White matter is the infrastructure of the brain, providing conduits for communication between neural regions. White matter continues to mature from birth until early adulthood, particularly in regions of brain critical for higher cognitive functions. However, the precise timing of white matter maturation in the various neural circuits is not well described, and the mechanisms controlling white matter developmental/maturation are poorly understood. White matter is conceptually like wires and their insulating sheath is a substance called myelin. It is clear that neural stem and precursor cells contribute significantly to white matter maturation by forming the cells that generate myelin. In the proposed experiments, we will map the precise timing of myelination in the human brain and changes in the populations of neural precursor cells that generate myelin from birth to adulthood and define mechanisms that govern the process of white matter maturation. The resulting findings about how white matter develops may provide insights for white matter regeneration to aid in therapy for diseases such as cerebral palsy, multiple sclerosis and chemotherapy-induced cognitive dysfunction.
Diseases of white matter account for significant neurological morbidity in both children and adults in California. Understanding the cellular and molecular mechanisms that govern white matter development the may unlock clues to the regenerative potential of endogeneous stem and precursor cells in the childhood and adult brain. Although the brain continues robust white matter development throughout childhood, adolescence and young adulthood, relatively little is known about the mechanisms that orchestrate proliferation, differentiation and functional maturation of neural stem and precursor cells to generate myelin-forming oligodendrocytes during postnatal brain development. In the present proposal, we will define how white matter precursor cell populations vary with age throughout the brain and determine if and how neuronal activity instructs neural stem and precursor cell contributions to human white matter myelin maturation.
Disruption of white matter myelination is implicated in a range of neurological diseases, including cerebral palsy, multiple sclerosis, cognitive dysfunction from chemotherapy exposure, attention deficit and hyperactivity disorder (ADHD) and even psychiatric diseases such as schizophrenia. The results of these studies have the potential to elucidate clues to white matter regeneration that may benefit hundreds of thousands of Californians.
The white matter of the brain provides for communication between distinct neural regions of the brain and is where oligodendrocytes, cells which are responsible for myelination, reside. While the white matter of the brain continues to mature from birth to early adulthood, little is known regarding the mechanism and timing of maturation of specific neural circuits. In this application, the investigator proposes to study the spatiotemporal pattern of myelination in the human brain (aim 1), utilize modern technologies to characterize changes in myelin generating neural progenitor populations (aim 2), and examine the contributions of a known signaling pathway in governing gliogensis, the process of oligodendrocyte formation (aim 3).
Significance and Innovation
- This proposal is of high significance and addresses issues regarding gliogensis, which is an understudied field.
- Data from the proposed experiments have the potential to impact a number of brain diseases by increasing the understanding of gliogenesis and myelination in the developing brain.
- The proposal is highly innovative. The investigator proposes to uses a wide breadth of innovative and state of the art technologies, all focused on a single mechanistic question.
- The tissue available to the investigator is an extremely rare and valuable asset.
Feasibility and Experimental Design
- The primary concern with this proposal is that the proposed research plan is extremely ambitious and technically challenging. Each aim is sufficiently ambitious that it could be the basis of its own grant proposal. While reviewers appreciated the applicant’s enthusiasm, they thought it to be extremely unlikely that all the aims could be completed during the funding period and a more focused application would have yielded a higher score.
- Achieving even a subset of the proposed aims and sub-aims would provide useful information about human brain development.
- Aim 3 is a weakness of the proposal. It was poorly articulated, lacking in details and not sufficiently connected to the rest of the proposal. Reviewers noted that this aim adds little to the project and could be its own proposal.
- The proposed experiments are generally feasible, though many of the proposed techniques are not currently utilized in the investigator’s laboratory. For some of the proposed techniques, the investigator is clearly aware of the potential difficulties and outlines appropriate alternative approaches, while for others, there appeared to be a lack of appreciation for the technical challenges.
- Reviewers raised concerns regarding the PI’s lack of expertise in stem cell biology, including generating myelinating oligodendrocyte precursor cells, and were not convinced that the investigator selected the appropriate protocol to generate the desired motor neuron cell population.
- The aims are somewhat disconnected and the experimental design does not allow for data collected in one set of experiments to be easily related to data collected in other experiments. Aim 3, in particular, seems disconnected from the other aims, and reviewers recommended it to be removed from the proposal.
Principal Investigator (PI) and Research Team
- The PI is a rising star in neurological research with an outstanding track record for a young investigator.
- The team includes appropriate collaborators with expertise in neural imaging and neuropathology.
- The investigator has little experience in culture of human embryonic stem cells (hESCs) and did not indicate any collaborators with this expertise. Reviewers encouraged the PI to develop a formal collaboration with an expert in this area.
Responsiveness to the RFA
- The proposal is highly responsive to the RFA.
- PROGRAMMATIC DISCUSSION
- A motion was made to move this application into Tier 1, Recommended for Funding with the additional recommendation that aim 3 not be funded. Reviewers raised this application for discussion based on the programmatic concern of supporting young investigators. The primary flaw in this proposal is its overly ambitious nature, which was described as a frequent mistake made by young investigators. Reviewers agreed that this is a unique program in an understudied area and that it is likely that the investigator will achieve as many of the aims as possible, and achievement of even a subset of the described aims would be worth funding. However, the panel noted that aim 3 is disconnected from the rest of the proposal and focused on work in a model system. The panel, therefore, recommended that aim 3 not be funded. The motion carried.