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Vascular cognitive impairment in hypertension; identification of an age appropriate model.

高血压引起的血管性认知障碍；

基本信息

批准号：
10461131
负责人：
ANNE M. DORRANCE
金额：
$ 23.48万
依托单位：
MICHIGAN STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-15 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10461131
关键词：
1 year old Adrenal Cortex Age Aging Agreement Aldosterone Alzheimer&apos s Disease Alzheimer&apos s disease patient Animal Model Autopsy Behavior Biochemical Blood Pressure Blood Vessels CYP11B2 gene Cerebrovascular Circulation Cerebrovascular Disorders Cerebrovascular system Cerebrum Chronic Clozapine Cognition Disorders Coupled Dementia Demyelinations Development Disease Progression Disease model Drug Delivery Systems Drug Targeting Drug Utilization Enzymes Epidemic Euthanasia Female Functional disorder Funding Goals Hippocampus (Brain)Human Hyperaldosteronism Hypertension Impaired cognition Impairment Incidence Individual Knowledge Laser Speckle Imaging Lead Life Link Measures Mediator of activation protein Methods Modeling Molecular Mus Nerve Degeneration Nutrient Oxides Oxygen Pathway interactions Patients Population Populations at Risk Pre-Clinical Model Preclinical Testing Primary Hyperaldosteronism Production Public Health Receptor Activation Research Signal Pathway Testing Time Translating Vascular Cognitive Impairment Vascular Dementia age effect aged aging population behavior test cerebral artery cerebral hypoperfusion clinically relevant cognitive function comorbidity dementia risk designer receptors exclusively activated by designer drugs frontal lobe hypertensive juvenile animal male middle age mixed dementia model development neurogenesis new therapeutic target novel synaptogenesis therapeutic target vascular injury white matter injury

项目摘要

Abstract The number of patients suffering from dementia is expected to reach epidemic proportions within 30 years. Cerebrovascular disease leads to the development of a specific spectrum of cognitive disorders that range from mild vascular cognitive impairment (VCI) to life altering vascular dementia (VaD). VaD is the second most common type of dementia following Alzheimer’s disease (AD). VaD exists lone in 5-10% of dementia cases, but more commonly appears with, and exacerbates, other dementias including AD. This presents the possibility that the cerebral vasculature is a therapeutic target to slow or stop the development of dementia. Functional cerebral arteries are crucial for nutrient and oxygen delivery, and they could also serve as a conduit for neuroprotective/restorative drug delivery. Any potential dementia treatment will need to undergo preclinical testing in appropriate animal models but the availability of models for VaD is surprisingly limited; the studies proposed will fill this knowledge gap. Strong evidence links midlife hypertension to dementia development later in life. This connection is likely the result of hypertension associated impairments in vascular function and chronic cerebral hypoperfusion. Many signaling pathways have been identified as mediators of the effects of hypertension on cerebral arteries. It is not clear how well these pathways translate to humans because most studies utilized young animals; these models do not account for the combined effects of hypertension and aging. To identify and validate therapeutic targets it is vital that we model that disease progression appropriately; this requires that hypertension does not begin until middle-age. A new model of hypertension has been developed that could be used to recapitulate the time course of hypertension development in the population. In this model, designer receptors exclusively activated by designer drugs (DREADDs) are utilized to induce hyperaldosteronism and hypertension. The AS+/Cre hM3Dq mice express the Gq-coupled DREADD specifically in the adrenal cortex, where receptor activation induces aldosterone synthase expression resulting in primary hyperaldosteronism. Our central hypothesis is that the AS+/Cre hM3Dq mice will be a useful model VCI/VaD that appropriately reflects the aging population and their dementia related co-morbidities. In aim 1 we will evaluate the development of hypertension in AS+/Cre hM3Dq mice when DREADD activation with clozapine N-oxide (CNO) is delayed until middle-age. Aims 2 and 3 will utilize behavioral testing and molecular methods to assess cognitive function. We know that aging and hypertension individually impair cerebral artery function; we do not know if the two conditions have an additive effect. The proposed studies will provide the field with a viable model for preclinical testing of potential therapies for VaD. This model will also allow for the elucidation of the mechanisms linking hypertension to cerebral small vessel dysfunction and cognitive decline in an age appropriate manner. This could lead to the identification of novel therapeutic targets for hypertension associated VaD.

摘要