Basic Biology IV
Mitochondria are essential cellular structures critical for energy production in cells such as neurons and skeletal muscle. Sick mitochondria play a role in common aging diseases such as heart failure, Alzheimer's and Parkinson's and are found in some children with autism. Genetic mitochondrial disease causes devastating and often fatal disease in both and children and adults. This research team is dedicated to the discovery of treatments for mitochondrial disease. This research project will study muscle and nerve cells derived from skin fibroblasts collected from adults and children with gene defects causing mitochondrial disease. With the demonstration of mitochondrial disease in stem cell derived differentiated nerve and muscle cells and we plan to study treatments to correct the mitochondrial deficit. This project will compare the function of mitochondria in stem cell derived nerve and muscle cells and reprogrammed cells with the goal of determining which type of cell is best to screen for drug treatments. Treatments for mitochondrial disease will benefit children and adults with mitochondrial disease as well as common diseases in older people. This this collaborative CIRM project between two research groups brings together expertise in mitochondrial disease, cardiac disease, neurodegenerative disease and stem cell technology to improve understanding of mitochondrial function in stem cells with the goal of finding treatments for life-threatening diseases.
Statement of Benefit to California:
Californians have invested heavily in stem cell research with its promise of treatments for many serious diseases. For stem cell technology to fulfill its promise it must be safe and effective. This research collaboration brings together physicians and basic researchers to investigate the important role of mitochondria in stem cells. Mitochondria are critical energy producing organelles within cells. Despite their importance there is little known about the function of mitochondria in stem cells or in nerve and muscle cells derived from stem cells. One important aim is to find out if disease carrying mitochondrial DNA mutations which occur with aging and even at birth are carried into stem cells and affect cell metabolism. This research will provide a better understanding of stem cell biology and may help avoid problems in future stem cell treatments. Our focus is on mitochondrial disease and the use of stem cell technology to search for treatments. Mitochondrial diseases are devastating and often fatal. 50% of cases occur in children without effective treatments at present. The role of mitochondrial DNA and nuclear DNA mutations that impact mitochondrial function is extremely important. Assays of mitochondrial function will be used to screen candidate molecules, and those available in an library of FDA approved drugs. If successful, this study will have a high impact on potential treatments for a group of serious diseases and may benefit patients treated with stem cells.
This proposal is focused on developing disease-in-a-dish models for mitochondrial disease and exploring the use of these models to investigate pathogenesis mechanisms and to screen candidate drugs. Mitochondrial diseases affect 1 in 2000 individuals, and very few treatments are currently available. The first specific aim is to generate induced pluripotent stem cell (iPSC) lines from fibroblasts of patients with several mitochondrial disorders. The second aim is to derive neurons and skeletal myotubes from patient fibroblasts by direct reprogramming. The third specific aim is to compare mitochondrial DNA and mitochondrial function in differentiated cells derived via IPSC and via direct reprogramming. The fourth aim is to use derived cells for screening of drug candidates that correct metabolic defects. Significance and Innovation - Reviewers agreed that the project is concerned with a critical health problem and that effective treatments for mitochondrial disorders are severely lacking. - The studies could provide new insights into mitochondrial disease, but reviewers felt that the proposal lacked substantial innovation. - Reviewers felt that aims 2 and 3 lacked justification or a compelling rationale. Feasibility and Experimental Design - Reviewers expressed serious concerns about the projectís feasibility, citing a lack of clear experimental design, unclear objectives and the absence of a unifying hypothesis. - Much of the proposed work is comprised of a list of methods without a clear indication of how they will be used to address the project aims. - Preliminary data were insufficient and did not adequately support the specific aims. - Reviewers identified a number of deficiencies including inadequate experimental detail, lack of critical controls and inadequate statistical analysis. Principal Investigator (PI) and Research Team - The PI and research team members have solid expertise in mitochondrial disease. - Reviewers expressed concerns about the PIís recent productivity and apparent lack of other research support. - The research team includes co-investigators with excellent qualifications and appropriate experience. Responsiveness to the RFA - The proposed research is responsive to the RFA.