The broad objectives of our research are to understand the mechanisms by which astroglial cells sense neuronal injury, triggering a complex set of phenotypic changes and functional alterations. Phagocytosis is a fundamental cellular process intensely studied in the immune system, required for ingestion and destruction of microorganisms, apoptotic cells and abnormal particles. Recent advances have elucidated core mechanisms and molecular components of two major engulfment pathways enabling recognition, engulfment and disposal of apoptotic cells without damaging neighboring healthy cells and tissues. The phagocytic removal of degenerating neural cells, their processes and synapses is carried out by both astroglia and microglia, although the vast majority of work has focused on the latter. However, there is a small but compelling body of evidence implicating astroglia (broadly defined here as GFAP-expressing neuroglia) as highly capable phagocytes in certain physiological and pathophysiological contexts. This proposal addresses two key questions at both the cellular and molecular levels: -Do astroglial cells have specific roles in the physiological clearance of apoptotic neurons, axons, and synapses during CNS development? -Does the ELMO1/BAI1 complex serve an essential role in astroglial phagocytic clearance? We propose to employ state-of-the art astroglial-specific conditional knockouts to selectively inactivate Rac1 and ELMO1, two key components of the phagocytic machinery. This project will be the first to directly test in vivo the ability of astroglia to perform phagocytic clearance of neurons, processes and terminals. Cell culture phagocytosis assays will complement the conditional knockout approaches.
Aim 1 : Test the importance of astroglial phagocytosis in CNS development and degeneration using an inducible, astroglial-specific knockout of Rac1 as a potent phagocytosis-disabling manipulation.
Aim 2. Test the necessity of ELMO1 and/or BAI1 in vivo for astroglial phagocytosis using an inducible, astroglial specific knockout mouse
During brain development and following brain injury, the corpses of dying nerve cells and their long extensions, axons, must be removed in order to ensure proper function. This process, known as phagocytosis, is intensely studied in the immune system but not in the nervous system. This proposal seeks to understand the roles of one brain cell type, the astrocyte, and intracellular mechanisms involved in the phagocytic clearance of degenerating neurons and axons.
| Sokolowski, Jennifer D; Nobles, Suzanne L; Heffron, Daniel S et al. (2011) Brain-specific angiogenesis inhibitor-1 expression in astrocytes and neurons: implications for its dual function as an apoptotic engulfment receptor. Brain Behav Immun 25:915-21 |
| Sokolowski, Jennifer D; Mandell, James W (2011) Phagocytic clearance in neurodegeneration. Am J Pathol 178:1416-28 |
| Daubert, Elizabeth A; Heffron, Daniel S; Mandell, James W et al. (2010) Serotonergic dystrophy induced by excess serotonin. Mol Cell Neurosci 44:297-306 |
