The Effect of Systemic Nicotine on Brain Inflammation and Aging
Description: Aging and nicotine use are well-known independent risk factors for cardiovascular disease and stroke due to their promotion of systemic inflammation that can result in tissue dysfunction, metabolic syndrome, and dementia. The impact of high systemic nicotine exposure on inflammation and mitochondrial damage in the brain remains largely unknown. In this grant we will examine whether the protein called PHLPP (PH domain leucine-rich repeat protein phosphatase), a known regulator of cell survival due to its role in regulating intracellular inflammatory pathways is a key link between nicotine exposure and an aging brain phenotype in young mice. Preliminary data suggests that exposure to nicotine increases PHLPP1 levels and inflammation in the mouse brain, which are associated with an aged mouse. We have previously demonstrated that removal of PHLPP1 protects astrocytes and the brain from oxidative damage, thus nicotine may alter the susceptibility of the brain to aging and injury. Based on our findings we hypothesize that PHLPP1 removal will decrease oxidative stress and alter mitochondria function in the brain in response to nicotine exposure leading to reduced inflammation and injury. Proposed work will examine the role of PHLPP1 on inflammatory signaling, mitochondrial function, and cognitive function following nicotine exposure using in vitro and in vivo systems. To this end, I have designed experiments that assess the effects of oxidative damage on signaling pathways involved in metabolic homeostasis in primary astrocytes and the brain of PHLPP1 gene targeted mice. These findings will provide insight into whether affecting PHLPP is critical for altering neuroinflammation and oxidative damage following nicotine exposure which leads to aging and cognitive decline. Understanding the signaling pathways altered with nicotine exposure by PHLPP isoform removal could ultimately impact strategies to improve cardiovascular disease and stroke outcome and etiology from tobacco use.
Funder: American Heart Association
Amount: $300,000
Funding type: research
Funder scheme: Transformational Project Award
Start date: 2024-07-01
End date: 2027-06-30
Investigators: Nicole Purcell, Nicole Purcell
Institution: Huntington Medical Research Institutes
Subfield: Molecular Biology
Domain: Life Sciences
Funded outputs count: 2
Funder award ID: 24TPA1292400
OpenAlex ID: G7526035124