Metabolic and Hormonal Mechanisms of VCID

VCID 的代谢和激素机制

• 批准号: 9912207
• 负责人: Kristen Leanne Zuloaga
• 金额: $ 36.1万
• 依托单位: ALBANY MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-15 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9912207
• 关键词: 4-vinylcyclohexene diepoxide; Aromatase; Aromatase Inhibition; Astrocytes; Blood - brain barrier anatomy; Blood Vessels; Blood flow; Brain; Cells; Cerebrum; Chronic; Cognitive deficits; Data; Dementia; Diabetes Mellitus; Diet; Endothelium; Enzymes; Estradiol; Estrogens; Failure; Female; Future; Goals; High Fat Diet; Hormonal; Human; Impaired cognition; Impairment; Injections; Intervention; Knock-out; Knockout Mice; Knowledge; LoxP-flanked allele; Menopause; Metabolic; Metabolic Diseases; Microspheres; Modeling; Mus; Operative Surgical Procedures; Ovary; Pathology; Patients; Perfusion; Perimenopause; Plasma; Postmenopause; Prediabetes syndrome; Premenopause; Prevention strategy; Preventive treatment; Production; Risk; Risk Factors; Rodent; Role; Source; Testing; Time; Tissues; Vascular Cognitive Impairment; Viral Vector; Woman; aromatase deficiency; behavior test; brain endothelial cell; cardiovascular disorder risk; cerebral hypoperfusion; cerebrovascular; cognitive function; dementia risk; diabetic; high risk population; improved; insight; men; middle age; mixed dementia; mouse model; neuroinflammation; non-diabetic; novel strategies; novel therapeutic intervention; overexpression; protective effect; sham surgery; therapy development; vascular cognitive impairment and dementia; white matter damage

PROJECT SUMMARY/ABSTRACT Half of all dementia patients have evidence of vascular contributions to cognitive impairment and dementia (VCID), either as a single pathology or as a mixed dementia. Diabetic women have a 2.3-fold greater risk to develop VCID than non-diabetic women. However, even though prediabetes causes cognitive deficits and is 3 times more common than diabetes, little is known regarding the effects of prediabetes on VCID. Further, why metabolic disease is a larger risk factor for VCID in women than in men is unknown. Women are unique in that they go through menopause. Menopause accelerates mid-life risk factors for dementia, by increasing risk for cardiovascular and metabolic diseases. Despite the fact that nearly all women with VCID are post-menopausal, the influence of menopause on VCID is a critical gap in knowledge. The objective of this proposal is to understand the important interaction between menopause and prediabetes on VCID pathology and identify a novel therapeutic approach to treat VCID in post-menopausal females. Our preliminary data in a mouse model of VCID demonstrate that prediabetes reduces blood flow and accelerates cognitive deficits in peri- menopausal females, the underlying mechanism is unknown but may be related to neuroinflammation or vascular damage; effects in post-menopausal females have not been assessed. In post-menopausal women, the major source of estrogen is local synthesis of 17-β estradiol by the enzyme aromatase in a variety of tissues. Brain aromatase and brain estradiol levels are drastically decreased in women with other forms of dementia, however, the role of aromatase in VCID has yet to be explored. We have discovered that inhibition of aromatase severely impairs cerebrovascular function in female mice suggesting that targeting aromatase in females may be an effective strategy for increasing blood flow to the brain, thereby reducing VCID pathology. We hypothesize that cerebral hypoperfusion, cognitive deficits, and neuroinflammation induced by prediabetes will be exacerbated in post-menopausal females and will be reversed by increasing production of brain-derived estradiol. In Aim 1, using a mouse model of VCID, we will determine if menopause exacerbates cerebral hypoperfusion, neuroinflammation, and cognitive deficits induced by prediabetes. In Aim 2, we will determine if loss of endothelial or astrocytic aromatase causes cerebral hypoperfusion and exacerbates cognitive deficits and neuroinflammation in post-menopausal female mice. In Aim 3, we will determine if increasing estradiol specifically in the brain improves vascular function and reduces cognitive deficits and neuroinflammation in prediabetic post-menopausal female mice. We anticipate these studies will provide mechanistic insight that will facilitate future interventions to decrease the burden of dementia by identifying a novel approach to treat VCID in post-menopausal females: enhancement of brain estradiol. Without knowledge of the effects of menopause on VCID in prediabetic females, development of therapies to treat this high-risk population remains unlikely.

项目摘要/摘要 所有痴呆症患者中有一半对认知障碍和痴呆症有血管贡献 （VCID），无论是单一病理学还是混合痴呆症。 但是，尽管糖尿病会导致认知缺陷，但发展与非糖尿病女性相比 对于糖尿病对VCID的影响，比糖尿病更常见的时代更为常见。 代谢疾病是女性VCID的危险因素，而不是男性的危险因素。 他们经历更年期。 尽管几乎所有患有VCID的女性都是绝经后，但心血管疾病和代谢性疾病 更年期对知识的VCIDTICTIC差距的影响是。 了解更年期和糖尿病前期在VCID病理学上的重要相互作用，并确定 新的治疗方法可以在绝经后女性中信任VCID。 VCID表明，糖尿病前期会减少群集，并加速某种认知缺陷 更年期女性，潜在机制尚不清楚，但可能与神经炎症或 尚未评估血管损害； 雌激素的主要来源是通过多种酶芳香酶局部合成17-β雌二醇 组织。 然而，痴呆症在VCID中的作用尚未探索。 芳香化酶的表情会损害雌性小鼠的脑血管功能，暗示靶向芳香酶 女性可能是增加血液流向大脑的有效策略，从而减少VCID病理学。 我们假设糖尿病前诱导的脑灌注不足，认知缺陷和神经炎症 将在绝经后女性中加剧 雌二醇在AIM 1中使用VCID的小鼠模型 糖尿病前期诱发的灌注不足，神经炎症和认知缺陷。 内皮或星形胶质细胞芳香酶的丧失会导致脑灌注不足并加剧认知缺陷 在青春期雌性小鼠3中，我们将确定雌二醇是否增加 特别是在大脑中改善血管功能，并减少认知缺陷和神经炎症 糖尿病后雌性小鼠。 通过确定一种新颖的信任VCID的方法来促进未来的干预措施，以减轻痴呆症的负担 在绝经后女性中：增强脑雌二醇。 在糖尿病前女性的VCID上，治疗这种高危人群的疗法的发展仍然不可能。