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The Rise and Fall of the Stars in the Brain: Astroglia in Disease and Inflammation

  • Author(s): David, Clement Nicolas
  • Advisor(s): Wilson, Emma H
  • et al.
Abstract

The brain is an extremely complex organ composed of neuronal and non-neuronal cells working en concerto to maintain what we perceive as emotions, thoughts, memories, speech, movement, and much more. Although neurons, and their networks, are the cells responsible for the functional outcome of the brain; glial cells play a crucial role in maintaining homeostasis and are increasingly thought of as active modulators of neuronal function. Astrocytes are large, star shaped glial cells responsible for a multitude of functions including glutamate homeostasis, potassium buffering, metabolic support and some immune functions. Because astrocytes are so critical for normal brain functioning, a loss of function or a gain of deleterious function can severely alter brain chemistry, cause neurodegeneration or worsen an underlying disease. In this thesis, Chapter 2 and 3 discuss potential therapeutics for glioblastoma multiforme (GBM). GBMs usually occur spontaneously, following severe genetic mutations in astrocytes, which then proliferate uncontrollably and cause large, metastasizing tumors and eventually death. GBMs modify their environment, causing neighboring astrocytes and other cells to create a permissive environment for tumor growth. Chapter 2 investigates the changing immune environment in GBMs while Chapter 3 focuses on a direct chemical therapeutic. Chapter 4 of this thesis examines the extent of neuropathology associated with a loss in astrocytes' primary function: the control of extracellular glutamate. Although losing a degree of this critical function is associated with many diseases such as Alzheimer's, amyotrophic lateral sclerosis, epilepsy and more; here, we will investigate it in the context of a prevalent chronic infection with the protozoan parasite Toxoplasma gondii. Whether gaining a deleterious genetic mutation, or losing a critical homeostatic function; disruption of astrocyte functioning in the brain has profound detrimental effects and should be considered as therapeutic targets.

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