Mechanisms of swallowing dysfunction and rescue in a translational rat model of Alzheimer's disease
阿尔茨海默病转化大鼠模型吞咽功能障碍及救援机制
基本信息
- 批准号:10752510
- 负责人:
- 金额:$ 76.81万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-08-01 至 2028-06-30
- 项目状态:未结题
- 来源:
- 关键词:AddressAdherenceAffectAge MonthsAgingAlzheimer&aposs DiseaseAlzheimer&aposs disease modelAlzheimer&aposs disease pathologyAlzheimer&aposs disease patientAmyloid beta-ProteinAmyloidosisAnalysis of CovarianceAspiration PneumoniaBehaviorBehavioralBehavioral AssayBiochemistryBioenergeticsBiologicalBiological AssayBiteBolus InfusionBrainBrain PathologyBrain StemBrain regionCaregiver BurdenCaringCentral Nervous SystemCharacteristicsClinicalClinical ProtocolsClinical TrialsControlled StudyDataDegenerative DisorderDeglutitionDeglutition DisordersDiseaseDisease ProgressionEarly InterventionEffectivenessEvidence based treatmentExerciseExperimental DesignsFemaleFunctional disorderFutureGliosisGoalsHealthHealthcare SystemsHigh PrevalenceHumanImmunohistochemistryImpaired cognitionImpairmentInflammationIntakeIntervention StudiesKnowledgeLaboratoriesLinkLogistic RegressionsMasticationMeasuresModelingMorphologyMotorMuscleMuscle functionNeurobiologyOralOropharyngealOutcomeParkinson DiseasePathologicPathologyPeripheralPeripheral Nervous SystemPersonal SatisfactionPersonsPhosphorylationPhysiologicalPhysiologyPolymerase Chain ReactionPopulationPositioning AttributePreparationPrevalencePreventionProcessPropertyQuality of lifeRandomizedRattusRehabilitation therapyResearchSigns and SymptomsStructureSystemTestingTissuesTongueTranslatingTranslational ResearchWorkabeta oligomerbehavioral impairmentclinical practiceclinically relevantcomorbiditycostdesignexercise interventionfunctional declineimprovedin vivoinflammatory markerinnovationinsightmalemicroPETmuscular structuremuscular systemneuralneuroimagingneuron lossnovelpre-clinicalpreventskeletaltau Proteinstau-1translational approachtreatment optimization
项目摘要
Abstract
Dysphagia is a major consequence of Alzheimer’s disease (AD) that is understudied and thus undertreated
despite high prevalence and high cost to heath care systems. Pathology in AD (inflammation, amyloidosis,
phosphorylated tau) occurs in the central and peripheral nervous systems early in disease progression and in
brain regions and muscle systems associated with swallowing functions. Barriers to effectively treating
dysphagia in AD are the lack of: (a) an understanding of central and peripheral pathology associated with
dysphagia, and (b) controlled studies of interventions at crucial timepoints, including early versus later in the
disease process. The proposed research is significant in addressing these barriers and rigorous in that we
will apply established translational research approaches currently used in our labs in models of aging and
Parkinson disease. Our scientific premise is that pathology in AD occurs in the central and peripheral nervous
systems early in disease progression and that exercise interventions can mitigate deficits induced by the
presence of pathology and potentially change the course of sensorimotor decline in function. Because tongue
muscles are primary actors in the swallowing process, our central hypotheses are that pathology manifests in
tongue muscle and brainstem, subcortical, and cortical regions associated with oropharyngeal swallowing and
that early implementation of tongue exercise leads to better swallowing outcomes. We will gain insight into
mechanisms by using the well-established TgF344-AD rat model and conducting physiological, morphological,
bioenergetic, neuroimaging, and behavioral assays in the brain and tongue muscles. Feasibility data show the
oromotor and swallowing dysfunction, evidence of inflammation in the brainstem, and increased beta-amyloid
in brain regions associated with swallowing in 12-month-old TgF344-AD rats. The tongue exercise intervention
is modeled after those used in clinical practice. However, these clinical protocols are not optimized due to
barriers in human research, such as presence of co-morbidities, adherence confounds, and limited access to
tissues. Aim 1 will test the hypothesis that TgF344-AD rats demonstrate deficits in oromotor and swallowing
behaviors and manifest pathology in tongue muscles and brain structures critical to swallowing function. Aim 2
will test the hypothesis that early implementation of tongue exercise improves oromotor and swallow function
and modulates pathology in TgF344-AD rats. This research is innovative and will provide a new
understanding of mechanisms that underlie swallowing deficits in AD, query relationships among relatively
unexplored AD pathology and physiological function in swallow-related systems, and establish the
effectiveness of early versus late tongue exercise intervention for AD. Rehabilitation is often not provided to
patients with AD due to uncertain benefit. To advance evidence-based treatment, we must provide preclinical
data. This foundational work has a high impact because of the large and increasing population of people
with AD-associated dysphagia who can benefit from treatments optimized in the proposed studies.
摘要
吞咽困难是阿尔茨海默病(AD)的一个主要后果,对此研究不足,因此治疗不足
尽管发病率很高,卫生保健系统的成本也很高。阿尔茨海默病(炎症、淀粉样变性、
磷酸化tau)出现在中枢和外周神经系统中,在疾病进展的早期和在
与吞咽功能相关的大脑区域和肌肉系统。有效治疗的障碍
阿尔茨海默病的吞咽困难是缺乏:(A)对与以下相关的中枢和外周病理的了解
吞咽困难,以及(B)对关键时间点干预的对照研究,包括早期干预和后期干预
疾病过程。拟议的研究对解决这些障碍具有重要意义,并具有严谨性,因为我们
将把我们实验室目前使用的成熟的翻译研究方法应用于老化和
帕金森氏症。我们的科学前提是阿尔茨海默病的病理发生在中枢和外周神经
系统在疾病进展的早期,运动干预可以减轻由
病理的存在,并可能改变感觉运动功能下降的过程。因为舌头
肌肉是吞咽过程中的主要参与者,我们的中心假设是病理表现在
舌肌和脑干、皮质下和皮质区域与口咽吞咽和
及早实施舌头练习会带来更好的吞咽效果。我们将深入了解
利用已建立的TgF344-AD大鼠模型,从生理、形态、病理等方面探讨其发病机制。
脑部和舌部肌肉的生物能量、神经成像和行为分析。可行性数据表明,
口腔运动和吞咽功能障碍,脑干发炎的证据,以及β-淀粉样蛋白增加
在12月龄TgF344-AD大鼠与吞咽相关的脑区。舌头运动干预
是仿照临床实践中使用的那些。然而,这些临床方案并未得到优化,原因是
人类研究中的障碍,如并存疾病的存在、坚持治疗令人困惑,以及有限的机会
纸巾。目标1将验证TgF344-AD大鼠表现出口部运动和吞咽障碍的假设
舌肌和大脑结构中对吞咽功能至关重要的行为和明显的病理。目标2
我将检验这样一种假设,即早期实施舌头练习可以改善口腔运动和吞咽功能
并调节TgF344-AD大鼠的病理。这项研究具有创新性,将提供一种新的
对AD吞咽缺陷的机制的理解,询问相对
未探索AD在吞咽相关系统中的病理和生理功能,并建立
早期与晚期舌操干预对阿尔茨海默病的疗效比较。康复服务通常不提供给
AD患者因受益不确定。为了推进循证治疗,我们必须提供临床前治疗
数据。由于人口的庞大和不断增加,这项基础性工作产生了很大的影响
与AD相关的吞咽困难患者可以从拟议研究中优化的治疗中受益。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
NADINE P CONNOR其他文献
NADINE P CONNOR的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('NADINE P CONNOR', 18)}}的其他基金
Mechanisms of Down syndrome-associated swallowing dysfunction in mouse models
小鼠模型中唐氏综合症相关吞咽功能障碍的机制
- 批准号:
10444405 - 财政年份:2022
- 资助金额:
$ 76.81万 - 项目类别:
Influence of neuromuscular pathology on parkinsonian communication deficits
神经肌肉病理学对帕金森沟通缺陷的影响
- 批准号:
8969759 - 财政年份:2015
- 资助金额:
$ 76.81万 - 项目类别:
Influence of neuromuscular pathology on parkinsonian communication deficits
神经肌肉病理学对帕金森沟通缺陷的影响
- 批准号:
9318494 - 财政年份:2015
- 资助金额:
$ 76.81万 - 项目类别:
相似海外基金
An innovative, AI-driven prehabilitation platform that increases adherence, enhances post-treatment outcomes by at least 50%, and provides cost savings of 95%.
%20创新、%20AI驱动%20康复%20平台%20%20增加%20依从性、%20增强%20治疗后%20结果%20by%20at%20至少%2050%、%20和%20提供%20成本%20节省%20of%2095%
- 批准号:
10057526 - 财政年份:2023
- 资助金额:
$ 76.81万 - 项目类别:
Grant for R&D
Improving Repositioning Adherence in Home Care: Supporting Pressure Injury Care and Prevention
提高家庭护理中的重新定位依从性:支持压力损伤护理和预防
- 批准号:
490105 - 财政年份:2023
- 资助金额:
$ 76.81万 - 项目类别:
Operating Grants
I-Corps: Medication Adherence System
I-Corps:药物依从性系统
- 批准号:
2325465 - 财政年份:2023
- 资助金额:
$ 76.81万 - 项目类别:
Standard Grant
Unintrusive Pediatric Logging Orthotic Adherence Device: UPLOAD
非侵入式儿科记录矫形器粘附装置:上传
- 批准号:
10821172 - 财政年份:2023
- 资助金额:
$ 76.81万 - 项目类别:
Nuestro Sueno: Cultural Adaptation of a Couples Intervention to Improve PAP Adherence and Sleep Health Among Latino Couples with Implications for Alzheimer’s Disease Risk
Nuestro Sueno:夫妻干预措施的文化适应,以改善拉丁裔夫妇的 PAP 依从性和睡眠健康,对阿尔茨海默病风险产生影响
- 批准号:
10766947 - 财政年份:2023
- 资助金额:
$ 76.81万 - 项目类别:
CO-LEADER: Intervention to Improve Patient-Provider Communication and Medication Adherence among Patients with Systemic Lupus Erythematosus
共同领导者:改善系统性红斑狼疮患者的医患沟通和药物依从性的干预措施
- 批准号:
10772887 - 财政年份:2023
- 资助金额:
$ 76.81万 - 项目类别:
Pharmacy-led Transitions of Care Intervention to Address System-Level Barriers and Improve Medication Adherence in Socioeconomically Disadvantaged Populations
药房主导的护理干预转型,以解决系统层面的障碍并提高社会经济弱势群体的药物依从性
- 批准号:
10594350 - 财政年份:2023
- 资助金额:
$ 76.81万 - 项目类别:
Antiretroviral therapy adherence and exploratory proteomics in virally suppressed people with HIV and stroke
病毒抑制的艾滋病毒和中风患者的抗逆转录病毒治疗依从性和探索性蛋白质组学
- 批准号:
10748465 - 财政年份:2023
- 资助金额:
$ 76.81万 - 项目类别:
Improving medication adherence and disease control for patients with multimorbidity: the role of price transparency tools
提高多病患者的药物依从性和疾病控制:价格透明度工具的作用
- 批准号:
10591441 - 财政年份:2023
- 资助金额:
$ 76.81万 - 项目类别:
Development and implementation of peer-facilitated decision-making and referral support to increase uptake and adherence to HIV pre-exposure prophylaxis in African Caribbean and Black communities in Ontario
制定和实施同行协助决策和转介支持,以提高非洲加勒比地区和安大略省黑人社区对艾滋病毒暴露前预防的接受和依从性
- 批准号:
491109 - 财政年份:2023
- 资助金额:
$ 76.81万 - 项目类别:
Fellowship Programs