Rodney Shackelford, DO, PhD, Assistant Professor of Pathology, has been awarded a $40,000 grant from the A-T Children’s Project for his research project titled, “Pharmacologic Correction of the Cellular Sulfide Pool as a Treatment for Ataxia-Telangiectasia,” which will officially begin on August 1, 2019.
Ataxia-telangiectasia mutated (A-T) is a rare genetic autosomal recessive disorder, which means that two copies of an abnormal gene are present and making the disorder develop. A-T is a characterized by progressive ataxia (a group of uncommon neurological disorders characterized by problems with balance and coordination) secondary to cerebellar Purkinje cell loss, pre-mature aging, oculocutaneous telangiectasias (visibly dilated blood vessels in the eye), immune dysfunction, increased cellular oxidative stress, and an approximately one-thousand fold increased cancer risk, particularly for leukemias (blood cancers).
The clinical course of A-T is progressive and unrelenting, with most affected individuals living only into their early twenties, often dying from leukemia, pneumonia, failure to thrive, or choking on food due to poor motor function. At the molecular level, A-T results from loss of the ataxia-telangiectasia mutated (ATM) gene product function on chromosome eleven. ATM plays a central role in the sensing and repair of double-stranded DNA breaks, cellular responses to oxidative stress and subsequent p53 induction and cellular checkpoint initiation, and the regulation of mitochondrial function. Dysregulated ATM activity has also been implicated in Type II Diabetes. The cause of A-T is the inability of A-T cells to efficiently repair double-stranded DNA breaks, resulting in persistent broken DNA, increased mutagenesis, cell death, and an elevated cancer risk.
Dr. Shackelford’s work involves identifying pharmacologic agents that will lower double-stranded DNA breaks in A-T cells to increase cell viability and ultimately lead to a treatment for A-T.