The Platelet Metabolome in Obesity

描述（由申请人提供）：本指导研究科学家发展计划的主要目标是在代谢组学和血栓研究领域创造一个密集的研究培训环境，这将在不久的将来导致独立的研究。该项目联合了在代谢失调和血栓形成方面具有专业知识的知名导师和一位在健康和疾病中血小板分子表型方面具有经验的新兴年轻研究者。该申请得到了强有力的机构对候选人的承诺、健全的培训环境和指导计划以及支持每个具体目标的初步数据的支持。因此，该提案响应了指导学员倡议，努力增加代谢组学研究的网络和能力。该提案的中心研究假设是肥胖通过涉及mitofusin-2 （Mfn-2）的机制诱导血小板代谢组和转录组的协调变化。这些变化导致血小板高反应性，从而增加肥胖患者血栓形成的风险。这个研究假设将用3个特定的目标进行测试，这些目标在主题上是相关的，但不依赖于另一个来完成。具体的

DESCRIPTION (provided by applicant): The primary goal of this Mentored Research Scientist Development Proposal is to create an intensive research training environment in the field of metabolomics and thrombosis research that will lead to independent investigation in the near future. This project unites established mentors that have expertise in metabolic dysregulation and thrombosis with an emerging young investigator who has experience in the molecular phenotyping of platelets in health and disease. The application is supported by strong institutional commitment to the candidate, a robust training environment and mentoring plan, and preliminary data that supports each of the specific aims. Thus, the proposal is responsive to the mentored trainee initiative that strives to increase the network and capacity of metabolomics research. The central research hypothesis of the proposal is that obesity induces coordinate changes in the platelet metabolome and transcriptome through mechanisms that involve mitofusin-2 (Mfn-2). These changes lead to platelet hyperreactivity and, as a result, increased risk for thrombosis in the setting of obesity. This research hypothesis will be tested with 3 specific aims that are thematically related but do not rely on one another for completion. Specific aim 1 will determine the role of mitofusin-2 on the platelet metabolome-transcriptome network and related functional activities. By specifically knocking down Mfn-2 in platelets, these studies will reveal the roles for Mfn-2 in controlling mitochondrial fusion/fission, metabolic stress, and the in vitro and in vivo function of platelets. They will also determine if Mfn- 2 alters the basal metabolome and transcriptome or the activated metabolome footprint of platelets. Specific aim 2 will build on the first aim but nonetheless independently test the role of platelet Mfn-2 in a mouse model of obesity. It is hypothesized that Mfn-2 deficient platelets will be more susceptible (i.e., fail to compensate) to a high fat environment. As a result, Mfn-2 deficient platelet will display exaggerated metabolic stress and functional responses that are consistent with an inability to compensate at the metabolite and transcript level. The third specific aim will extend the functional and mechanistic data obtained in mice to humans. Specifically, the studies will determine if Mfn-2 expression (i.e., mRNA and protein) and related mitochondrial activities differs in platelets isolated from obese and normal weight human subjects. Aim 3 will also determine if obesity induces coordinate changes in the platelet metabolome and transcriptome that predict platelet hyperreactivity. Studies in human subjects will result in new, clinically relevant information that may explain why platelets are prone to thrombose in obese individuals. Together, these preclinical and clinical studies will explore new paradigms in metabolism and thrombosis research in an environment that enhances research career development.