Several respiratory pathophysiologies including SIDS, Rett syndrome, and CCHS feature both disordered breathing and are associated with brainstem noradrenergic system (NA) abnormalities. However, the central NA system is diverse, spread across 10 anatomically distinct nuclei in the brainstem, and sends projections throughout the nervous system to server a multitude of behavioral and physiological functions. Thus, it remains unclear how the central NA system is organized to regulate breathing and how this NA neurons may play a role in pathophysiologies such as SIDS and Rett Syndrome. To determine the role of the central NA system in respiratory control and disease, we have built a number of dual recombinase intersectional genetic tools for precise and non-invasive circuit mapping and pair these models with our custom designed equipment to measure cardio-respiratory and metabolic function in mice.
Screening for genes and pre-natal exposures in Sudden Infant Death Syndrome
Sudden Infant Death Syndrome claims the lives of as many as 14 infants each day in the United States alone. SIDS is typically defined as the death of an otherwise healthy infant, which leave few clues to understand how this devastating disease may occur. However, carefully controlled post-mortem studies have identified subtle brainstem abnormalities in areas critical to breathing. It remains unclear if these subtle abnormalities stem from genetic mutations, pre-natal exposures such as smoking and alcohol or both. To answer that question, we have developed a closed loop automated neonate respiratory measurement platform (https://www.youtube.com/watch?v=FiOV1F6fnFA). Using these robotic platforms, we are able to simultaneously test the breathing of large numbers of neonate mice under SIDS like conditions. We are currently leveraging these platforms to first screen a wide array mouse genetic mutants for SIDS like phenotypes and as well as to better understand how pre-natal exposures including alcohol, tobacco, stress, and diet and influence protective neonate respiratory reflexes.
Mapping the innervation of the knee joint to understand pain pathways
Pain caused by degenerative joint diseases such as osteoarthritis (OA) are a major cause of morbidity and mortality with primary impact on quality of life as well, and secondaryconsequences associated with opioid use and dependence. The current opiate epidemic claims more than 70,000 lives annually, driving a massive unmet medical need. In osteoarthritis, therehave been few therapies that effectively modify disease course (e.g., in osteoarthritis, OA) while modifying pain that would reduce opiate use in the patient population. An important requirement for developing optimal combinatorial approaches to complex degenerative diseases of the joint, like OA, will be to understand and to map the multidimensional neuronal innervation of join associated tissues including bone, cartilage, joint capsule, ligament, tendon, fascia, and muscle. Thus, we aim to identify patterns of neuronal connectivity in the knee joint to clear a path for understanding functional and anatomical circuits that mediate pain perception in the course OA and the set the stage for safer and efficacious pain treatments.