Deficient interaction between FKBP12 and ryanodine receptors (RyRs) underlies several neuromuscular, cardiac and neurodegenerative diseases, such as RyR-related myopathies, Alzheimer’s disease and Duchenne muscular dystrophy. This deficiency, which may be caused by nitro-oxidative stress and genetic mutations, results in leaky RyR channels and ultimately leads to dysregulation of calcium homeostasis, endoplasmic reticulum stress, oxidative stress, and cellular dysfunction.

We hypothesized that AHK compounds, novel ligands of FKBP12 developed by our research group, may alleviate this cascade of pathological events and delay the progression of these diseases. The specific objectives of this project are: 1) In vitro evaluation of AHK activity in several RyR1 and RyR2 mutations; 2) Analysis of FKBP12/RyR interaction in mouse models of rare diseases; and 3) Evaluation of AHK activity in disease models with deficient FKBP12/RyR interaction. We are using cellular and animal models of various rare diseases to identify those with deficits in FKBP12/RyR interaction.

We are currently interested in Duchenne muscular dystrophy, RyR1-related myopathies, CPVT cardiomyopathy and retinitis pigmentosa.