Single-Cell Multiomics to Understand Mitochondrial Disease
Abstract
FY21 PRMRP Topic Area: Mitochondrial Disease. Project Overview: Mitochondrial disease affects more than 1 in 5,000 people in the U.S., including many U.S. military Service Members, Veterans, and beneficiaries. We still understand little about mitochondrial disease, which hinders development of effective therapies. Mitochondrion contains its own DNA genome (mtDNA), and disease-causing mtDNA mutations can occur in some mitochondria but not the others, a phenomenon called mtDNA heteroplasmy. The higher the mtDNA heteroplasmy, the more severe the mitochondrial disease symptoms often are. Each cell in a patient’s body may have different mtDNA heteroplasmy levels, and a big challenge is that we don’t currently have an accurate method to measure mtDNA heteroplasmy in a single cell and determine how it affects gene expression and function of that same cell. We have developed a new single-cell technology that addresses this fundamental challenge. We can use this technology to measure simultaneously mtDNA heteroplasmy, mitochondrial and nuclear gene expression, and nuclear chromosome states from the same cell for thousands of cells. We have validated our technology in cell culture and propose to apply it to clinically relevant blood samples from mitochondrial disease patients. Statement of Problem: It is now well established that mitochondrial disease is quite common, with an incidence of more than 1 in 5,000 in adults. It is estimated that 1 in 200 newborn babies harbor one of the 10 common pathogenic mtDNA mutations. Many U.S. military Service Members, Veterans, and beneficiaries are living with mitochondrial disease. There is no cure for mitochondrial disease. Significant knowledge gaps remain in our understanding of the underlying mechanisms of mitochondrial disease, which have slowed the development of effective treatment. One particular challenge in both diagnosis and understanding of mitochondrial disease is how to accurately measure mtDNA heteroplasmy level in individual cells and determine how that affects cellular function. Innovation: Our studies have both conceptual and technological innovations: • We have developed a state-of-the-art new technology that can study the mitochondria state and nuclear gene expression in cells one by one and in a large number of cells. • This will be the first time that we are able to have a comprehensive understanding of all the changes happening in both mitochondria and in nuclear gene expression/genome status in individual blood cells from patients with mitochondrial disease. • In addition to know what, we will also know why. That is, we will gain further understanding of how mtDNA heteroplasmy impacts nuclear gene expression and genome states. Impact: We believe that our proposed studies will generate significant scientific and clinical impact: • Our study will significantly advance our understanding of mitochondrial disease that affects many people including many U.S. military Service Members, Veterans, and beneficiaries. • Our new technology will address a big challenge in the mitochondrial disease field, which is how to accurately measure mtDNA heteroplasmy in a single cell and determine how it affects gene expression and function of that same cell. • We will gain more mechanistic understanding on how and why mtDNA heteroplasmy impact nuclear gene expression and genome states.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210058
Entities
People
- Liming Pei
Organizations
- United States Army