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

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 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.