BLRD Research Career Scientist Award Application

BLRD 研究职业科学家奖申请

• 批准号: 10594024
• 负责人: WILLARD M FREEMAN
• 金额: --
• 依托单位: OKLAHOMA CITY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10594024
• 关键词: Affinity Chromatography; Age; Age related macular degeneration; Aging; Alzheimer' s Disease; Animal Model; Astrocytes; Award; Basal Ganglia; Biochemical; Bioinformatics; Biological; Biological Assay; Biology; Blindness; Blood; Brain; Caloric Restriction; Caring; Cell Aging; Cell Nucleus; Cell Separation; Cell physiology; Cells; Central Nervous System; Chromatin; Chronology; Cities; Collaborations; Colon; Communication; Communities; Complement; Country; DNA; DNA Methylation; DNA Modification Methylases; DNA Modification Process; DNA methylation profiling; Data; Dioxygenases; Disease; Elderly; Epigenetic Process; Equipment; Estradiol; Faculty; Female; Fertility; Foundations; Functional disorder; Funding; Future; Gene Expression Regulation; Genetic Transcription; Genome; Genomic Segment; Genomics; Goals; Grant; Health; Hippocampus; Impaired cognition; Institution; Intervention; Intervention Studies; Intestines; Joints; Knowledge; Label; Laboratory Finding; Malignant Neoplasms; Maps; Measures; Mentors; Methylation; Microglia; Mission; Mitochondria; Modeling; Modernization; Molecular; Molecular Analysis; Muller' s cell; Mus; Muscle; Nervous System Physiology; Neurons; Nuclear; Oklahoma; Ovary; Parabiosis; Participant; Pathway interactions; Plasma; Population; Postdoctoral Fellow; Preparation; Prevention; Process; Proteins; Proteomics; Quality of life; RNA; Recording of previous events; Regulation; Rejuvenation; Research; Research Personnel; Resolution; Retina; Ribosomes; Risk Factors; Scientist; Sex Differences; Sheep; Shock; Sirolimus; Site; System; Teacher Professional Development; Techniques; Technology; Testing; Therapeutic; Tissues; Training; Transgenic Mice; Translating; United States Department of Veterans Affairs; United States National Institutes of Health; Veterans; Vision research; Work; age effect; age related; aging brain; analytical tool; anti aging; base; body system; career; cell type; cost; epigenome; epigenome editing; epigenomics; functional outcomes; genome sciences; genome-wide; genomic locus; healthy aging; improved; insight; male; mouse model; neurophysiology; novel; novel strategies; prevent; programs; recruit; sarcopenia; sex; student training; success; therapy design; tool; transcriptomics

Project Summary/Abstract The overarching goal of Dr. Freeman’s research has been to understand how alterations of the genome/epigenome contribute to aging and how therapies could potentially target these changes to maintain a ‘youthful’ epigenome that retards aging, delays/prevents age-related diseases, and improves the health and quality of life of the elderly. Epigenetic dysregulation is a hallmark of aging, but exactly how this contributes to cellular dysfunction and disease is not known. To elucidate this contribution, Dr. Freeman’s VA research has focused on epigenomic regulation in astrocytes, microglia, and neurons in the hippocampus with aging. Using novel cell isolation and advanced sequencing approaches, cell-type specific base resolution maps of both methylation (mC) and hydroxymethylation (hmC) in CG and non-CG contexts are being generated. With paired RNA expression data, bioinformatic techniques are being used to understand the regulation of gene expression with aging. This type of base-specific, genome-wide, and cell-type specific studies have not been performed in aging research and will potentially offer the most in-depth view of epigenomic changes with aging to date. Further, to demonstrate the prevention of age-related epigenomic changes, caloric restriction is being used. In total, these studies will not only increase the understanding of the neuroepigenomics of aging but also provide targets for future interventional studies using epigenome editing. Importantly these studies examine both males and females to provide sex-informed insight as his prior studies have demonstrated that the majority of age- related epigenomic changes are sexually divergent. Dr. Freeman is also PI or co-PI on three NIH projects and one foundation funded project. These studies extend his VA research in aging through use of novel transgenic mouse models and anti-aging interventions in the brain, retina, and GI system. These models developed by his lab allow temporally controlled, cell-type specific tagging of nuclei and ribosomes to isolate DNA for epigenomic analysis and RNA for expression analysis without the need for cell sorting. In the brain and retina, heterochronic plasma transfer, in which plasma from young mice is administered to old mice for rejuvenation, is being used to determine if age-related epigenomic changes can be reversed after they have occurred. In parallel, using proteomic approaches, DNMT and TET interacting proteins are being identified that target them to specific genomic regions for epigenomic alteration. More broadly, Dr. Freeman also has an extensive collaborative portfolio with other OKC VAMC investigators. In these VA and NIH funded studies, Dr. Freeman is examining cell-type specific mechanisms of aging in muscle, brain, ovary, joints, and colon. In addition to bringing molecular and biochemical expertise to these studies, a common thread of epigenetics of aging allows comparisons and contrasts to be made across the organ systems. These collaborations are paired with his work as Director of the Genomics Sciences Core of a recently renewed P30 NIA Center grant: the Oklahoma Nathan Shock Aging Center. This core provides epigenomic and transcriptomic analyses as well as mitochondrial genomic assays for aging researchers across the country. Additionally, Dr. Freeman leads many cross-institution (OMRF, OUHSC) initiatives focused on trainee and faculty development, including training students and post-docs (F-Troop) and junior faculty (NeuroGrant Seekers) in successful preparation and submission of grants. He has also worked with leaders at the OKC VAMC to help recruit new, highly successful investigators to the VA system, one of which has received a MERIT award with three more investigators having MERIT applications currently under review.

项目概要/摘要 弗里曼博士研究的首要目标是了解基因的改变是如何发生的。 基因组/表观基因组导致衰老，以及治疗如何潜在地针对这些变化以维持衰老 “年轻”的表观基因组可以延缓衰老，延缓/预防与年龄相关的疾病，并改善健康状况 老年人的生活质量。表观遗传失调是衰老的一个标志，但这到底是如何导致衰老的 细胞功能障碍和疾病尚不清楚。为了阐明这一贡献，弗里曼博士的 VA 研究 专注于星形胶质细胞、小胶质细胞和海马神经元随衰老的表观基因组调控。使用 新颖的细胞分离和先进的测序方法，两者的细胞类型特定碱基分辨率图 CG 和非 CG 环境中的甲基化 (mC) 和羟甲基化 (hmC) 正在生成。与配对 RNA表达数据、生物信息技术被用来了解基因表达的调控 随着衰老。此类碱基特异性、全基因组和细胞类型特异性研究尚未在 衰老研究，并有可能提供迄今为止与衰老相关的表观基因组变化的最深入的观点。 此外，为了证明预防与年龄相关的表观基因组变化，正在使用热量限制。在 总而言之，这些研究不仅将增加对衰老神经表观基因组学的理解，而且还提供 未来使用表观基因组编辑进行干预研究的目标。重要的是这些研究检查了男性 和女性提供性别信息洞察力，因为他之前的研究表明，大多数年龄- 相关的表观基因组变化存在性别差异。 Freeman 博士还是 3 个 NIH 项目和 1 个基金会资助项目的 PI 或联合 PI。这些研究扩展了 他通过使用新型转基因小鼠模型和大脑抗衰老干预措施进行衰老研究， 视网膜和胃肠道系统。他的实验室开发的这些模型允许进行时间控制的细胞类型特定标记 细胞核和核糖体分离 DNA 用于表观基因组分析和 RNA 用于表达分析，无需 需要细胞分选。在大脑和视网膜中，异时血浆转移，其中来自年轻小鼠的血浆被 给予老年小鼠以使其恢复活力，用于确定是否可以与年龄相关的表观基因组变化 发生后逆转。同时，使用蛋白质组学方法，DNMT 和 TET 相互作用蛋白 正在鉴定将它们靶向特定基因组区域以进行表观基因组改变。 更广泛地说，Freeman 博士还与其他 OKC VAMC 研究人员有着广泛的合作。在 在这些 VA 和 NIH 资助的研究中，弗里曼博士正在研究肌肉衰老的细胞类型特异性机制， 大脑、卵巢、关节和结肠。除了为这些研究带来分子和生化专业知识之外， 衰老表观遗传学的共同点允许跨器官系统进行比较和对比。 这些合作与他作为最近更新的基因组科学核心主任的工作相结合 P30 NIA 中心拨款：俄克拉荷马州内森休克老化中心。该核心提供表观基因组和 为全国老龄化研究人员提供转录组分析和线粒体基因组分析。 此外，Freeman 博士还领导了许多针对学员和教师的跨机构（OMRF、OUHSC）举措 发展，包括培训学生和博士后（F-Troop）以及初级教师（NeuroGrant Seekers） 成功准备并提交赠款。他还与 OKC VAMC 的领导者合作，帮助 为 VA 系统招募新的、非常成功的调查员，其中一名获得了优异奖 另外三名研究人员的 MERIT 申请目前正在审查中。