Impact of disordered mineral metabolism on stroke and cognitive impairment

矿物质代谢紊乱对中风和认知障碍的影响

• 批准号: 8417283
• 负责人: Orlando M Gutierrez
• 金额: $ 30.67万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8417283
• 关键词: 1,25 (OH) vitamin D; 25-hydroxyvitamin D; Accounting; Adult; Adverse effects; African American; Biological Markers; Black race; Blood specimen; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cerebrovascular Disorders; Cessation of life; Clinical; Cognitive; Data; Deficiency Diseases; Diabetes Mellitus; Disease; Epidemiology; General Population; Health; Healthcare; Heart Diseases; High Prevalence; Homeostasis; Hormones; Hypertension; Impaired cognition; Individual; Inflammation; Insulin Resistance; Interleukin-6; Intervention Trial; Leptin; Link; Measures; Mediating; Mediator of activation protein; Metabolism; Minerals; Modeling; Outcome; Parathyroid gland; Participant; Pathway interactions; Phosphorus; Plasma; Play; Prospective Studies; Proteins; Race; Reasons for Geographic And Racial Differences in Stroke; Risk Factors; Role; Sampling; Specific qualifier value; Stroke; Stroke prevention; Testing; Ursidae Family; Vitamin D; Vitamin D Deficiency; Work; adiponectin; adverse outcome; blood pressure regulation; bone; calcium phosphate; cerebrovascular; cohort; design; disability; experience; fibroblast growth factor 23; geographic difference; high risk; improved; indexing; inorganic phosphate; insulin sensitivity; multidisciplinary; novel; novel therapeutics; nutrition; phosphorus metabolism; racial difference; resistin

DESCRIPTION (provided by applicant): Stroke and cognitive impairment are major causes of death and disability in the US and disproportionately impact blacks. While traditional stroke risk factors such as hypertension and diabetes contribute to racial disparities in cerebrovascular outcomes, they are not sufficient to completely explain these findings, suggesting that non-traditional risk factors play an important role. Disturbances in vitamin D and phosphorus metabolism have emerged as non-traditional risk factors for adverse cardiovascular outcomes. Low 25-hydroxyvitamin D (25D) levels are associated with heart disease and death via broad effects on inflammation, insulin resistance and blood pressure control. Disturbances in phosphorus metabolism stimulate the secretion of fibroblast growth factor 23 (FGF23), a bone-derived hormone that maintains phosphorus homeostasis in part by inhibiting the conversion of 25D to its activated metabolite, 1,25-dihydroxyvitamin D (1,25D). Our group and others showed that higher FGF23 levels were associated with adverse outcomes through direct and indirect effects promoting cardiovascular disease and 1,25D deficiency. Moreover, preliminary data from our group suggest that low vitamin D is an independent risk factor for stroke and cognitive impairment. The primary focus of the current proposal is to build upon this prior work by determining whether low plasma 25D levels and excess plasma FGF23 levels are associated with incident stroke and cognitive impairment in a large, national cohort (Aim 1). In addition, since disorders of vitamin D and phosphorus metabolism are more common and severe in blacks than whites, we will determine if they partly underlie racial disparities in stroke (Aim 2). Finally, given that inflammation, insulin resistance and hypertension are key risk factors for cerebrovascular disease, and are interconnected with disturbances in vitamin D and phosphorus metabolism, we will determine whether they partly mediate the associations of 25D and FGF23 with stroke and cognitive decline. We will test these hypotheses by measuring plasma 25D, FGF23 and other key mediators of mineral metabolism including 1,25D, parathyroid hormone, calcium and phosphate in stored blood samples from a specified case cohort of 2,085 participants of the REasons for Geographic and Racial Differences in Stroke (REGARDS) study, a national prospective study of black and white adults designed to identify novel risk factors for racial disparities in stroke. The case-cohort to be used for this study has available measures of inflammation and insulin resistance, making it uniquely well-suited to test our hypotheses. The results of these studies may have an important impact on the treatment and/or prevention of stroke and cognitive decline. Indeed, 25D deficiency and FGF23 excess are common in the general population, disproportionately impact blacks, and can be treated with safe and relatively inexpensive therapies. Thus, if vitamin D deficiency and excess FGF23 are risk factors for cerebrovascular disease, this would support intervention trials testing the treatment of these disorders in reducing rates of incident stroke and cognitive impairment, particularly among black individuals. PUBLIC HEALTH RELEVANCE: Disorders of vitamin D and phosphorus metabolism are strongly linked to cardiovascular disease. The studies proposed herein will clarify the role of vitamin D deficiency and excess levels of fibroblast growth factor 23 in stroke, cognitive impairment, and racial disparities in these outcomes. Since vitamin D deficiency and elevated fibroblast growth factor 23 levels are common and disproportionately impact blacks, these studies may uncover novel therapeutic strategies for improving cerebrovascular outcomes in the general population, particularly among African Americans.

描述（由申请人提供）：中风和认知障碍是美国死亡和残疾的主要原因，并且不成比例地影响黑人。尽管高血压和糖尿病等传统的中风危险因素在脑血管结局中导致种族差异，但它们不足以完全解释这些发现，这表明非传统危险因素起着重要作用。维生素D和磷代谢的扰动已成为不良心血管结局的非传统危险因素。低25-羟基维生素D（25D）水平与心脏病和死亡有关，通过对炎症，胰岛素抵抗和血压控制的广泛影响。磷代谢的紊乱刺激成纤维细胞生长因子23（FGF23）的分泌，这是一种骨衍生的激素，部分通过抑制25D向活化的代谢物的转化为1,25-二羟基抗毒素D（1,25-羟基维敏D（1,1,25D））。我们的小组和其他人表明，较高的FGF23水平通过促进心血管疾病和1,25D缺乏的直接和间接影响与不利结果有关。此外，我们小组的初步数据表明，低维生素D是中风和认知障碍的独立危险因素。当前提案的主要重点是通过确定低血浆25D水平和过量血浆FGF23水平是否与大型国家组合的事件中风和认知障碍有关（AIM 1）。此外，由于黑人的维生素D和磷代谢的疾病比白人更普遍，更严重，因此我们将确定它们是否部分是中风中种族差异的基础（AIM 2）。最后，鉴于炎症，胰岛素抵抗和高血压是脑血管疾病的关键危险因素，并且与维生素D和磷代谢的干扰相互联系，我们将确定它们是否部分介导25D和FGF23的关联与中风和认知能力下降。我们将通过测量血浆25D，FGF23和其他矿物质代谢的其他关键介质来检验这些假设Streos（nork）研究是一项针对黑白成年人的国家前瞻性研究，旨在确定中风中种族差异的新风险因素。用于本研究的病例可容纳炎症和胰岛素抵抗的方法，使其非常适合测试我们的假设。这些研究的结果可能对中风和认知能力下降的治疗和/或预防有重要影响。确实，25D缺陷和FGF23过量在普通人群中很常见，不成比例地影响黑人，并且可以通过安全且相对便宜的疗法进行治疗。因此，如果维生素D缺乏症和过量FGF23是脑血管疾病的危险因素，这将支持测试这些疾病治疗这些疾病的干预试验，以降低事件中风和认知障碍的速度，尤其是黑人个体中。 公共卫生相关性：维生素D和磷代谢的疾病与心血管疾病密切相关。本文提出的研究将阐明维生素D缺乏症和成纤维细胞生长因子23在中风，认知障碍和种族差异中的过量水平。由于维生素D缺乏症和成纤维细胞生长因子23水平很普遍，并且不成比例地影响黑人，因此这些研究可能会发现新的治疗策略，以改善普通人群的脑血管结局，尤其是在非裔美国人中。