Congratulations to the two investigators who have received the KL2 Award! The KL2 award is a multidisciplinary mentored career development program which will provide Sadiya Khan, MD, MS, Assistant Professor of Medicine (Cardiology) and Tracy Gertler, MD, PhD, Instructor of Pediatrics (Neurology) with career development resources, educational opportunities, salary support and career guidance.
Sadiya Khan, MD, MS, Assistant Professor of Medicine (Cardiology)
Dr. Khan will use this award to foster her scientific and professional development into an independent physician-scientist and a leader in translational cardiometabolic research. With the help of her mentors, Drs. Lloyd-Jones, Vaughan, and Hou, she has designed a specific training plan to build upon her background in basic and epidemiologic investigation that involves didactic coursework, analytic experience through a supervised research project, and interaction with a multidisciplinary team of sponsors with expertise in cardiovascular epidemiology, vascular biology, and epigenetics.
The overall scientific goal of this project is to investigate the role of DNA methylation in the development of cardiometabolic diseases across the lifecourse utilizing both candidate-pathway approach (adipogenesis pathways) and epigenome-wide association studies in two complementary cohorts, including the Coronary Artery Disease Risk in Young Adults and an Old Order Amish cohort.
Tracy Gertler, MD, PhD, Instructor of Pediatrics (Neurology)
Dr. Gertler will use KL2 funding to further investigate the relationship between Malignant migrating partial epilepsy of infancy (MMPEI) a type of epileptic encephalopathy (EE) and a gain-of-function mutation within the KCNT1 gene encoding Slack, a sodium-activated potassium channel. Quinidine has been reported as a uniquely efficacious anticonvulsant, suggesting that targeting neuronal excitability in EE is therapeutically beneficial, yet its use is limited by non-specific channel block in the brain and heart. Advances in EE are further complicated by a lack of understanding of the neuronal subtype within the brain driving the epileptogenic circuit. This project seeks to delineate the molecular mechanisms governing gain-of-function of Slack channels in a mammalian heterologous expression system and in human neurons differentiated from patient-derived induced pluripotent stem cells (iPSCs), representing a novel attempt to model pathogenic ion channels in mammalian cells and human neurons.
Automated electrophysiology will be used to screen a limited panel of potassium channel blockers and quinidine-like compounds to identify selective and potent blockers of Slack channels for use in additional experiments as well as potential therapies for MMPEI. By identifying the mechanism of ‘overactive’ Slack channels and developing a select panel of drugs which block its gain-of-function, she hopes to refine a more precise approach to treating patients with severe global impairment and intractable epilepsy due to KCNT1 mutation.