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Principal Investigator: Eric Gerald Krause
Organization: UNIVERSITY OF FLORIDA
Fiscal Year: 2019
Award: $381,250
Funding agency: National Heart Lung and Blood Institute
Project Summary
Stressful life events contribute to the etiology of anxiety and hypertension and increase the risk for cardiovascular
disease, which is the leading cause of death in the U.S. Despite a myriad of research, nearly one-third of patients
with anxiety and/or hypertension are resistant to current treatments and understanding the pathophysiology
underlying these disorders is necessary to identify novel therapeutics. Stressors perceived in the environment
or those arising from the internal milieu create neural signals that converge on the paraventricular nucleus of the
hypothalamus (PVN), which integrates these signals and transduces them into cardiovascular, neuroendocrine
and behavioral responses. Chronic unpredictable stress elicits gene x environment interactions that promote
neurochemical plasticity within the PVN that heighten stress responsiveness and promote affective and
cardiovascular disorders. A premise of this proposal is that angiotensin receptor signaling within the PVN is a
key mediator of gene x environment interactions that control cardiovascular reactivity, neuroendocrine axes and
anxiety subsequent to chronic stress. Traditionally, the RAS is considered an endocrine system that elevates
blood pressure by increasing the binding of angiotensin II (Ang-II) to its angiotensin type-1 receptor (AT1R).
However, we recently found that optogenetic activation of neurons in the PVN that express AT1R(s) augment,
but optogenetic inhibition or selective deletion of AT1R(s) from the PVN dampen stress responding in mice.
Concomitantly, we evaluated the influence of brain angiotensin converting enzyme 2 (ACE2) on stress
responding. Angiotensin converting enzyme 2 metabolizes Ang-II into angiotensin 1-7 which promotes cardio-
protection, in part, by activating Mas receptors. Interestingly, we discovered that up-regulating ACE2 activity in
the brain potently dampens stress responding in mice. Collectively, these observations have led to our
overall hypothesis that balance between AT1R stimulation and ACE2 activity dictates excitation or
inhibition of specific neuronal phenotypes within the PVN to promote susceptibility or resiliency to
stress-related disease. We propose the following specific aims to substantiate or refute this hypothesis. Aim
1 uses mice with Cre recombinase directed to AT1R(s) and in vivo optogenetics to test the hypothesis that chronic
excitation of AT1R-expressing neurons in the PVN recapitulates the pathophysiology that follows chronic stress.
Aim 2 uses mice with AT1R selectively deleted from the PVN to test the hypothesis that such receptors mediate
gene x environment interactions that exaggerate stress responding subsequent to chronic stress. Aim 3 uses
mice with ACE2 overexpression directed to neurons that synthesize corticotrophin-releasing-hormone (CRH) to
test the hypothesis that CRH-ACE2 interactions relieve chronic stress-induced pathophysiology. Collectively,
the proposed research will reveal, at a very detailed and mechanistic level, how brain angiotensin signaling
contributes to the etiology of stress-related disease and will inform on novel therapeutics.
Terms: <ACTH-Releasing Factor><Adrenal Glands><Adrenals><Affective Disorders><Angiotensin AT1 Receptor><Angiotensin Converting Enzyme><Angiotensin I-Converting Enzyme><Angiotensin II Type 1 Receptor><Angiotensin Receptor><Angiotensins><Anxiety><Anxiety Disorders><Behavioral><Binding><Blood Pressure><Brain><Brain Nervous System><CD143 Antigens><CRE Recombinase><CRF-41><Carboxycathepsin><Cardiovascular><Cardiovascular Body System><Cardiovascular Diseases><Cardiovascular Organ System><Cardiovascular system><Causality><Cause of Death><Cell Communication and Signaling><Cell Nucleus><Cell Signaling><Chronic><Chronic stress><Comorbidity><Corticoliberin><Corticotropin-Releasing Factor><Corticotropin-Releasing Factor-41><Corticotropin-Releasing Hormone><Corticotropin-Releasing Hormone-41><Cre Lox technology><Cre LoxP system><Cre lox recombination system><Cre lox system><Cre recombinase/LoxP technology><Development><Dipeptidyl Peptidase A><Disease><Disorder><Dysfunction><Encephalon><Endocrine system><Endocrine/Metabolic Organ System><Enterobacteria phage P1 Cre recombinase><Environment><Equilibrium><Etiology><Event><Extremities><Functional disorder><Gene Transfer><Gene x Environment Interaction><Genetic><GxE interaction><Heart Vascular><Hormonal System><Hypertension><Hypophysis><Hypophysis Cerebri><Hypothalamic structure><Hypothalamus><Intracellular Communication and Signaling><Kininase A><Kininase II><Knock-out><Knockout><Laboratories><Life><Limb structure><Limbs><Mediating><Mediator><Mediator of Activation><Mediator of activation protein><Mental Health><Mental Hygiene><Metabolic/Endocrine Body System><Mice><Mice Mammals><Molecular Interaction><Mood Disorders><Murine><Mus><Nerve Cells><Nerve Impulse Transmission><Nerve Transmission><Nerve Unit><Neural Cell><Neurocyte><Neuroendocrine><Neuroendocrine System><Neuronal Transmission><Neurons><Neurosecretory Systems><Non-Trunk><Nucleus><Optics><Paraventricular Hypothalamic Nucleus><Patients><Peptidyl-Dipeptidase A><Pharmacology><Phenotype><Physiologic><Physiological><Physiopathology><Pituitary><Pituitary Gland><Pituitary Nervous System><Predisposition><Production><Psychological Health><Receptor Activation><Receptor Protein><Receptor Signaling><Receptor, Angiotensin, Type 1><Renin-Angiotensin System><Research><Resistant Hypertension><Signal Transduction><Signal Transduction Systems><Signaling><Stress><Susceptibility><Sympathetic Nervous System><Testing><Therapeutic><Thyroid><Thyroid Gland><Thyroid Head and Neck><Vascular Hypertensive Disease><Vascular Hypertensive Disorder><Vasodilatation><Vasodilation><Vasorelaxation><Viral><anxiety-like behavior><axon signaling><axon-glial signaling><axonal signaling><bacteriophage P1 recombinase Cre><balance><balance function><behavior response><behavioral response><biological adaptation to stress><biological signal transduction><cardioprotectant><cardioprotection><cardioprotective><cardiovascular disease risk><cardiovascular disorder><cardiovascular disorder risk><cardiovascular health><causation><circulatory system><co-morbidity><corticotropin releasing hormone><developmental><disease causation><endocrine gland/system><environment effect on gene><gene environment interaction><glia signaling><glial signaling><high blood pressure><hyperpiesia><hyperpiesis><hypertensive disease><hypothalamic><in vivo><indexing><nerve signaling><neural signaling><neurochemical><neurochemistry><neuronal><neuronal signaling><neurotransmission><new drug treatments><new drugs><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel therapeutics><novel therapy><optical><optogenetics><overexpress><overexpression><paraventricular nucleus><pathophysiology><prevent><preventing><reaction; crisis><receptor><recombinase-mediated cassette exchange><resilience><stress response><stress; reaction><stressor><suprarenal gland>