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.

项目总结