FSH - an Aging Hormone?

FSH——一种衰老激素？

• 批准号: 10356114
• 负责人: CLIFFORD JAMES ROSEN
• 金额: $ 229.85万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10356114
• 关键词: Adipocytes; Adipose tissue; Affect; Aging; Antibodies; Antibody Formation; Appearance; Archives; Bioenergetics; Bioinformatics; Biology of Aging; Biometry; Body Composition; Bone Density; Bone Marrow; Bone Resorption; Bone remodeling; California; Cells; Chronic; Clinical Trials; Collaborations; Collection; Data; Data Set; Disease; Dose; Elderly; Ensure; Epidemiology; Epitopes; Equipment; Estrogens; Fatty acid glycerol esters; Female; Follicle Stimulating Hormone; Follicle Stimulating Hormone Receptor; Foundations; Fracture; Future; Goals; Health; Health Hazards; High Fat Diet; Hormones; Human; Individual; Interdisciplinary Study; Intervention; Joints; Laboratories; Leadership; Link; Longevity; Longitudinal Studies; Maine; Marrow; Measures; Mediating; Medical center; Menopause; Mitochondria; Modeling; Molecular Mechanisms of Action; Monoclonal Antibodies; Mus; Musculoskeletal; Nature; Obesity; Osteogenesis; Osteoporosis; Ovariectomy; Perimenopause; Persons; Pharmacology; Phenotype; Physiological Processes; Physiology; Pituitary Hormones; Positioning Attribute; Postmenopause; Public Health; Publishing; Rattus; Reagent; Reporting; Research; Research Institute; Resources; Sampling; San Francisco; Serum; Services; Signal Pathway; Signal Transduction; Site; Stromal Cells; Subgroup; Sum; Surrogate Markers; Technology; Testing; Texas; Therapeutic Intervention; Thinness; Time; Universities; Visceral fat; Woman; base; bone loss; bone mass; cloud storage; cohort; design; diet-induced obesity; epidemiology study; female fertility; fracture risk; gain of function; improved; insight; lipid biosynthesis; lipidome; medical schools; men; metabolic phenotype; mouse model; multidisciplinary; novel strategies; older men; older women; polyclonal antibody; population based; pre-clinical; prevent; programs; receptor binding; sex; side effect; skeletal; therapeutic target; transcriptome

PROGRAM SUMMARY Obesity and osteoporosis are global public health hazards that commonly affect older individuals and often co-exist in postmenopausal women. While a restricted armamentarium of therapies is available for osteoporosis, the five approved agents for obesity are limited by poor efficacy and unacceptable side effects. Hence, new approaches to treat these two chronic conditions of aging require a collaborative and rigorous integrative program between independent, but fully interactive laboratories. This U19 builds on a firm foundation of rigorous and transparent research, born from a longstanding collaboration between Drs. Mone Zaidi and Clifford Rosen, the results of which were published last year (Nature, 2017, PMID: 28538730). We identified FSH as a unique target to prevent both obesity and osteoporosis. We raised a polyclonal antibody to Fshβ, which, by blocking its access to the Fsh receptor (Fshr), prevented high-fat-diet-induced obesity and ovariectomy-induced osteoporosis. In addition, our Fsh antibody triggered the appearance of energy- producing ‘beige’ adipocytes in white adipose tissue. Based on these studies and others, we now postulate that FSH may also be a critical aging hormone. We therefore propose to undertake a comprehensive, multipronged and interdisciplinary study of the effects of blocking Fsh signaling, either pharmacologically using our monoclonal anti-Fsh antibodies or genetically in Fshr-/- mice, on lifespan, fat gain, bone marrow adiposity, and skeletal health in mice. We will also study the mechanism of Fsh action on fat cells using ThermoMice that report ‘beiging,’ AdipoChaser mice that measure de novo adipogenesis, and state-of-the-art technologies for transcriptome, lipidome and bioenergetic profiling. To buttress our preclinical observations and, with a view of testing our monoclonal antibodies in people, we propose an epidemiological study of older women and men in the AGES-Reykjavik Cohort. We will examine whether serum FSH can be used as a surrogate marker for bone loss, visceral fat gain, bone marrow adiposity, and ultimately, fracture risk. To provide necessary resources across the four investigative sites–Icahn School of Medicine at Mount Sinai, Maine Medical Center Research Institute, University of Texas Southwestern Medical Center and the University of California at San Francisco–we propose three overarching multifunctional cores: a Skeletal and Metabolic Phenotyping Core, an Antibody Production and Testing Core, and an Administrative and Biostatistics Support Core. In sum, our U19 proposal should allow us to break new ground in our understanding of two prevalent disorders of aging, in addition to opening new avenues for therapeutic interventions for our increasing numbers of older adults.

计划概要 肥胖和骨质疏松症是全球公共卫生危害，通常影响老年人和老年人 常并存于绝经后妇女。虽然治疗方法有限 骨质疏松症方面，五种已批准的治疗肥胖症的药物因疗效不佳和不可接受的副作用而受到限制。 因此，治疗这两种慢性衰老疾病的新方法需要合作和严格的 独立但完全互动的实验室之间的综合计划。这支U19建立在坚定的基础上 严格而透明的研究基础，源于博士之间的长期合作。莫内 Zaidi 和 Clifford Rosen，其结果于去年发表（Nature，2017，PMID：28538730）。我们 确定 FSH 是预防肥胖和骨质疏松症的独特目标。我们提出了一种多克隆抗体 Fshβ，通过阻断其与 Fsh 受体 (Fshr) 的接触，预防高脂肪饮食引起的肥胖， 卵巢切除术引起的骨质疏松症。此外，我们的 Fsh 抗体引发了能量- 在白色脂肪组织中产生“米色”脂肪细胞。基于这些研究和其他研究，我们现在假设 FSH 也可能是一种重要的衰老激素。因此，我们建议开展全面的、 对阻断 Fsh 信号传导效果的多管齐下和跨学科研究，无论是药理学上还是使用 我们的单克隆抗 Fsh 抗体或 Fshr-/- 小鼠的基因抗体，对寿命、脂肪增加、骨髓肥胖、 和小鼠骨骼健康。我们还将使用 ThermoMice 研究 Fsh 对脂肪细胞的作用机制 报告“beiging”的 AdipoChaser 小鼠测量脂肪从头生成，以及最先进的技术 用于转录组、脂质组和生物能量分析。支持我们的临床前观察，并着眼于 为了在人体中测试我们的单克隆抗体，我们建议对老年女性和男性进行流行病学研究 在 AGES-雷克雅未克队列中。我们将检查血清 FSH 是否可以作为替代标记物 骨质流失、内脏脂肪增加、骨髓肥胖，以及最终的骨折风险。提供必要的 四个研究地点的资源——西奈山伊坎医学院缅因州医疗中心 德克萨斯大学西南医学中心和加州大学圣路易斯分校研究所 Francisco——我们提出了三个总体多功能核心：骨骼和代谢表型核心、 抗体生产和测试核心，以及行政和生物统计支持核心。综上所述，我们的U19 该提案应该使我们能够在理解两种普遍的衰老疾病方面开辟新的天地， 除了为越来越多的老年人开辟新的治疗干预途径之外。