FSH - an Aging Hormone?

计划摘要 肥胖和骨质疏松症是全球性的公共健康危害，通常影响老年人和 通常在绝经后妇女中并存。虽然有限的治疗手段可以用来治疗 骨质疏松症，五种被批准的肥胖剂，由于疗效差和不可接受的副作用而受到限制。 因此，治疗这两种慢性老龄化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。这款U19是在一家公司的基础上建造的 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(《自然》，2017年，PMID：28538730)。我们 确定促卵泡激素是预防肥胖和骨质疏松症的唯一目标。我们提出了一种多克隆抗体来 卵泡刺激素β，通过阻断其与卵泡刺激素受体的通路，防止高脂饮食诱导的肥胖和 卵巢切除引起的骨质疏松症。此外，我们的FSH抗体引发了能量的出现- 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 FSH也可能是一种关键的衰老荷尔蒙。因此，我们建议进行一项全面的、 阻断FSH信号转导效应的多管齐下跨学科研究 我们的抗FSH单抗或在FSHR-/-小鼠中遗传，对寿命、脂肪增加、骨髓肥胖症、 和老鼠的骨骼健康。我们还将利用ThermoMice研究FSH对脂肪细胞的作用机制 这份报告称，AdipoChaser老鼠测量了新生脂肪生成，以及最先进的技术 用于转录组、脂组和生物能量分析。以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抗，我们建议对老年女性和男性进行流行病学研究 在时代中-雷克雅未克队列。我们将研究血清FSH是否可以作为替代标记物 骨质流失，内脏脂肪增加，骨髓肥胖症，最终导致骨折风险。以提供必要的 四个调查地点的资源-西奈山伊坎医学院、缅因州医疗中心 得克萨斯大学西南医学中心研究所和加州大学旧金山分校 我们提出了三个主要的多功能核心：骨骼和新陈代谢表型核心，以及 抗体生产和检测核心，以及行政和生物统计学支持核心。总而言之，我们的U19 该提案应该使我们在理解两种普遍存在的衰老障碍方面取得新的突破， 此外，还为越来越多的老年人开辟了治疗干预的新途径。

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.