Using pre-clinical biomarkers and epidemiological models to assess the effects of cannabinoids on disease

 描述（由申请人提供）：在糖尿病流行病学、肥胖流行病学和大麻吸烟流行病学的交叉点上，有几个科学难题有待解决。一方面，吸食大麻后报告的“零食”可能会让人认为大麻会导致肥胖，也可能是大麻导致的2型糖尿病。此外，来自动物模型的临床前证据表明，大麻素暴露可能通过激活大麻素-1（CB 1）受体加速2型糖尿病，激活大麻素-1（CB 1）受体在中枢并因此刺激白色脂肪细胞或肝细胞中的摄食过多，或在外周，并在这种情况下促进从头脂肪酸合成和随后的胰岛素抵抗。另一方面，从基于大规模人口的跨部门研究中严格收集的流行病学证据支持这样一种观点，即吸食大麻与肥胖发生率降低、糖尿病发生率降低以及指示葡萄糖代谢改变的生物标志物水平降低有关。大麻吸烟-糖尿病难题的解决方案可能通过观察导致2型糖尿病的氧化应激和免疫反应途径来找到，但有临床前证据和一些最近发表的人类数据表明，一些大麻素具有免疫调节作用，可能是抗氧化剂。这个应用程序是五年的K99/R 00奖支持临床转化研究职业发展，这将使我有可能把我的注意力集中在有趣的可能性，大麻吸烟可能是预防2型糖尿病，并产生更明确的证据从我自己的工作台到床边到社区研究大麻素和健康结果，即使大麻与糖尿病的关联被证明是虚假的。作为一名流行病学医生，我已经为流行病学分析的许多方面做好了充分的准备，正如我在初步研究部分所指出的那样。持续的转化大麻素健康研究是我研究开发计划的两个相互关联的部分的动力：（1）我对临床前和实验室科学技能的掌握，使我能够设计新的实验室科学实验，以获得关于大麻暴露与健康之间联系的可疑机制的更明确的证据，以及（2）我掌握了大样本流行病学前瞻性研究和现场实验的设计和实施，以提高我们对大麻健康影响的理解。

 DESCRIPTION (provided by applicant): There are several scientific puzzles to be solved at the intersection of diabetes mellitus epidemiology, obesity epidemiology, and cannabis smoking epidemiology. On one hand, the 'munchies' reported after cannabis smoking might lead one to think there would be cannabis-attributable obesity and also possibly cannabis attributable type 2 diabetes. Moreover, there is preclinical evidence from animal models that cannabinoid exposure might accelerate type 2 diabetes via the activation of cannabinoid-1 (CB1) receptors, both centrally and hence stimulating hyperphagia, or peripherally in the white adipose cells or the liver cells and in that case promoting de novo fatty acid synthesis and subsequent insulin resistance. On the other hand, rigorously gathered epidemiological evidence from cross-sectional large population based studies supports the idea that cannabis smoking is associated with a reduced occurrence of obesity, a reduced occurrence of diabetes, and lower levels of biomarkers indicative of altered glucose metabolism. Solutions to the cannabis smoking- diabetes puzzle might be found by looking at oxidative stress and immune response pathways that lead toward type 2 diabetes, but for which there is preclinical evidence and some recently published human data that some cannabinoids are immunomodulatory and possibly anti-oxidant in the direction of protection from diabetes. This application is for five years of K99/R00 award support of clinical translational research career development that will make it possible for me to focus my attention on the intriguing possibility that cannabis smoking might be protective against type 2 diabetes, and to produce more definitive evidence from my own bench-to-bedside-to- community studies of cannabinoids and health outcomes, even if the cannabis-diabetes association turns out to be spurious. As a physician epidemiologist, I already am well-prepared for many facets of epidemiological analyses, as noted in my preliminary studies section. Sustained translational cannabinoid-health research is what motivates the two inter-connected parts of my research development plan: (1) my mastery of preclinical and laboratory science skill sets that will prepare me to design new bench science experiments to gain more definitive evidence on the suspected mechanisms linking cannabis exposure and health, and (2) my mastery of the design and conduct of large sample epidemiological prospective studies and field experiments, as required to enhance our understanding of cannabis health effects.