FSH - an Aging Hormone?

FSH——一种衰老激素？

基本信息

批准号：
10577830
负责人：
CLIFFORD JAMES ROSEN
金额：
$ 229.52万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10577830
关键词：
Adipocytes Adipose tissue Affect Age Aging Antibodies Antibody Formation Antibody-mediated protection Appearance 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 Institution 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 Phenotype Physiological Processes Physiology Pituitary Hormones Positioning Attribute Postmenopause Productivity Public Health Publishing Rattus Reagent Reporting Research Research Institute Resources Sampling San Francisco Serum Services Signal Pathway Signal Transduction Site Stromal Cells Subgroup Surrogate Markers Technology Testing Texas Therapeutic Intervention Thinness Time Universities Visceral fat Woman archive data 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 loss of function medical schools men metabolic phenotype mouse model multidisciplinary novel strategies older men older women pharmacologic polyclonal antibody population based pre-clinical prevent programs receptor binding sex side effect skeletal therapeutic target transcriptome

项目摘要

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通常在绝经后妇女中同时存在，但可用的治疗方法有限。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 U19 是独立但完全互动的实验室之间的综合项目。严格和透明的研究基础，诞生于 Mone 博士之间的长期合作。 Zaidi 和 Clifford Rosen，其结果于去年发表（Nature，2017，PMID：28538730）。确定 FSH 是预防肥胖和骨质疏松症的独特靶标，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，此外，我们的 Fsh 抗体引发了能量-的出现。根据这些研究和其他研究，我们现在假设在白色脂肪组织中产生“米色”脂肪细胞。 FSH 也可能是一种重要的衰老激素，因此我们建议进行全面的、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、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、脂质组和生物能分析，以支持我们的临床前观察。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 是否可以用作替代标志物。骨质流失、内脏脂肪增加、骨髓肥胖，最终导致骨折风险。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总而言之，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。