Midlife Obesity, Neurovascular Senescence and Cognitive Decline

Stefano Tarantini博士是一名初级衰老研究人员，其首要目标是开发一种独立的 研究计划，以了解和应用营养生活方式干预领域的脑血管老化 改善与年龄相关的血管性认知障碍和痴呆（VCID）。为了实现这一目标， K01提案旨在进一步培训塔兰蒂尼博士，使他能够探索中年肥胖对 神经血管衰老，因为它与血管性认知障碍的发展和相关的 痴呆症候选人：Tarantini博士是系里的助理教授。生物化学与分子生物学 在俄克拉荷马州大学HSC。这个K01提案完美地建立在他以前的培训基础上，并扩展了他的 研究的逻辑方向，越来越相关的认知老化领域。这项建议 确定了5个培训目标：1）获得营养领域的新培训; 2）接受数据整合培训， 生物统计学、单细胞转录组学和分析; 3）高级活体成像技术培训; 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：导师团队将协助候选人确保其通过K01考试取得成功 培训和研究活动。拟议的计划将利用新成立的中心的资源， 老年科学和健康的大脑老化，美国国立卫生研究院支持内森休克中心，和NIGMS资助的CobRE 培训补助金。该部门完全致力于支持塔兰蒂尼博士独立的结果，这一点 K01应用程序。研究：中年肥胖促进细胞衰老。衰老诱导的衰老， 神经血管单位（NVU）细胞与神经血管功能障碍和认知障碍有关。然而 肥胖诱导的衰老对NVU细胞成分及其功能的影响尚不清楚。 我们假设肥胖加速了NVU衰老，损害了NVU的结构和功能质量。 脑血管系统由此导致的脑血流量下降和神经炎症增加有助于 认知障碍我们预测，消除衰老细胞使NVU恢复活力， 功能和结构的完整性，这赋予认知的好处。该项目旨在描述中年人的特征， 肥胖诱导的神经血管单位衰老（目标1），衰老对NVC反应的影响， 脑血流量和认知（目的2），以及衰老如何改变微血管密度和血脑屏障的完整性 在中年肥胖症的小鼠模型中（目标3）。摘要：本K01提案采用先进的成像技术， 在中年肥胖的相关模型中使用复杂的测序和数据整合技术， 大脑NVU中的衰老。了解脑细胞衰老与 受损的BBB功能和减少的脑血管血流动力学反应（这是导致 维持完整的认知功能）对于解决潜在的营养干预治疗至关重要， 肥胖引起的认知功能障碍的衰老，并制定一个独立的研究方向。

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.