Midcareer Investigator Award in Amylin, Cognition, and Alzheimer's Disease

胰淀素、认知和阿尔茨海默病领域的职业生涯中期研究员奖

• 批准号: 9298592
• 负责人: WEI QIAO Wendy QIU
• 金额: $ 17.03万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9298592
• 关键词: Address; Affect; Age; Aging-Related Process; Alleles; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid; Amyloid beta-Protein; Attenuated; Award; Blood; Blood - brain barrier anatomy; Brain; Brain Diseases; Brain imaging; CCL2 gene; Clinical; Clinical Research; Cognition; Communities; Cross-Sectional Studies; Data; Data Set; Dementia; Deposition; Development; Diabetes Mellitus; Drug Targeting; Elderly; Ethnic Origin; FDA approved; Faculty; Framingham Heart Study; Generations; Goals; Hormones; Horns; ICAM1 gene; IL6 gene; Image; Impaired cognition; Incidence; Individual; Inflammation; Insulin; Intraperitoneal Injections; Isoprostanes; Learning; Leptin; Lipids; Measures; Mediating; Memory; Mentors; Nerve Degeneration; Non-Insulin-Dependent Diabetes Mellitus; Pancreas; Pathologic; Pathology; Patients; Peptides; Pharmaceutical Preparations; Phase; Phase III Clinical Trials; Plasma; Pramlintide; Research; Research Personnel; Safety; Sampling; Structure; Study Subject; TNFRSF1B gene; Testing; Therapeutic; Thick; Time; Translational Research; Urine; Vascular Diseases; Visuospatial; aging brain; amnestic mild cognitive impairment; analog; apolipoprotein E-4; base; blood glucose regulation; brain morphology; brain volume; career; cerebral atrophy; cerebrovascular; cognitive change; cognitive function; cohort; diabetic; ethnic minority population; executive function; genetic risk factor; glucose metabolism; improved; inflammatory marker; innovation; islet amyloid polypeptide; lipoprotein-associated phospholipase A(2); member; mild cognitive impairment; mouse model; offspring; patient oriented research; population based; prevent; programs; prospective; public health relevance; sex

 DESCRIPTION (provided by applicant): The goal of this K24 application is to provide protected time for the candidate to conduct patient-oriented research and to expand her current program of mentoring. While the candidate has established a record of clinical research in neurodegeneration, she also has track record of advancing her mentees' careers and research as well. Recent studies have shown that mild cognitive impairment (amnestic MCI) and Alzheimer's disease (AD) patients have a lower concentration of amylin in plasma than the elderly who had normal cognition. In cross-sectional analyses, higher concentrations of plasma amylin are related to better cognitive function, especially in memory and executive domains. Amylin is a gut-brain axis hormone, which readily crosses the blood brain barrier (BBB) and mediates activities including regulating glucose metabolism, relaxing cerebrovascular structure and modulating inflammation, all of which could be beneficial for AD. From the Framingham Heart Study Offspring and Omni Generation 1 cohorts, we propose using plasma samples collected from 1995-1998 to relate to incident change in cognition and brain structure up to 15 years later. We posit that high levels of plasma amylin are protective for cognitive decline and brain atrophy in aging process. We have five specific aims including 1) studying the distribution of plasma amylin in FHS community based population; 2) determining the relationship between baseline plasma amylin and cognitive changes, including incident mild cognitive impairment and dementia; 3) examining the association between plasma amylin and changes in brain morphology; 4) stratifying these analyses by the presence of ApoE4 allele, diabetes and other vascular diseases and 5) studying the relationship between amylin, A¿, lipids, other gut- brain axis peptides and inflammation in FHS. Pramlintide is an amylin analog and an FDA approved drug for diabetes with a favorable safety profile in clinical use. Should we find that high levels f plasma amylin are protective for the incidence of AD; our study will provide additional rationale for a large phase 2 or 3 trial with pramlintide to determine if amylin type peptides can prevent and treat AD. We anticipate that this study may help open a new and unconventional avenue for the therapeutic of AD.

 描述（由申请人提供）：此K24应用程序的目标是为候选人提供受保护的时间进行以患者为导向的研究，并扩大她目前的辅导计划。虽然候选人已经建立了神经退行性疾病的临床研究记录，但她也有推进学员职业和研究的记录。 最近的研究表明，轻度认知障碍（遗忘型MCI）和阿尔茨海默病（AD）患者血浆中胰淀素浓度低于认知正常的老年人。在横断面分析中，较高浓度的血浆胰淀素与更好的认知功能相关，特别是在记忆和执行领域。胰淀素是一种肠-脑轴激素，能迅速穿过血脑屏障（blood brain barrier，BBB），参与调节糖代谢、舒张脑血管结构和调节炎症反应，对AD的治疗有重要意义。从Frachial Heart Study Offspring和Omni Generation 1队列中，我们建议使用1995-1998年收集的血浆样本与15年后认知和大脑结构的事件变化相关。我们认为高水平的血浆胰淀素对衰老过程中的认知能力下降和脑萎缩具有保护作用。我们有五个具体目标，包括1）研究血浆胰淀素在FHS社区人群中的分布; 2）确定基线血浆胰淀素与认知变化（包括偶发轻度认知障碍和痴呆）之间的关系; 3）检查血浆胰淀素与脑形态学变化之间的关联; 4）通过ApoE 4等位基因、糖尿病和其他血管疾病的存在对这些分析进行分层，以及5）研究胰淀素、A、脂质、其他肠-脑轴肽与FHS中的炎症之间的关系。普兰林肽是一种胰淀素类似物，是FDA批准的糖尿病药物，在临床使用中具有良好的安全性。如果我们发现高水平的血浆胰淀素对AD的发病率有保护作用，我们的研究将为普兰林肽的大型2期或3期试验提供额外的理论依据，以确定胰淀素型肽是否可以预防和治疗AD。我们期望这项研究可能有助于为AD的治疗开辟一条新的和非传统的途径。