Midlife Obesity, Neurovascular Senescence and Cognitive Decline

中年肥胖、神经血管衰老和认知能力下降

• 批准号: 10458047
• 负责人: Stefano Tarantini
• 金额: $ 12.02万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10458047
• 关键词: Abbreviations; Address; Aging; Alzheimer' s disease related dementia; American; Astrocytes; Attenuated; Biochemistry; Biometry; Blood - brain barrier anatomy; Blood capillaries; Brain; Cell Aging; Cells; Cerebrovascular Circulation; Cerebrovascular system; Cerebrum; Chimeric Proteins; Cognition; Cognitive aging; Cognitive deficits; Complex; Confocal Microscopy; DNA Damage; Data; Dementia; Development; Dietary Intervention; Doctor of Philosophy; Endothelial Cells; Endothelium; Ensure; Environment; Flow Cytometry; Functional Magnetic Resonance Imaging; Functional disorder; Funding; Ganciclovir; Geroscience; Goals; Grant; Health; High Fat Diet; Homeostasis; Hyperemia; Image; Imaging Techniques; Impaired cognition; Impairment; Intervention; Laboratory Research; Laser Speckle Imaging; Lead; Life; Link; Magnetic Resonance Imaging; Maintenance; Mediating; Mentors; Methods; Microcirculation; Microglia; Modality; Modeling; Molecular Biology; Mus; Muscle Cells; National Institute of General Medical Sciences; Neurons; Nutritional; Obese Mice; Obesity; Obesity Epidemic; Oklahoma; Outcome; Pathogenesis; Pathway interactions; Pericytes; Phenotype; Play; Population; Publishing; Radiation therapy; Regulation; Reporter; Research; Research Activity; Research Personnel; Resources; Role; Shock; Techniques; Testing; Therapeutic Intervention; Training; Training Activity; United States; United States National Institutes of Health; Universities; Vascular Cognitive Impairment; Vascular Diseases; Vascular blood supply; Work; age related; aging brain; base; blood-brain barrier disruption; blood-brain barrier function; career development; cell type; cerebrovascular; cognitive benefits; cognitive function; cognitive performance; data integration; density; endothelial dysfunction; epidemiology study; experimental study; feeding; genetic manipulation; hemodynamics; human old age (65+); improved; intravital imaging; lifestyle intervention; middle age; mouse model; multiphoton imaging; network architecture; neuroinflammation; neurovascular; neurovascular coupling; neurovascular unit; novel; nutrition; preservation; professor; programs; red fluorescent protein; response; senescence; skills; success; transcriptomics; two-photon; vascular cognitive impairment and dementia

Stefano Tarantini, PhD, is a junior aging researcher whose overarching goal is to develop an independent research program to understand and apply nutritional lifestyle interventions to the field of cerebrovascular aging to ameliorate age-related vascular cognitive impairment and dementias (VCID). To achieve this, the following K01 proposal aims to further Dr. Tarantini's training to enable him to explore the role of midlife obesity on neurovascular senescence as it relates to the development of vascular cognitive impairment and related dementias. Candidate: Dr. Tarantini is an Assistant Professor in the Dept. of Biochemistry and Molecular Biology at the University of Oklahoma HSC. This K01 proposal perfectly builds on his previous training and extends his research in a logical direction that is becoming growingly relevant in the field of cognitive aging. This proposal identifies 5 training goals: 1) Acquire novel training in the field of nutrition; 2) Receive training in data integration, biostatistics, single-cell transcriptomics, and analysis; 3) training in advanced intra-vital imaging techniques; 4) Improve skills in magnetic resonance imaging (MRI); 5) Establish and lead an independent research laboratory. Mentors/Environment: The mentoring team will assist the candidate to ensure his success through the K01 training and research activity. The proposed plan will leverage resources of the newly established Center for Geroscience and Healthy Brain Aging, the NIH supported Nathan Shock Center, and the NIGMS-funded CoBRE training grant. The department is fully committed to support Dr. Tarantini independently of the outcome of this K01 application. Research: Mid-life obesity promotes cellular senescence. Aging-induced senescence among cells of neurovascular unit (NVU) associates with neurovascular dysfunction and cognitive impairment. Yet, the impact of obesity-induced senescence on the cellular components of the NVU and its function is not understood. We hypothesize that obesity accelerates NVU senescence, impairing structural and functional qualities of the cerebral vasculature. The resulting decline in cerebral blood flow and increased neuroinflammation contribute to cognitive impairment. We predict that elimination of senescent cells rejuvenates the NVU, restoring its youthful functional and structural integrity, which confers cognitive benefits. This project aims to characterize mid-life obesity-induced senescence in the neurovascular unit (Aim 1), the effects of senescence on NVC responses, cerebral blood flow and cognition (Aim 2), and how senescence alters microvascular density and BBB integrity in mouse models of mid-life obesity (Aim 3). Summary: This K01 proposal utilizes advanced imaging and sophisticated sequencing and data integration techniques in a relevant model of mid-life obesity to detect senescence in the NVU of the brain. Understanding the relationship between brain cellular senescence and impaired BBB function and diminished cerebrovascular hemodynamic responses (which are responsible to maintain intact cognitive function) will be critical to address potential nutritional interventional therapies to avoid obesity-induced cognitive deficits in aging and develop an independent research direction.

Stefano Tarantini博士是一位初级老龄化研究人员，其总体目标是发展独立 研究计划，以了解和将营养生活方式干预措施应用于脑血管衰老领域 改善与年龄有关的血管认知障碍和痴呆症（VCID）。为了实现这一目标，以下 K01提案旨在进一步进一步的塔兰蒂尼博士的培训，以使他能够探索中年肥胖的作用 神经血管衰老与血管认知障碍的发展有关 痴呆症。候选人：Tarantini博士是生物化学和分子生物学系的助理教授 在俄克拉荷马大学HSC大学。这个K01提案完美地建立在他以前的培训的基础上，并扩展了他的 在认知衰老领域变得越来越重要的逻辑方向研究。这个建议 确定5个培训目标：1）在营养领域获得新颖的培训； 2）接受数据集成培训， 生物统计学，单细胞转录组学和分析； 3）培训高级重要成像技术； 4） 提高磁共振成像（MRI）的技能； 5）建立并领导独立的研究实验室。 导师/环境：指导团队将协助候选人通过K01确保他的成功 培训和研究活动。拟议的计划将利用新成立的中心的资源 GEROSCIENCE和健康的大脑衰老，NIH支持Nathan冲击中心和NIGMS资助的鞋底 培训补助金。该部门完全致力于支持Tarantini博士的结果 K01申请。研究：中年肥胖会促进细胞衰老。衰老引起的衰老 神经血管单元（NVU）的细胞与神经血管功能障碍和认知障碍相关。但是， 肥胖引起的衰老对NVU细胞成分及其功能的影响尚不清楚。 我们假设肥胖会加速NVU衰老，损害结构和功能质量 脑脉管系统。导致脑血流和神经炎症增加的下降有助于 认知障碍。我们预测，消除衰老细胞会恢复NVU，恢复其年轻 功能性和结构完整性，赋予认知益处。该项目旨在表征中年 肥胖引起的神经血管单位衰老（AIM 1），衰老对NVC反应的影响， 脑血流和认知（AIM 2），衰老如何改变微血管密度和BBB完整性 在中期肥胖的小鼠模型中（AIM 3）。摘要：此K01提案利用高级成像和 中期肥胖相关模型中的复杂测序和数据整合技术以检测 大脑NVU中的衰老。了解脑细胞衰老与 BBB功能受损并减少脑血管血流动力学反应（这是负责 保持完整的认知功能）对于解决潜在的营养介入疗法至关重要 肥胖引起的衰老中的认知缺陷并发展一个独立的研究方向。