Abstract: Nearly 1 in 20 children are diagnosed with a neurodevelopmental disorder (NDD). Sequencing efforts have identified hundreds of genes whose loss-of-function will cause a NDD; despite knowing the genetic causes of many NDDs, we will lack targeted treatments for these disorders. The convergence of symptomology across NDDs suggests there may also be underlying molecular convergence across NDDs that drive brain dysfunction. We use the gene methyl-CpG-binding protein 2 (MECP2) as an exemplar gene whose genetic disruption causes two severe NDDs: Rett syndrome and MECP2 duplication syndrome (MDS). Studying the converging and diverging molecular pathways dysregulated in Rett and MDS revealed that MECP2 directly regulates growth-differentiation factor 11 (GDF11) in the brain; however, the role of GDF11, a TGF-beta ligand, in normal or abnormal brain development has not been deeply studied. Understanding how GDF11 functions is critical, as we discovered that mutations in GDF11 drive neurological dysfunction in patients. The Bajikar lab studies the interplay between genes that drive monogenic NDDs, like MECP2 and GDF11, to discover the underlying mechanisms that are broadly important for brain development in function and how these mechanisms go awry in NDDs.
Abstract: Central nervous system (CNS) metastases in breast cancer patients account for approximately 30% of patient deaths. The curative efficacy of current treatments for brain metastases is almost nonexistent, highlighting a critical need to design novel therapies for metastatic breast cancer patients. One drug development strategy involves activating the immune system to identify and eliminate metastatic tumor cells. Tissue-resident macrophages, including microglia of the CNS, operate as innate immune sentinels that are optimally positioned to interact with insults such as transformed cells. The goal of our lab’s research program is to establish a better understanding of the specific signaling mechanisms that promote protective microglial immunosurveillance of brain metastases. Our current work has identified a beneficial role for the inflammatory kinase RIPK3 and type I interferon (IFN) in promoting tumor immunosurveillance by microglia. Ongoing work in our lab is centered on defining the molecular mechanisms underlying how type I IFN and RIPK3 coordinate microglial activation and function in the context of CNS metastasis. By exploring the pre-clinical efficacy of manipulating these pathways, we aim to identify novel immunotherapy targets in tissue-resident macrophages that could be leveraged in future translational studies aimed at restoring functional tumor immunosurveillance within the CNS.
“COMPLEX MECHANISMS OF IMMUNE REGULATION AND CANCER PATHOGENESIS”
Hosted by Kevin Monahan's Lab
