Modeling Ataxia - Telangiectasia with Induced Pluripotent Stem Cell-Derived Purkinje Cells
Abstract
One of the main difficulties in studying the Fiscal Year 2018 Peer Reviewed Medical Research Program topic area of cerebellar ataxia is having a model system that reflects changes seen in human patients. Often model systems such as mice are not affected by diseases and genetic disorders in the same way as humans. Induced pluripotent stem cells (iPSCs) provide a model system to study actual human cells derived from patients. In this technique, a biopsy is taken from patients with a genetic disorder to isolate cells. These cells are then converted into iPSCs, which subsequently have the ability to generate any cell type in the human body. In the proposed research, we will use iPSCs to model a specific genetic form of cerebellar ataxia, called ataxia-telangiectasia (A-T). Ataxia-telangiectasia (A-T) is a genetic disorder caused by mutations in the ATM gene and characterized by cerebellar degeneration, telangiectasia, increased susceptibility to cancer, and immunodeficiency affecting ~1:40,000-1:100,000 live births worldwide for which there is no cure. It has been particularly difficult to study the cerebellar aspects of the disease because mouse models do not show the same deficits as human patients. Within the cerebellum, the Purkinje cell (PC) is highly affected, resulting in dysfunction and cell death. The critical question is therefore what are the molecular differences between human and mouse PCs that cause PCs to die in humans but not in mice? In the proposed research, we will create a model system using iPSCs from A-T patients to study human cerebellar PCs affected by A-T for the first time. We will focus on defining molecular differences in gene expression and protein profiles of patients with A-T compared with mouse PCs that lack the ATM gene, allowing us to search for drug targets. Finally, we will test new approaches for therapies and create a platform for future drug screening.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910110
Entities
People
- Mary E. Hatten
Organizations
- The Rockefeller University
- United States Army