Sunday, May 11, 2025
5/11/2025
Genome Stability in Glia & Disease - Abstract Genome stability is essential for human health. This is apparent from the multitude of inherited human syndromes characterized by defective DNA damage responses. The nervous system is particularly prone to the consequences of genome damage, and most inherited DNA repair deficiency syndromes involve neurodegeneration, neurodevelopmental disorders or brain tumors. Defective maintenance of genome integrity is also increasingly being linked to broader neurologic health issues, including age-related neurodegenerative events that mar cognitive ability and quality of life. Understanding the mechanistic connections between faulty DNA damage signaling and human disease is therefore of fundamental biomedical importance. Most studies dealing with genome instability associated neuropathology focus on neuronal loss, such as the impact on cerebellar granule or Purkinje neurons associated with various spinocerebellar ataxias. However, other features of genome instability associated neurodegenerative syndromes include white matter defects, resulting from oligodendrocyte dysfunction. Given the widespread alterations and reduction in white matter in these diseases, and that most disease-causing gene mutations are ubiquitously expressed throughout the nervous system, it’s very likely that other glial populations are also affected. For instance, neuroinflammation linked to astrocyte and microglia activation also characterize certain diseases caused by DNA repair defects. However, direct mechanistic studies to reconcile the contribution of glia to the pathobiology of genome instability syndromes are sparse. The experiments proposed in this application will provide key data illuminating the glial DNA damage response and how glia contribute to disease pathogenesis. We propose leveraging novel mouse models of neurodegenerative disease with defective DNA damage signaling to determine the critical DNA strand break repair pathways that support glial cell function in the mammalian brain. Accordingly, we will evaluate the oligodendrocyte lineage for DNA damage susceptibility to determine how dysfunction in these glia occur in human genome instability syndromes. Oligodendrocyte responses to DNA damage will also be assessed using chromatin architecture as a predictor of genotoxic susceptibility. Finally, the impact of DNA damage on microglia will be explored in a new model of the neuroinflammatory Aicardi Goutières Syndrome resulting from defective ribonucleotide excision repair. Collectively, these data will provide critical information regarding the central mechanisms that maintain the glial genome and how genome instability in these cells contribute to disease pathogenesis. As effective therapeutic intervention for many neurological diseases is becoming possible, it’s now critical to understand the full spectrum of degenerative changes that occur. Thus, data from this proposal will provide an important framework for understanding progressive aspects of neurological disease resulting from genome instability and will inform therapeutic strategies for treatment.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).