White Matter Injury in Congenital Heart Disease: Oligodendrocytes at the Intersection of Development and Injury

Doctor's Name: 
Srinivas Manideep Chavali
University of California, San Francisco

Collaboratively awarded through the CHF and AHA Congenital Heart Defect Research Awards

(Total Grant Amount $103,328; CHF portion = $31,915.95)

Newborns with congenital heart disease (CHD), although treated by surgery, develop a range of neurological disorders later-on in their lives. Research suggests that these neurodevelopmental disabilities are a result of delayed brain maturation. My research focuses on oligodendrocytes, a special brain cell that is responsible for generation of myelin which insulates axons to ensure proper nerve signal transmission and brain development. This process is called myelination. Oligodendrocytes need an adequate supply of oxygen and nutrients from blood to achieve proper myelination. But newborns with CHD have an irregular blood flow to their brain, resulting in insufficient/delayed myelination which leads to neurological disorders. My research is focused on understanding this process further.        

My preliminary data suggests that oligodendrocytes can directly induce blood vessel formation in brain during development, presumably to obtain oxygen and nutrients to kick start myelination. Oligodendrocytes express a molecular signal called Wnt7, through which they induce this blood vessel formation. I want to understand how this process is affected in congenital heart disease (CHD). I generated a mouse lacking this Wnt7 signal specifically in oligodendrocytes, using which I plan to determine if this signal is crucial for myelination and blood vessel development in brain. I will also investigate what happens to these oligodendrocytes in a genetically engineered mouse that mimics CHD condition, which will help us understand what goes wrong in brain development of children with CHD.

While poor neurodevelopmental outcomes in the survivors of congenital heart disease (CHD) remain a serious concern, the underlying pathology is not yet clearly understood. The results from this proposal will improve our understanding of delayed brain maturation seen in newborns with CHD. Furthermore, it will also elucidate a possible role for oligodendrocytes as "neuroprotective" cells during low oxygen conditions as seen in CHD. Understanding the interactions between oligodendrocytes and blood vessels during normal development and how these interactions will be altered in CHD conditions will further aid in identifying therapeutic approaches that can enhance myelin recovery/repair and brain development.

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