Skip Navigation
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Internet Explorer is no longer a supported browser.

This website may not display properly with Internet Explorer. For the best experience, please use a more recent browser such as the latest versions of Google Chrome, Microsoft Edge, and/or Mozilla Firefox. Thank you.

Your Environment. Your Health.

ENGINEERING FAITHFUL ANIMAL MODELS OF MITOCHONDRIAL DISEASE

Export to Word (http://www.niehs.nih.gov//portfolio/index.cfm/portfolio/grantdetail/grant_number/DP2ES030449/format/word)
Principal Investigator: Mishra, Prashant
Institute Receiving Award Ut Southwestern Medical Center
Location Dallas, TX
Grant Number DP2ES030449
Funding Organization National Institute of Environmental Health Sciences
Award Funding Period 30 Sep 2018 to 30 Jun 2023
DESCRIPTION (provided by applicant): Project Abstract/Summary Mutations in mitochondrial DNA (mtDNA) cause untreatable disease in ~1:5000 humans. There is a fundamental gap in studying mtDNA diseases due to a lack of faithful animal models. In particular, our complete inability to engineer the mitochondrial genome has prevented us from creating animal models containing the same deletions/mutations present in the human population. The key technical gap in mtDNA editing is our inability to introduce nucleic acids into the mitochondrion. Bridging this gap is extremely important in order to enhance our understanding of disease pathophysiology, as well as provide a platform for the development and testing of therapeutics. Our long-term goal is to understand the progression of mtDNA disease over an organism's lifespan, and develop appropriate therapeutics. The overall objective is to develop faithful mouse models of mtDNA disease which recapitulate the genetics and physiology seen in human patients. The central hypothesis is that engineering mtDNA deletions or mutations in mouse tissues should recapitulate key features of human mtDNA disease. Our rationale is that studying such models has the potential to enhance our understanding of disease progression in humans. This proposal utilizes multiple approaches to engineer mtDNA disease in mice. First, we will engineer a “competency” system of mitochondria, utilizing evolutionarily conserved bacterial species as a model. By screening through the known competency machineries in bacteria, we will discover and design a protocol for introducing nucleic acids into mammalian mitochondria. In combination with CRISPR/Cas9 technology, this tool will allow the precise engineering of mtDNA for the first time. We envision this approach can be utilized to create animal models containing the same precise genetic mutations found in the human population. Second, we will utilize cybrid technology in order to create mouse cells containing human mtDNA. These cells can then be utilized to create genetic models with the complement of mtDNA from human patients. At the end of the project period, we will have created mice containing engineered mtDNA mutations from human patients. These approaches are innovative in that they attempt to recapitulate the genetics of mtDNA disease as it occurs in patients, thus departing from current models which utilize nuclear-gene knockout alleles to mimic mtDNA mutations. The research is significant in that it will create new animal models which recapitulate the genetics of human disease – a characteristic lacking in currently available models. We expect the availability of these models to the scientific community will accelerate the development of effective therapeutics for patients.
Science Code(s)/Area of Science(s) Primary: 64 - Mitochondrial Disorders
Secondary: 03 - Carcinogenesis/Cell Transformation
Publications No publications associated with this grant
Program Officer Daniel Shaughnessy
Back
to Top