experiment may not result in greater depth of sequence coverage, as the strongest interactions may continue to dominate throughout experimental repeats. Instead, it was suggested that identification of additional targets may require deeper sequencing of the same experiment rather that a repeat of that experiment. - Aim 2 is substantially stronger than Aim 1. Reviewers were unsure that the outcome measures selected by the investigator would yield useful data because only small effects of transcription factor level modification are anticipated, and there is a lack of evidence for the robustness of the assays themselves. - Another concern was the small number of animals to be used for behavioral measurements, suggesting the need for power calculation. - A detailed identification of the types of transplant-derived cells using a substantial array of markers is proposed. The investigators appear fully cognizant of potential pitfalls and have made some provision for alternative strategies. Principal Investigator (PI) and Research Team - The PI is clearly a contributor to the success of the line of research that led to this proposal. However, there was a concern that the PI was a middle author on most publications leading to questions regarding the magnitude of past contributions by the PI and the degree of actual independence. Confounding this concern was that a number of the key personnel are not in the PI’s laboratory. - The group of collaborators is an impressive assembly of talent that expertly covers all of the necessary technologies and analyses. Responsiveness to the RFA - The project is in line with the RFA, in that it will study the effect of the extracellular environment on the cell fate of transplanted hNSCs in an animal model. The project also has the potential to inform post-stroke therapies, although more in a phenomenological rather than in a mechanistic way.