This proposal describes a five-year career development program in the neurobiology of inborn errors of mitochondrial metabolism. The principal investigator (PI) has completed postgraduate training in neurochemistry and residency training in pediatric neurology at UT Southwestern. He has a strong background in the study of neurometabolism and, over the course of this K08 award at The Rockefeller University, he aims to expand his skills in advanced microscopy, transcriptomics, and metabolomics to study how defective mitochondrial metabolism compromises brain development and causes disease. Mitochondrial disorders represent the most common form of inborn errors of metabolism (1:3000 births). These disorders frequently disrupt the development of the brain, particularly of the cerebellum, which is affected in ~70% of patients. The cerebellar phenotype is especially pronounced in pyruvate dehydrogenase deficiency (PDHD), one of the most common mitochondrial disorders in children, presenting clinically from severe cerebellar hypoplasia to intermittent ataxia. The lack of mechanistic understanding of cerebellar deficits in mitochondrial diseases has prevented the expansion of therapeutic options, which are currently limited to symptomatic treatments. The overall objective of this project is to identify mechanisms that underlie cerebellar developmental disease in mitochondrial disorders and apply effective therapies accordingly. To achieve this goal, the PI will investigate developmental and metabolic mechanisms involved in abnormal cerebellar formation in the prototypical mitochondrial disease with cerebellar involvement: PDHD. The PI will be mentored via customized tutorial interactions with his primary advisor, Dr. Mary E. Hatten (neurodevelopment), and three co-mentors, Dr. Nathaniel Heintz (molecular neurobiology), Dr. Justin Cross (metabolomics), and Dr. Thomas Carroll (bioinformatics). Preliminary data from a mouse model of PDHD reveal that glucose metabolism in the cerebellum is impaired and that proliferation and migration of granule cells (GC) is compromised. The central hypothesis is that PDHD disrupts cerebellar formation by limiting GC development as a result of impaired glucose metabolism.
Two specific aims are proposed: 1) to elucidate developmental processes that underlie abnormal cerebellar formation in PDHD; and 2) to identify metabolic mechanisms relevant to the cerebellar disease in this condition. Under the first aim, key steps of GC development will be studied using advanced microscopy. For the second aim, proven transcriptomics and metabolomics will be applied to identify and treat metabolic defects in the PDHD cerebellum. The research proposed is significant because it is expected to advance our understanding of how mitochondrial diseases disrupt cerebellar development and translate promising findings to patients. This proposal is innovative because it combines advanced methodologies from developmental neurobiology and biochemistry to address previously unanswerable questions. Long-term, the PI aims to apply the skills learned to expand the understanding of mitochondrial disorders that compromise cerebellar development in order to improve patient care.
The proposed project is relevant to public health because it represents a new strategy to identify mechanisms by which mitochondrial disorders impair brain development and cause disease. Understanding how these conditions cause neurological dysfunction, particularly of the cerebellum, will facilitate the design of novel therapies, which are currently limited to life-long palliative efforts. Thus, the research proposed is relevant to the NIH?s mission because it aims to reduce illness and disability.
