Funding opportunities

Stretch-activated ion channels in human neural stem cell mechanotransduction

Funding Type: 
Basic Biology V
Grant Number: 
Funds requested: 
$611 307
Funding Recommendations: 
Recommended if funds allow
Grant approved: 
Public Abstract: 
Stem cells therapy aims to replace damaged tissue with healthy stem-cell-derived tissue. In the brain it is being pursued as a strategy to treat conditions such as multiple sclerosis, stroke, Parkinson’s disease and spinal cord injury. For the promise of stem cell therapy to be realized, one needs to be able to precisely control the conversion of stem cells into the required cell type, through a process called differentiation. For instance, how can neural stem cells be experimentally manipulated to become neurons rather than a housekeeping glial cells? Stem cells can detect the physical properties of the tissue surrounding them, such as its rigidity, and these properties strongly influence the process of differentiation. This project aims to answer the questions: how does a stem cell assess whether it is surrounded by a rigid or soft tissue? And how is this information factored into the decision to become a specific cell type? We address these problems in human neural stem cells by focusing on proteins that let ions pass through the cell membrane in response to mechanical stimulation. Successful completion of the project will provide new drug targets that can be exploited to manipulate stem cell commitment to alternative cell fates, with applications in regenerative medicine and tissue engineering.
Statement of Benefit to California: 
The California Stem Cell Research and Cures Act of 2004 aims to translate stem cell research into clinical therapies. The Act notes that “About half of California’s families have a child or adult who has suffered or will suffer from a serious, often critical or terminal, medical condition that could potentially be treated or cured with stem cell therapies”. Successful stem cell therapy requires a better grasp of how stem cells differentiate into specialized cells. Here we study how environment mechanics instructs stem cell differentiation and aim to identify a key molecular player. We focus on neural stem cells, which could potentially cure conditions like multiple sclerosis, stroke, Parkinson’s disease and spinal cord injury. Our findings will offer new guidelines for improved stem cell differentiation. They will also shed light on how the rigidity of matrices and scaffolds used in tissue engineering affects the growth of reconstructed organs and tissues. Anticipated benefits to Californians include: 1. Better means for generating specific brain cells types for treating neurological diseases. 2. Application of similar techniques to stem cell therapy involving mesenchymal and embryonic stem cells. 3. New opportunities for drug discovery and screening, based on knowing a key molecule involved in stem cell fate. 4. Creation of biotechnology start-ups using our findings to improve tissue engineering and prosthetic implants. 5. Jobs creation in the biotechnology/health sector.
Review Summary: 
This Exploratory Concepts Track application investigates the hypothesis that stress-activated ion channels (SACs) mediate matrix mechanotransduction in neural stem cells (NSC) by affecting differentiation. To test the hypothesis, Aim 1 will apply SAC inhibitors to NSCs cultured on substrates of different stiffness and monitor differentiation to astrocytes and neurons. Then, the applicant will use electrophysiology to monitor ion channel conductance in hNSCs (Aim 2) and genetics (Aim 3) to identify specific channels that mediate ion conductance. Significance and Innovation -The reviewers were concerned about the overall impact of the proposed research since it is well known that substrate stiffness affects stem cell differentiation, and effective protocols already exist to produce neurons or glial cells from hNSCs. -The applicant does not seek to link specific ion channels to stem cell fate, diminishing the potential impact. - Reviewers appreciated that the hypothesis may increase awareness of the role of SACs. Feasibility and Experimental Design - The applicant presented strong and convincing preliminary data regarding the activation of SACs. - Reviewers acknowledged that the feasibility is strong. For example, reagents, tools, and the approaches proposed are readily available and well established. - However, reviewers expressed reservations regarding the experimental design. For example, there was a disconnect between the aims in addressing the central hypothesis. - Reviewers criticized that a broad based non-specific inhibitor is proposed instead of specific inhibitors to identify SACs. - The reviewers had concerns about the characterization of cell-fate as it is not adequately addressed and should have included multiple markers and phenotypic assessment. - Reviewers suggested that the applicant should better tie-in existing literature on mechanically induced stem cell differentiation. Principal Investigator (PI) and Research Team - The PI is an expert in ion channel mechanotransduction and electrophysiology. - The collaborator brings in complementary expertise to the project in stem cells and is a strength of the proposal. - The two investigators have a joint publication of preliminary data used to support this project, demonstrating an active collaboration. Responsiveness to the RFA - The application is responsive to the RFA as it studies a novel mechanism of regulation of human neural stem cell fate.

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