Marrow Adipose Tissue as a Novel Regulator of Systemic Metabolism and Inflammation During Aging.

骨髓脂肪组织作为衰老过程中全身代谢和炎症的新型调节器。

• 批准号: 10689661
• 负责人: Stephen A Martin
• 金额: $ 18.13万
• 依托单位: MONTANA STATE UNIVERSITY - BOZEMAN
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10689661
• 关键词: Adipose tissue; Adult; Age; Aging; Arterial Fatty Streak; Biological; Biology; Bone Marrow; Characteristics; Data; Diabetes Mellitus; Disease; Endocrine; Endocrine Glands; Etiology; Female; Functional disorder; Genetic Transcription; Goals; Health; Heart Diseases; Homeostasis; Hormonal; Inflammation; Inflammatory; Insulin Resistance; Knowledge; Life; Lipids; Longevity; Malignant Neoplasms; Marrow; Metabolic; Metabolism; Modeling; Molecular; Molecular Profiling; Morbidity - disease rate; Nature; Neoplasms; Nerve Degeneration; Obesity; Peptides; Phenotype; Physiological; Plasma; Play; Prevention; Process; Property; Proteome; Public Health; Rattus; Research; Resolution; Risk Factors; Role; Sex Differences; Signal Pathway; Signaling Molecule; Strategic Planning; Stroke; Testing; Tissues; Transference; Visceral; adipokines; age related; aged; autocrine; burden of illness; cytokine; decrease resilience; disorder risk; functional outcomes; healthspan; innovation; lipidome; male; metabolome; middle age; new therapeutic target; novel; paracrine; pharmacologic; prevent; programs; response; sex; sexual dimorphism; subcutaneous; therapeutic target; translational impact; treatment response

ABSTRACT Aging is the strongest risk factor for a range of diseases including diabetes, heart disease, neurodegeneration, cancer, and stroke. A central characteristic of aging is increased adiposity. Adipose tissues are endocrine organs, and it is hypothesized that aging-induced adipose dysfunction causally influences disease etiology through the secretion of molecules that act across a diverse range of tissues to coordinate organismal homeostasis. Adipose is located in distinct depots throughout the body, and it is likely that specific depots differentially contribute to disease vulnerability. The role of the bone marrow adipose tissue (MAT) depot in aging-related disease etiology is not well established, and there is a fundamental knowledge gap regarding the qualitative phenotype and secretory profile of MAT during aging. The long-term objective of this research is to define the roles and mechanisms by which MAT influences health and disease throughout the lifespan. The objective of this R21 proposal is to determine the impact of aging on MAT phenotype and establish the potential contribution of MAT to the systemic profile of adipose-derived molecules during aging. Our central hypothesis is that aging induces a transcriptional response in MAT that alters its secretory profile, which influences systemic metabolic and inflammatory homeostasis by directly impacting circulating peptide, lipid, and metabolite composition; we further hypothesize the impact of aging on the MAT phenotype and secretome is sexually dimorphic. Our rationale for this project is that once it is known how aging influences MAT’s phenotype and contribution to circulating adipose- derived factors, it is likely we can pharmacologically target MAT to reprogram its secretome, producing novel and innovative approaches to maximize healthspan and reduce age-related disease vulnerability. Guided by strong preliminary data, our central hypothesis will be tested by pursuing two specific aims: 1) define the sex- specific transcriptional response of MAT to aging and determine the extent to which the transcriptional response relates to functional outcomes (i.e., proteome, metabolome, lipidome) and 2) establish the extent of transference from MAT to circulating peptide, lipid, and metabolite profiles during aging. At the completion of this project, we expect to have established that 1) MAT phenotype is sensitive to aging and the temporal impact of aging on MAT phenotype is sex-specific, 2) the molecular response to aging is unique in MAT compared to other adipose depots, and 3) MAT is a central contributor to the circulating pool of adipose-derived signaling molecules during aging. Such results will fundamentally advance the field of adipose tissue biology and will provide a positive translational impact by identifying MAT, and specific signaling pathways within MAT, as a prime therapeutic target for the prevention and treatment of aging-related diseases.

抽象的 衰老是一系列疾病的最强危险因素，包括糖尿病、心脏病、神经退行性疾病、 衰老的一个主要特征是脂肪组织是内分泌器官。 人们重新认识到，衰老引起的脂肪功能障碍通过以下方式因果影响疾病病因： 分泌在多种组织中发挥作用以协调生物体内平衡的分子。 位于全身不同的仓库中，并且特定的仓库可能对 骨髓脂肪组织（MAT）库在衰老相关疾病病因学中的作用。 尚未得到很好的确立，并且在定性表型和 本研究的长期目标是确定 MAT 在衰老过程中的作用和作用。 MAT 在整个生命周期中影响健康和疾病的机制 本 R21 的目标。 提案旨在确定衰老对 MAT 表型的影响并确定 MAT 的潜在贡献 我们的中心假设是衰老会导致衰老。 MAT 中的转录反应会改变其分泌特征，从而影响全身代谢和 我们进一步通过直接影响循环肽、脂质和代谢物组成来调节炎症稳态； 维持衰老对 MAT 表型和分泌体的影响是性别二态性的。 该项目的目的是，一旦了解衰老如何影响 MAT 的表型以及对循环脂肪的贡献， 衍生因素，我们很可能可以通过药理学靶向 MAT 来重新编程其分泌组，从而产生新的 以及最大限度地延长健康寿命并减少与年龄相关的疾病脆弱性的创新方法。 有了强有力的初步数据，我们的中心假设将通过追求两个具体目标来检验：1）定义性别 MAT 对衰老的特异性转录反应，并确定转录反应的程度 与功能结果（即蛋白质组、代谢组、脂质组）相关，2) 确定转移的程度 从 MAT 到衰老过程中的循环肽、脂质和代谢谱。 希望确定 1) MAT 表型对衰老敏感，并且衰老对时间的影响 MAT 表型具有性别特异性，2) 与其他脂肪相比，MAT 对衰老的分子反应是独特的 3) MAT 是脂肪来源信号分子循环库的核心贡献者 这些结果将从根本上推动脂肪组织生物学领域的发展，并将提供积极的结果。 通过识别 MAT 以及 MAT 内的特定信号通路作为主要治疗靶点来产生转化影响 用于预防和治疗与衰老相关的疾病。