Neuronal mitochondrial quality control in vivo: live imaging of mitophagy in dopamine neurons during aging and age-related neurodegeneration
Edward A. Burton, MD, DPhil, FRCP
Associate Professor, Department of Neurology, School of Medicine
Sarah B. Berman, MD, PhD
Assistant Professor, Department of Neurology, School of Medicine
Claudette M. St. Croix, PhD
Associate Professor, Department of Environmental and Occupational Health, School of Public Health
Mitochondrial quality control, including degradation of irretrievably damaged mitochondria by mitophagy, is likely central to understanding the chronic progressive decline in mitochondrial function that characterizes aging and diseases of aging such as Parkinson’s disease. This project seeks to test the hypothesis that loss of mitophagy underlies PD onset and pathophysiology.
The novel zebrafish transgenic lines generated in this work will enable the determination, for the first time, of how mitophagy is altered during disease pathogenesis or in the presence of nuclear DNA mutations that cause accelerated aging. This will also enable the investigation of an unexplored area in aging research in vivo, in post-mitotic neurons relevant to age-related neurological disease.
$50,000 (requested amount $51,500), 2 years
Mitochondrial calcium in aging and degenerating neurons
Charleen T. Chu, MD, PhD
Professor, A. Julio Martinez Chair in Neuropathology, Department of Pathology, School of Medicine
Arjumand Ghazi, PhD
Assistant Professor, Department of Pediatrics, School of Medicine
Zachary Wills, PhD
Assistant Professor, Department of Neurobiology, School of Medicine
Changes in mitochondrial biology and calcium signaling are implicated in aging and a wide range of aging-related diseases. While model organisms are available to study cytosolic calcium, the potential involvement of altered mitochondrial calcium handling in aging-related processes has typically been inferred rather than directly measured. This pilot proposal aims to translate recent advances in the development of sensitive and specific mitochondrial calcium sensors into a genetically tractable, transparent model organism that could benefit mitochondrial, aging and metabolism researchers in general.
This project investigates whether physiological changes in mitochondrial calcium transport that occur during aging affect the risk of the kinase LRRK2-mediated neurodegeneration, e.g., Parkinson’s disease, by modulating the homeostatic “response to” increased synaptic calcium stress.
$50,000 (requested amount $53,859), 1.5 years
Study of the utility of oral nitrate therapy to improve skeletal muscle bioenergetics and physical capacity in older heart failure patients
Daniel Forman, MD
Professor, Department of Medicine, School of Medicine
Mark Gladwin, MD
Professor, Department of Medicine, School of Medicine
Sruti Shiva, PhD
Associate Professor, Department of Pharmacology & Chemical Biology, School of Medicine
Ana Mora, MD
Assistant Professor, Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, School of Medicine
Anne Newman, MD, MPH
Professor and Chair, Department of Epidemiology, Medicine and Clinical &Translational Science, School of Public Health
The investigators of this project seek to assess the effect of nitrite therapy on patients with reduced and preserved ejection fraction heart failure as compared to age-matched controls. Specifically, this pilot analysis we will focus on the utility of daily nitrite supplements to moderate aerobic (maximal and submaximal) and strength (maximal, endurance, and power) indices as well as underlying skeletal muscle mechanisms (skeletal muscle mitochondrial performance, gene expression, and capillarity).
These goals will be achieved by the completion of two aims: 1) demonstrate that oral nitrite pills provide skeletal muscle physiological benefit in old HFrEF and HFpEF patients; and 2) to demonstrate that improved skeletal physiology achieved using oral nitrate pills is associated with improved clinical indices in old HFrEF and HFpEF patients. Completion of this study will inform important insights regarding nitrite benefits in skeletal muscle physiology and physical function in normal aging, heart failure with reduced ejection fraction, and heart failure with preserved ejection fraction.
$50,000 (requested amount $58,000), 1 year. C3M will cost share the $8,000.
Assessment of peripheral mtDNA damage and dysfunction as a biomarker of Parkinson’s disease
Laurie Sanders, PhD
Assistant Professor, Pittsburgh Institute for Neurodegenerative Diseases, Department of Neurology, School of Medicine
Sruti Shiva, PhD
Associate Professor, Department of Pharmacology and Chemical Biology, School of Medicine
Samay Jain, PhD
Assistant Professor, Department of Neurology, School of Medicine
Aging is the greatest risk factor for the development of Parkinson’s disease (PD), the most common neurodegenerative movement disorder. Currently, no cures or disease modifying therapies for PD exist. This is partially due to the inability to detect the disease before it has progressed to a stage of significant dopaminergic neuronal loss resulting in movement symptoms. The identification and validation of high throughput biomarkers to measure disease progression (as well as identify pre-clinical disease onset) is critical to the development of disease-modifying or even preventative therapies.
This pilot project is designed to characterize and validate mitochondrial DNA (mtDNA) damage and mitochondrial function (in leukocytes and platelets) together as potential biomarkers of PD and PD progression. This pilot project is responsive to the MAM call for proposals in that it broadly addresses the role of metabolic alterations as a predictor of pathological frailty (movement disorder and neurodegeneration) in the context of an important aged population.
$50,000 (requested amount $75,000), 2 year. C3M will cost share $25,000.
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