Alejandro Ocampo obtained his PhD in 2012 from the University of Miami for his work under the supervision of Antoni Barrientos on the role of mitochondria in neurodegenerative proteinopathies and aging. Between 2013 and 2017, he performed a post-doctoral training with Juan Carlos Izpisua-Belmonte at the Salk Institute for Biological Studies in La Jolla, California. During his post-doctoral training at the Salk, he developed a novel technology to prevent the transmission of mitochondrial diseases and demonstrated the amelioration of age-associated hallmarks by partial cellular reprogramming. In August 2018, he joined the Department of Pharmacology and Toxicology as Assistant Professor and will continue his work on aging, cellular reprogramming and mitochondrial diseases.
Keywords: aging, epigenetics, cellular reprogramming, stem cells, mitochondrial diseases
Our group conducts research in the areas of epigenetics, stem cells, aging and mitochondrial diseases with the goal of elucidating disease mechanisms and develop novel therapeutic approaches to improve the quality of life of patients.
1) Epigenetic reprogramming of aging and disease
Aging, which is the highest risk factor for most human diseases, can be defined as the progressive decline in the ability of a cell or an organism to resist damage, stress and disease. Aging has been identified as one of the major challenges of modern societies with the world population over 65 estimated to double by 2050.
Aging is characterized by a series of molecular hallmarks including among others genomic instability, mitochondrial dysfunction, telomere shortening, cellular senescence and epigenetic alterations. Epigenetic dysregulation during aging has been observed at multiple levels of organismal complexity ranging from lower organisms to mammals. Similarly, major epigenetic remodeling is observed during cellular reprogramming to pluripotency by expression of the Yamanaka factors (Oct4, Sox2, Klf4 and cMyc). Interestingly, rejuvenation of age-associated phenotypes has been observed during cellular reprogramming. In this line, we have previously demonstrated the amelioration of aging phenotypes and extension of lifespan in a living organism by in vivo cellular reprogramming (Figure 1).
Our goal in the lab is to understand the role of epigenetic dysregulation as driver of aging and disease and develop novel strategies based on epigenetic reprogramming to prevent or revert the manifestation of aging and disease phenotypes.
Figure 1. Amelioration of age-associated phenotypes in vitro and in vivo by partial cellular reprogramming (adapted from Ocampo A. et al. Cell, 2016).
2) Novel therapeutic approaches for the treatment of mitochondrial diseases
Mitochondrial diseases are a group of devastating disorders cause by mutations in mitochondrial DNA (mtDNA) that lead to defects in mitochondrial respiration and energy production. Mitochondrial diseases are present in 1:5000 births and affect primarily highly energetic tissues and organs including heart, brain and skeletal muscle. Currently there is no cure for mitochondrial diseases. In addition, due to the non-Mendelian segregation of mtDNA, preimplantation genetic diagnosis (PGD) can only partially reduce the risk of transmission of mitochondrial diseases.
In most mitochondrial diseases, mutant mtDNA coexists with wild type mtDNA in a situation known as heteroplasmy. The level of heteroplasmy, which determines the severity and age of onset of the disease, can be altered by elimination of mutant mtDNA in a process known as heteroplasmy shift. We have previously developed a novel technology to prevent the transmission of mitochondrial diseases based on the selective elimination of mutated mtDNA (heteroplasmy shift) in oocytes and embryos using mitochondrial-targeted nucleases (Figure 2).
Our goal in the lab is to use induced pluripotent stem cells derived from mitochondrial disease patients to develop novel therapeutic approaches based on the induction of heteroplasmy shift for the treatment of mitochondrial disease patients.
Figure 2. Preventing the transmission of mtDNA mutations by selective elimination of mutated mtDNA using mitochondrial-targeted nucleases (adapted from Reddy P. et al. Cell, 2015).