Adipokine physiology

肥胖的流行，这是一种导致包括高血压在内的几种共病的疾病， 在美国，血脂异常、冠心病、中风以及几种恶性肿瘤呈上升趋势 在全世界范围内导致发病率和死亡率增加。其发病机制的研究进展 肥胖症及其相关疾病尚未阐明，目前也没有可用的治疗方法。 都远远不是最理想的。在过去的几年里，科学界认识到脂肪组织不是一种 惰性仓库储存器官，但分泌多种荷尔蒙的活跃内分泌器官。我们就是这样被 研究其生化、生理学、病理生理学意义及治疗意义 脂肪组织分泌荷尔蒙，即脂肪因子，旨在阐明它们在人类中的功能。虽然 重要的和临床上有用的新信息已经积累起来，新的化合物已经被 人类第三阶段临床试验(瘦素、脂联素诱导剂等)仍有几个问题 留下来。新型脂肪因子的作用是什么？它们有什么生理功能？我们怎样才能 证明他们的临床疗效的概念？它们如何与其他已知的荷尔蒙或新奇的肌肉相互作用 分泌荷尔蒙，以改变能量平衡和新陈代谢？我们怎样才能利用新奇的信息 创建抗击肥胖及其并发症的临床干预措施？解决这些和类似的问题并 培训专注于这些问题的科学家，他们将发挥力量倍增器的作用，可以领导 对临床医学和公众健康产生了重大的有益影响。现在是一个经验丰富的职业生涯中期 作为临床研究人员，我进行了一系列以患者为中心的研究，这些研究对 致力于解决这些重要问题。这项提议的K24奖励将允许我和我的学员 今后五年将继续把重点放在这一研究领域，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， 但通过K24奖项的设计，主要将是培养 这一领域的下一代以患者为中心的研究人员。这项建议的具体目的是：1. 为初学者的培训和职业发展提供良好的职业环境 临床研究人员，他们将在正在进行的以患者为中心的研究项目中进行研究 生理学和治疗使用的分子在调节能量稳态方面的重要作用，以及2. 补充已经资助的研究项目，旨在研究脂肪因子、胃肠道 肥胖症、糖尿病及相关代谢性疾病中的途径分泌分子和肌动蛋白 合并症。正如预期的那样，根据NIH的指导方针，在K24拨款下进行的工作将是 根据前瞻性队列研究、药代动力学研究、“概念验证”提供的基础设施 临床试验，以及已经在进行或计划进行的多中心III-IV期临床试验。

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.