Mitochondrial encephalomyopathies are important causes of mental retardation. The investigators are focusing on disorders associated with mitochondrial DNA (mtDNA) point mutations, especially mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). In Project I, Dr. Petra Kaufmann will continue to characterize the natural history of MELAS, correlating clinical course in probands and oligosymptomatic relatives with cerebral and muscle biomarkers assessed by MRSI and 31P-NMR. She will also initiate a clinical trial with idebenone, an effective ROS scavenger already tested in other mitochondrial disorders. This is a placebo controlled, randomized, blinded three-year study of a large cohort of MELAS patients. In Project II, Dr Eric Schon will concentrate on pharmacological approaches to mtDNA-related disorders by evaluating the effectiveness of compounds designed to facilitate electron transport through the respiratory chain in cybrid cultures grown under the pressure of ketogenic medium replacing glucose. He will also assess whether heteroplasmic shifting in ketogenic media is due to selective autophagy of mitochondria harboring mtDNA mutations. In Project III, Dr Mercy Davidson will employ an in vitro model of the blood-brain barrier (BBB) that she has constructed to confirm neuropathological data suggesting a breakdown of BBB function in MELAS. She will also test candidate therapeutic agents on the BBB model in which the co-cultures of human astrocytes and endothelial celis will be either normal or homoplasmic for the m.3243A>G MELAS mutation. In the Administrative Core, Dr Salvatore DiMauro and Dr. Michio Hirano will provide direction, administration, and external consultation. In the Technical Core, Dr. Ali Naini will provide technical service (tissue culture, cybrid generation), diagnostic tools (histochemistry, biochemistry, molecular genetics), and manage shared equipment for the project as a whole.

Public Health Relevance

Mitochondrial encephalomyopathies due to mutations in mtDNA are generally devastating diseases for which there is no effective therapy. The relevance of this program project is two-fold: (i) it will explore rational therapeutic approaches both in a clinical trial and in experimental settings;and (ii) it will directly or indirectly explore pathogenic mechanisms, which, in turn, may lead to novel therapeutic strategies.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Program Projects (P01)
Project #
5P01HD032062-20
Application #
8616076
Study Section
Special Emphasis Panel (ZHD1-MRG-C (DS))
Program Officer
Parisi, Melissa
Project Start
1996-12-01
Project End
2015-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
20
Fiscal Year
2014
Total Cost
$1,198,089
Indirect Cost
$425,347
Name
Columbia University
Department
Neurology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Peverelli, Lorenzo; Gold, Carl A; Naini, Ali B et al. (2014) Mitochondrial myopathy with dystrophic features due to a novel mutation in the MTTM gene. Muscle Nerve 50:292-5
Tyynismaa, Henna; Schon, Eric A (2014) Mixing and matching mitochondrial aminoacyl synthetases and their tRNAs: a new way to treat respiratory chain disorders? EMBO Mol Med 6:155-7
Levy, Rebecca J; Ríos, Purificación Gutierrez; Akman, Hasan O et al. (2014) Long survival in patients with leigh syndrome and the m.10191T>C mutation in MT-ND3 : a case report and review of the literature. J Child Neurol 29:NP105-10
Yien, Yvette Y; Robledo, Raymond F; Schultz, Iman J et al. (2014) TMEM14C is required for erythroid mitochondrial heme metabolism. J Clin Invest 124:4294-304
Area-Gomez, Estela; Schon, Eric A (2014) Mitochondrial genetics and disease. J Child Neurol 29:1208-15
Weiduschat, Nora; Kaufmann, Petra; Mao, Xiangling et al. (2014) Cerebral metabolic abnormalities in A3243G mitochondrial DNA mutation carriers. Neurology 82:798-805
Garcia-Diaz, Beatriz; Garone, Caterina; Barca, Emanuele et al. (2014) Deoxynucleoside stress exacerbates the phenotype of a mouse model of mitochondrial neurogastrointestinal encephalopathy. Brain 137:1337-49
Garone, Caterina; Garcia-Diaz, Beatriz; Emmanuele, Valentina et al. (2014) Deoxypyrimidine monophosphate bypass therapy for thymidine kinase 2 deficiency. EMBO Mol Med 6:1016-27
DiMauro, Salvatore (2013) Mitochondrial encephalomyopathies--fifty years on: the Robert Wartenberg Lecture. Neurology 81:281-91
Emmanuele, Valentina; Sotiriou, Evangelia; Rios, Purificacion Gutierrez et al. (2013) A novel mutation in the mitochondrial DNA cytochrome b gene (MTCYB) in a patient with mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes syndrome. J Child Neurol 28:236-42

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