Document text
Principal Investigator: Kayleigh Marie Voos
Organization: UNIVERSITY OF PENNSYLVANIA
Fiscal Year: 2024
Award: $35,788
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
PROJECT SUMMARY
Human variants in the submembrane cytoskeleton-associated protein ankyrin-B (AnkB) have been identified as
risk factors for diabetes, obesity and cardiometabolic diseases. Mice harboring these human variants have AnkB
deficiency in multiple metabolic tissues, including skeletal muscle (SKM), and develop age-dependent obesity
and systemic glucose mishandling. While SKM is a primary target of AnkB deficiency, how AnkB contributes to
the regulation of SKM cellular metabolism and energetic capacity, and AnkB’s SKM-specific roles in promoting
systemic metabolic homeostasis have not been elucidated.
The goal of this study is to test the overarching hypothesis that AnkB forms a complex with mitochondria and
endoplasmic reticulum (ER) resident proteins to promote the formation of mitochondria-ER contact sites
and calcium transfer between the two organelles. I postulate that this function of AnkB is essential for
maintaining mitochondria homeostasis and for proper skeletal muscle metabolism and bioenergetics.
The first aim will define how AnkB interacts with mitochondria in skeletal muscle and the extent of its contribution
to the formation of mitochondria-ER contact sites and to mitochondria calcium flux. The second aim will define
the contribution of AnkB to SKM cellular respiration and the bioenergetic capacity of SKM. These studies will
provide mechanistic and functional insights into a novel role of AnkB in skeletal muscle metabolism that may
translate to other cell types with high energetic demand, and might be relevant to physiological processes,
including adaptation to exercise and ageing. Moreover, through the proposed work I will uncover novel
pathophysiological mechanisms of AnkB variants that will further explain their contribution to metabolic diseases.
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