The Role of Basic Helix-Loop-Helix (bHLH) Transcription Factors in Glioma-Associated Microglia
Abstract
Gliomas are the most common primary brain tumors and result in more years of life lost than does any other tumor. In the US, an estimated 24,000 new cases of primary malignant brain and central nervous system (CNS) tumors are diagnosed annually, and approximately 13,000 annual deaths are caused by primary brain tumors. Of the primary brain tumors, gliomas are the most common, and they comprise a heterogeneous group of neoplasms that differ in location, morphology, tendency, progression, and response to therapy. Over the past several years, it has been shown that glioma formation and growth are dependent on regulatory signals that emanate from constituents of the glioma microenvironment, such as CNS resident microglia, tumor-associated macrophages (TAMs), and myeloid-derived suppressor cells (MDSCs), amongst other cells. Gliomas are therefore considered complex microcosms in which the interaction between neoplastic and non-neoplastic cells influences gliomagenesis, progression, and response to therapy. Microglia are the resident macrophages of the CNS that are distributed throughout the CNS, where they function as key immune effector cells in health and disease. These cells are in a prime position to detect threats to the CNS and respond by mounting an effective immune response. However, the regulation of the development and function of microglia by transcription factors in health and disease is poorly understood. In glioma microenvironment, microglia interact with neoplastic cells; however, the nature and mediators of these interactions are still poorly understood. Elucidation of the transcriptional regulation of the development and functions of microglia in the glioma microenvironment represents initial steps toward developing anti-tumor immunotherapies and stroma-directed therapies that can be combined with anti-neoplastic cell-targeted therapies. The overall goal of this project is to investigate how transcription factors regulate the development, function, and maintenance of these essential CNS immune cells, namely microglia in health and disease. We believe that a thorough understanding of the roles of microglia in glioma cannot be achieved without a thorough understanding of the normal regulation of their development and functions, as this normal regulation is what is often disrupted in disease states. Our studies in this project will investigate the normal regulation of the development and function of microglia from their early embryonic to adult stages. We will then use mouse models of glioma to investigate the nature and mediators of the glioma-microglia interactions. Altogether, these experiments will contribute to the elucidation of the transcriptional regulation of microglia development and function in health and disease. This may not only lead to new discoveries in the biology of microglia, but it will also give us insight into how gliomas interact with microglia during glioma formation and progression, and hopefully pave the way for the identification of novel and less toxic therapeutic targets.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110360
Entities
People
- Babacar Cisse
Organizations
- United States Army
- Weill Cornell Medicine