Adipokine physiology

肥胖症的流行，导致包括高血压在内的几种合并症， 血脂异常、冠心病、中风以及几种恶性肿瘤在美国呈上升趋势， 导致发病率和死亡率上升。其发病机制 肥胖症和相关病症尚未阐明， 远远不是最佳的。在过去的几年里，科学界意识到脂肪组织不是一个 一个惰性的贮藏器官，但却是一个分泌多种激素的活跃的内分泌器官。因此，我们 研究生物化学，生理学，病理生理学的重要性和治疗意义， 脂肪组织分泌的激素，即脂肪因子，旨在阐明它们在人体中的功能。虽然 已经积累了重要的和临床上有用的新信息， 进入人体III期临床试验（瘦素、脂联素诱导剂等）， 保持。新型脂肪因子的作用是什么？它们的生理功能是什么？ 证明其临床疗效的概念？它们如何与其他已知的激素或新的，肌肉相互作用 分泌激素来改变能量平衡和新陈代谢？我们如何利用新的信息 创建临床干预措施来对抗肥胖及其并发症？针对这些问题和类似问题， 培养专注于这些问题的科学家，他们将发挥力量倍增器的作用， 对临床医学和公共卫生产生重大有益影响。现在一个经验丰富的职业生涯中期 作为一名临床研究人员，我进行了一系列以患者为导向的研究， 来解决这些重要问题。这个K24奖项将使我和我的学员能够 在今后五年里，继续集中精力研究这一领域，这是 这一领域的发展。重要的是，这个K24奖项不仅将扩大我的潜力， 在该领域的贡献，但将主要是，通过K24奖项的设计，适当的工具，培养 这一领域的下一代以病人为导向的研究人员。该提案的具体目标是：1.到 提供一个滋养的专业环境，为培训和职业生涯的进步， 临床研究人员，他们将在正在进行的以患者为导向的研究项目中进行研究， 在能量稳态调节中重要的分子的生理学和治疗用途领域，以及2. 为了补充已经资助的研究项目，旨在检查脂肪因子的作用，胃肠道 代谢性疾病包括肥胖症、糖尿病和相关疾病中的道分泌分子和肌因子 合并症。根据NIH指南的预期，在K24资助下进行的工作将建立 基于前瞻性队列研究、药代动力学研究、“概念验证”提供的基础设施， 临床试验和多中心III-IV期临床试验已经在进行或计划中。

The prevalence of obesity, a condition leading to several comorbidities including hypertension, dyslipidemias, coronary heart disease, stroke as well as several malignancies is on the rise in the US and worldwide leading to increasing morbidity and mortality. The mechanisms underlying the pathogenesis of obesity and associated conditions have not yet been elucidated and currently available therapeutic approaches are far from optimal. In the past few years, the scientific community realized that the adipose tissue is not an inert depot storage organ but an active endocrine organ secreting several hormones. We have thus been researching the biochemistry, physiology, pathophysiological importance and therapeutic significance of adipose tissue secreted hormones, i.e. adipokines, aiming at elucidating their function in humans. Although important and clinically useful new information has been accumulated and new compounds have been advanced to phase III clinical trials in humans (leptin, adiponectin inducing agents etc) several questions still remain. What is the role of novel adipokines? What physiological functions do they serve and how could we prove the concept of their clinical efficacy? How do they interact with other known hormones or novel, muscle secreted hormones, to alter energy homeostasis and metabolism? How could we exploit novel information to create clinical interventions to fight obesity and its complications? Addressing these and similar questions and training dedicated scientists, who by focusing on these questions will function as power multipliers, could lead to a substantial beneficial impact on clinical medicine and public health. Now an experienced mid-career clinical researcher, I have undertaken a series of patient-oriented research studies that contribute significantly towards addressing these important issues. This proposed K24 award will allow me and my mentees to continue focusing intensively on this area of research for the next five years, a critical period for the development of this field. Importantly, this K24 award will not only be expanding my potential for significant contributions in the field but will primarily be, by design of the K24 awards, the appropriate vehicle for nurturing the next generation of patient-oriented researchers in this field. The specific aims of this proposal are: 1. To provide a nourishing professional environment for the training and advancement of the careers of beginning clinical researchers, who will be conducting studies within ongoing patient-oriented research projects in the area of physiology and therapeutic use of molecules important in the regulation of energy homeostasis, and 2. To supplement already funded research projects aiming at examining the role of adipokines, gastrointestinal tract secreted molecules and myokines in metabolic diseases including obesity, diabetes and associated comorbidities. As expected based on NIH guidelines, the work performed under this K24 grant will be building upon the infrastructure provided by prospective cohort studies, pharmacokinetic studies, “proof of concept” clinical trials, and multicenter phase III-IV clinical trials already underway or planned.