Control of OCT4 abundance and function in human stem cells
Grant Award Details
Grant Type:
Grant Number:
DISC0-13801
Investigator(s):
Disease Focus:
Human Stem Cell Use:
Award Value:
$1,234,023
Status:
Active
Grant Application Details
Application Title:
Control of OCT4 abundance and function in human stem cells
Public Abstract:
Research Objective
Our work will reveal an essential pathway that establishes precise levels of the OCT4 transcription factor and protects stem cell identity despite genetic or environmental stress.
Impact
Our work will enhance our ability to generate and expand high-quality induced pluripotent stem cells from older patients or patients of neurodegenerative disease for use in regenerative medicine.
Major Proposed Activities
Our work will reveal an essential pathway that establishes precise levels of the OCT4 transcription factor and protects stem cell identity despite genetic or environmental stress.
Impact
Our work will enhance our ability to generate and expand high-quality induced pluripotent stem cells from older patients or patients of neurodegenerative disease for use in regenerative medicine.
Major Proposed Activities
- Aim 1: By identifying partners of the OCT4 species that is degraded through quality control, we will determine how OCT4 stabilization disrupts transcription factor complexes in stem cells.
- Aim 1: By following OCT4 in cells lacking quality control, we will determine how aberrant OCT4 complex formation impedes pluripotency gene expression and stem cell self-renewal.
- Aim 2: We will determine how the pluripotency transcription factor OCT4 drives expression of quality control components in stem cells to ensure its own activity.
- Aim 2: With help of CRISPR/Cas9-mediated editing, we will determine the importance of OCT4 activity for the expression and activity of its own quality control system in stem cells.
- Aim 3: Exploiting the Huntingtin protein, we will determine how aggregation-prone and neurotoxic proteins interfere with OCT4 function in stem cells.
- Aim 3: We will determine whether overexpression of quality control components enables more efficient generation and expansion of iPSCs from Huntington’s Disease patients.
Statement of Benefit to California:
Regenerative medicine is a promising approach to treat neurodegenerative diseases affecting thousands of Californians. However, disease mutations, older patients, or environmental stresses compromise the quality of transplanted cells and thus limit the benefits of regenerative medicine. By dissecting how stem cells maintain their identity despite mutations causing neurodegenerative disease, this work will spur the development of new therapeutic options for currently untreatable pathologies.