Our Program Project Grant (PPG) will determine if the mechanisms by which estrogens act to impact the brain and cognition diverge under conditions of cardiometabolic health and disease. Results will identify conditions under which estrogen treatment will (or will not) change the cognitive aging trajectory that could potentially reduce or delay age-related cognitive disease including Alzheimer’s disease and related dementias.
Our PPG is funded by the NIH through the National Institute on Aging (P01AG071746).
The PPG brings together a collaborative team of scientists from the Brain Institute at Tulane University to lead the four Research Projects and three Support Cores. Our Lead Investigators bring distinct yet complementary areas of expertise to the PPG, each of which is essential to the synergism required to achieve the Program’s overall objective.
Gary P. Dohanich Professor of Brain Science
Professor of Psychology, Tulane School of Science & Engineering
Project 1 Lead, Core A Lead
D. Barbara S. Beckman Professor in Pharmacology
Associate Professor of Pharmacology, Tulane School of Medicine
Project 3 Lead, Core B Co-Lead
Professor of Pharmacology, Tulane School of Medicine
Project 2 Lead
Professor and Chair of Cell & Molecular Biology, Tulane School of Science & Engineering
Core C Lead
Professor of Physiology, Tulane School of Medicine
Project 4 Lead, Core B Co-Lead
We hypothesize that mechanisms by which estrogens impact the brain and cognition diverge under conditions of cardiometabolic health and disease. First, status of cardiovascular and metabolic health alters mechanisms by which estrogens act directly on memory systems of the brain (blue arrows) including the hippocampus (Project 1) and cortex (Project 2). Second, cardiovascular and metabolic health impact mechanisms by which estrogens act directly on cardiovascular (Project 3) and metabolic (Project 4) systems (green arrows), which subsequently impact the brain.
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.
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.
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.
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.
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.
Our shared cores provide administrative oversight and provide critical consistencies in models and procedures to ensure scientific rigor and reproducibility of results across projects.
Activities of the Core A are integrated in all aspects of the PPG and ensure its development as a synergistic research program. Core A provides budgetary oversight and administrative and statistical support for all Projects and Cores.
Provides consistent models and measurements of cardiometabolic conditions & physiological function across all four projects.
Provides consistent models and measurements of midlife estradiol use and cognitive function across all four projects.