Calcitriol for the treatment of brain calcification through upregulation of SLC20A2 Primary Familial Brain Calcification (PFBC) is a neurodegenerative condition with calcium deposits forming in the basal ganglia and thalamus. Brain calcification has also been observed in 20% of individuals over the age of 65. Patients often display heterogeneity in term of symptoms, often including Migraine, Dysarthria, Dystonia and seizures. So far, mutations in SLC20A2 (Phosphate transporter), Platelet Derived Growth Factor-B (PDGF-B) and PDGF-receptor ? (PDGFR?) account for approximately 50% of reported PFBC patients. Mice null or hypomorphic for SLC20A2 or PDGF-B, respectively, display calcifications in the thalamus and mid-brain. In this project, we will use mice with conditional knock out (KO) of PDGF-B in endothelial cells as a model to study calcification of the brain. The central hypothesis of this project, formed from our previous publication, is that calcitriol decreases brain calcification through upregulating the phosphate transporter, SLC20A2 in the brains of PDGF-B conditional KO mice. The objective of this research will be accomplished through 2 main objectives. 1) will test whether calcitriol mediated inhibition of calcification in vitro is translatable to an in vivo mouse model. 2) Will identify the mechanism and receptor by which calcitriol works to upregulate expression of SLC20A2, a key phosphate transporter. If calcitriol is effective in reducing brain calcification in a mouse model, as it was in vitro, the data might be used and directly translated to a clinical setting. Further, the results might be directly transferable to other diseases where soft tissue calcification is a major factor, such as atherosclerosis.
Brain calcification occurs in ~20% of individuals over the age of 65, chiefly in the basal ganglia and hypothalamus. This can cause an array or symptoms including migraines, dysarthria and dystonia. Other than palliative care, no treatment exists for stopping the development of these calcium deposits in the brain. This proposal will build on our published work demonstrating that Vitamin D3 (Calcitriol) can be used to reduce calcification through upregulation of SLC20A2, a key phosphate transporter.
