FSH - an Aging Hormone?

FSH——一种衰老激素？

• 批准号: 10112794
• 负责人: CLIFFORD JAMES ROSEN
• 金额: $ 230.63万
• 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/10112794
• 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; 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; antibody test; 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.

程序摘要 肥胖和骨质疏松症是全球公共卫生危害，通常会影响老年人， 虽然可以使用受限的治疗方法 骨质疏松症，肥胖的五种批准药物受到效率差和不可接受的副作用的限制。 因此，治疗这两种慢性衰老条件的新方法需要协作和严格 独立但完全互动实验室之间的综合计划。该U19建立在公司的基础上 严格和透明的研究的基础，源于DR之间的长期合作。蒙特 Zaidi和Clifford Rosen，其结果于去年出版（自然，2017年，PMID：28538730）。我们 将FSH确定为预防肥胖和骨质疏松症的独特靶标。我们将多克隆抗体提高到 FSHβ通过阻止其进入FSH受体（FSHR）的访问，可以防止高脂抑制诱导的肥胖症和 卵巢切除术引起的骨质疏松症。此外，我们的FSH抗体触发了能量的出现 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 该FSH也可能是衰老的关键衰老。因此，我们建议进行全面的， 对阻断FSH信号的影响的多收益和跨学科研究，要么是使用药物 我们的单克隆抗FSH抗体或在FSHR - / - 小鼠中，寿命，脂肪增益，骨髓肥胖， 和小鼠的骨骼健康。我们还将使用Thermomice研究FSH对脂肪细胞的FSH作用机制 该报告的“存在”，脂肪体小鼠，测量了从头脂肪形成和最先进的技术 用于转录组，脂肪组和生物能量分析。支撑我们的临床前观察，并观察 通过测试人中的单克隆抗体，我们提出了一项关于老年男女的流行病学研究 在年龄 - 雷克雅未克队列中。我们将检查血清FSH是否可以用作替代标记 骨髓流失，内脏脂肪增加，骨髓肥胖以及最终骨折风险。提供必要 缅因州医学中心西奈山的四个调查地点的资源 - ICAHN医学院 德克萨斯大学西南医学中心和加利福尼亚大学SAN研究所 弗朗西斯科 - 我们提出三个总体多功能核心：骨骼和代谢表型核心，一个 抗体生产和测试核心，以及行政和生物统计学支持核心。总之，我们的U19 提案应使我们能够理解两种普遍衰老的疾病的新基础， 除了为我们越来越多的老年人数量的治疗干预措施打开新的途径。