Basic Biology V
$1 161 000
Spinal cord injury is a debilitating condition for which there is currently no effective treatment let alone cure. Stem cell based therapies represent a viable approach but much more need to be understood before we can develop an effective stem cell based treatment for spinal cord injury. A particular important question is how the transplanted cells interact with the host environment to influence the establishment of connections between transplanted nerve cells and the host nervous system. The nervous system distinguishes itself from the rest of our body based on the requirement for intricate connections between nerve cells that are required for proper function. Thus, it is particularly challenging to develop stem cell based nerve cell replacement therapies. Our proposed study will help elucidate how transplanted stem cell-derived nerve cells grow processes for long distance in the normally growth-inhibitory adult central nervous system, an important step towards functional rewiring and nervous system repair. Results from this study will have important implications for developing both stem cell and non-stem cell based therapies for spinal cord injury and a variety of other neurological conditions.
Statement of Benefit to California:
Neurological conditions affect millions of Californians each year. Spinal cord injury is one particularly debilitating neurological condition. The disability, loss of earning power, and loss of personal freedom associated with spinal cord injury is devastating for the injured individual, and creates a financial burden of an estimated $400 million annually for the state of California. Research is the only solution as currently there is no cure for spinal cord injury. The major underlying problem for lost function is the loss of connections between neurons after spinal cord injury. Stem cell based transplantation is one possible way to repair damaged nerve paths. Our proposal looks at a critical and widely applicable aspect of stem cell transplants: the interaction between stem cell transplants and the environment in the host that make it possible for the transplanted cells to make meaningful connections with host neurons. This will have important implications in the design of stem cell based treatment for spinal cord injury and many other neurological conditions because making appropriate neuronal connections is important for successful stem cell based therapies for a variety of diseases in the nervous system. Our proposed research will eventually help develop treatment to improve the quality of life for people with spinal cord injury and decrease the financial burden for the State of California.
The goal of this fundamental track proposal is to understand the molecular mechanisms governing the behavior of neural stem cells (NSCs) transplanted into fully developed spinal cords. More specifically, the focus is on how these cells extend neuronal processes through the white matter of the central nervous system, which inhibits this behavior in mature neurons. The hypothesis put forth is that NSCs interpret the normally inhibitory signals in spinal cord as stimulatory and a recent study implies, and that NSCs may use “neuron-intrinsic properties” that adult cells lack. Three specific aims have been proposed. First, they will assess the effect of normal inhibitory substances found in the central nervous system on neurite outgrowth in neurons derived from human pluripotent stem cells (hPSCs). In the second Aim, they will transplant hPSC-derived neurons into spinal cords of normal and genetically altered mice and compare neurite outgrowth under conditions where specific components of spinal cord are absent or degraded. In the third Aim, they will compare the global gene expression profile of hPSC-derived neurons capable of migration vs. that of cells that failed to migrate far. Significance and Innovation - The hypothesis proposed lacks innovation as it has already been advanced in a previous publication. - Unsolved problem in regenerative medicine. - If successful, the project potentially has significant impact on regenerative medicine approaches to spinal cord injury. Feasibility and Experimental Design - Several aspects of the technical approaches raised substantial concerns. These include (1) all preliminary data are from rat models but the proposed experiments will occur in mice, raising possible complications of a different host response to the human cells; (2) use of an immunosuppressant in specific aim 2 could limit the duration of animal experiments, but this is not discussed; (3) no preliminary data are provided to demonstrate feasibility of some of the techniques to be used in Aim 3; (4) the type of neural progenitor cells the team expects to produce from hPSC is not described, nor is it clear how or if this will impact their conclusions; (5) it is not clear whether the source of the purified substrate for aim 1 is human or mouse; (6) Aim 1 lacks an important control: embryonic spinal cord; (7) comparing young transplanted mouse neurons that grow to those older cells that do not migrate will confound the results, as age complicates the differences between the two populations; and (8) discriminating between these populations depends on failure of non-migratory cells to be labeled, rather than a specific behavior of these cells. - It is not clear how the genome profiling experiments will be analyzed, or how the resulting data will be used. - The proposal is ambitious, with a low likelihood that aim 3 will be successful within the proposed time. - The research facilities are satisfactory for completing the proposed experiments. Principal Investigator (PI) and Research Team - The applicant has an extensive publication record in spinal cord injury. - The collaborative team has already published the foundational work for this project. Responsiveness to the RFA - The studies will utilize human stem cells and will target important mechanisms governing stem cell treatment of spinal cord injury. Thus it is responsive to the RFA.