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My laboratory has two main research projects: a basic research project on mitochondrial biology and neurodevelopment, and a translational research project on designing novel therapeutic approaches for incurable mitochondrial diseases.
One of our goals is to understand how the neurogenic basic helix-loop-helix transcriptional factor NeuroD6 links neuronal differentiation to survival during neurogenesis. The gene set enrichment analysis of our genome-wide microarray studies has revealed a link between NeuroD6 and a cluster of mitochondrial biogenic and bioenergetic genes. Furthermore, our functional studies highlighted neuronal-specific regulation of mitochondrial biogenesis, an area that has remained largely unexplored. More specifically, we made three substantial findings: 1) NeuroD6 plays an integrative role in coupling mitochondrial biogenesis with the early stages of neuronal differentiation, the timing of which is critical for proper neuritogenesis; 2) NeuroD6 increases the mitochondrial bioenergetic capacity of neuronal progenitors, thereby conferring tolerance to mitochondrial stressors known to affect neural development; and 3) small-molecule drugs induce mitochondrial biogenesis and metabolic remodeling in differentiating neuronal cells and embryonic mouse brains.
Our findings on mitochondrial biogenesis and energy metabolism have shifted our goals toward translational research, with the chief objective to investigate a novel therapeutic approach for patients affected with the incurable mitochondrial disorder MELAS. Currently, no therapeutic options are available to patients affected with MELAS. The cardinal hallmark of this fatal neurodegenerative disease is a chronic energy deficit due to mutations in the mitochondrial genome, resulting in mitochondrial dysfunction. Despite our better understanding of the pathogenesis and diagnosis of MELAS, no pharmacological agents can mitigate the ATP deficit and stop the fatal progression of this disease. Presently, we are collaborating with Dr. Gropman, a pediatrician and neurologist specializing in mitochondrial disorders at our affiliated Children’s National Health System. Using fibroblasts derived from skin biopsies performed on MELAS patients, we screen a battery of small molecule drugs to identify the most promising pharmacological agents to rectify mitochondrial dysfunction and to mitigate the chronic energy deficit.
Our NINDS-funded study will advance our understanding of the molecular pathogenesis of MELAS. Our collaborative pre-clinical studies with Children’s National Health System and its Center for Translational Research lay the foundation for clinical studies to evaluate the therapeutic value of the most promising candidates on MELAS patients. Our ultimate goal is to combine translational research with personalized medicine to alleviate the debilitating symptoms of MELAS and other mitochondrial disorders.
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论文共 60 篇作者统计合作学者相似作者
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Neurotherapeuticsno. 4 (2024): e00397
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCESno. 3 (2024): 1386
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#Papers: 60
#Citation: 1245
H-Index: 22
G-Index: 35
Sociability: 4
Diversity: 0
Activity: 0
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