Friday, November 22, 2024
11/22/2024
Project Summary Strokes are a leading cause of mortality and disability worldwide. There is a dire need for new, effective pharmacotherapeutics that can be administered following stroke to reduce the burden of disease and disorder in the months after insult. The long-term goal of our laboratory is to understand how neuroendocrine modulators can be used to treat ischemic stroke and other neurological diseases associated with advanced age. Considering the inverse correlations between the levels of insulin-like growth factor-1 (IGF-1) and the risk and extent of damage with ischemic stroke in humans, our current goal is to understand the cellular mechanisms that mediate the protective effects of IGF-1. Following a stroke, the core and penumbral regions undergo drastic changes that lead to imbalances in ions, pH, as well as increased levels of extracellular glutamate. These changes instigate an expansion of neuronal death whereby secondary increases in reactive oxygen species, inflammatory cytokine production, and mitochondrial dysfunction in surrounding cells precipitates further damage in the days and weeks following initial insult. Importantly, administration of exogenous IGF-1 to rodent models of ischemia attenuates infarct size, neurological damage, and the functional deficits in commonly seen in spatial learning and memory and sensorimotor function. Evidence from our laboratory has shown that reductions of the IGF-1 receptor (IGF- 1R) in astrocytes reduces their ability to buffer excitotoxic levels of glutamate. Based on this, we proposed that loss of astrocytic IGF-1 signaling could increase the extent of stroke damage. On the other hand, exogenous IGF-1 has also been shown to directly protect neurons from stroke-like insults in vitro, and the extent of protection is significantly influenced by the presence of astrocytes. Thus, it is likely that IGF-1 protects neurons by directly modulating the neurons themselves and/or indirectly, by modulating astrocytes. Our hypothesis is that the functional regulation of both neurons and astrocytes by IGF-1 is critical to minimize damage in ischemic stroke. To address this, we will utilize our novel transgenic mouse models of inducible astrocyte-specific or neuron-specific Cre recombinase to reduce IGF-1R in specific cell populations in the adult brain. These mice will be subjected to ischemic stroke via middle cerebral artery occlusion and we will subsequently analyze the extent of tissue damage, sensorimotor dysfunction, as well as cellular and molecular changes within the surviving tissue. Special emphasis is placed on examining changes in glutamate handling, astrocytic activation and relocation, and key astrocyte functions. These experiments will determine whether astrocytes and/or neurons IGF-1 signaling is necessary and sufficient for the beneficial effects of IGF-1 on attenuating tissue and neurological damage in the time surrounding ischemic stroke. Conclusions from this project will underscore the role of IGF-1 as a master regulator of neuro-glial function in the aging, ischemic brain, and will provide insight on the potential for cell-targeted therapeutics in the days following stroke.
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