Our four interrelated projects support the type of integrated, comprehensive investigation necessary to achieve our ambitious objective and allow for the testing of concurrent multiple hypotheses involving multiple mechanisms that may act independently or interactively.
Project 1
Impact of hypertension and high-fat diet on mechanisms by which estradiol affects the hippocampal memory system
The overall hypothesis of Project 1 is that in aging females, cardiometabolic disease, due to associated dysfunction of the ubiquitin/proteasome system, disrupts the ability of estrogens to regulate levels of estrogen receptor (ER) ɑ in the hippocampus, regulation that is necessary for midlife estradiol treatment to exert lasting positive impacts on memory during aging.
Project 2
Impact of hypertension and high-fat diet on estradiol’s role in cortical synaptic plasticity
The overall hypothesis of Project 2 is that cardiometabolic disease prior to menopause impedes the beneficial cognitive effects of hormone therapy by blunting neurovascular coupling via endothelial nitric oxide synthase uncoupling, thus impairing the local network activity and synaptic plasticity required to preserve functional cortical circuits and therefore for cognition.
Project 3
Impact of estradiol on vascular health and subsequent implications for cognitive aging
The overall hypothesis of Project 3 is that cardiovascular disease alters estrogen receptor profile, disrupting the integration of estrogen’s molecular signaling pathways and attenuating estrogen’s cardiovascular effects and downstream protection from Alzheimer’s disease and vascular dementia.
Project 4
Impact of estradiol on the central regulation of glucose homeostasis and subsequent implications for hippocampal function
The overall hypothesis of Project 4 is that insulin resistance caused by high-fat diet impairs downstream signaling pathways necessary for estradiol’s beneficial influence on central regulation of glucose homeostasis, hippocampal LTP, and hippocampus-dependent cognitive function.
