Recipient Organization
UNIVERSITY OF FLORIDA
G022 MCCARTY HALL
GAINESVILLE,FL 32611
Performing Department
Food Science and Human Nutrition
Non Technical Summary
The growing epidemics of obesity and diabetes have increased healthcare and economy burden on the society. In the United States, over two-thirds of adults are overweight or obese, and diabetes has afflicted 29.1 million people (9.3% of the population). It is estimated that obesity care accounts for 21% of national health expenditures in the U.S., and 490 billion dollars were spent on diabetes care in 2012 alone. The related healthcare and economy needs are far greater given that obesity and diabetes increase risks of other diseases such as cardiovascular diseases and cancer. To discover effective treatments for obesity and diabetes and reduce the healthcare and economy burden, it is of critical importance to understand the molecular mechanism or pathways underlying the pathogenesis. To this end, our project is designed to understand how autophagy is dysregulated and leads to metabolic disorders in diabetic and obese subjects.We will use genetic tools to generate obese and diabetic models in mammalian cells and mice, and study adiposity and metabolism. The regulatory networks will be analyzed by molecular and cellular biology techniques. Mice are selected for these studies because they provide a well-controlled model for the analysis of nutrient and metabolic homeostasis, Considerable scientific literature demonstrates that mice reflect many of the characteristics of human physiology, including the relationship between central and peripheral regulatory mechanisms; thus, mouse model will provide a critical experimental tool to understand the molecular pathophysiology of metabolic diseases. This project will provide a platform of training and tutorial for students to learn knowledge and research skills. Research findings will be disseminated to the community through conferences, workshop, symposia, and publications. Sharing and exchanging science-based knowledge will facilitate our understanding of diabetes and obesity, which will lead to the discovery of new treatments and therapeutic options for these diseases.
Animal Health Component
(N/A)
Research Effort Categories
Basic
100%
Applied
(N/A)
Developmental
(N/A)
Goals / Objectives
Diabetes and obesity significantly affect individual's life quality and economy of the US, and of Florida. To date there has been no known cure for the metabolic diseases, largely because the underlying mechanism is not well understood. The main goal of this project is to dissect the molecular pathway by which autophagy is regulated or dysregulated and metabolic disorders develop. In the first objective, we aim to determine the role of energy sensor Sirt1 in the regulation of adipose autophagy. We will investigate how gain or loss of Sirt1 affects autophagy and metabolism under fasting and feeding conditions using pharmacologic (small molecule inhibitors or activators) and genetic (knock-in, knock-out, or knock-down) approach to modulate Sirt1 activity in adipocytes or mouse adipose tissue and. In the second objective, we will define the role of adipose FoxO1 in hormonal regulation of adipose autophagy. We will use pharmacologic and genetic approach to investigate how gain or loss of FoxO1 affects autophagy and metabolism under basal and hormone-stimulated conditions, including insulin signaling (IR/IRS), estrogen signaling (ERalpha), and a beta3-adrenergic receptor signaling (beta3AR). In the third objective, we propose to investigate epigenetic regulation of adipose autophagy. Using similar strategies as described above, we will modulate epigenetic reprograming (DNA methylation, histone modification, and miR) in adipocytes or mouse adipose tissue and investigate how the epigenetic modulation affects FoxO1 or Sirt1, autophagy, and metabolism under basal and hormone-stimulated conditions. Exploring the regulatory network of autophagy may reveal new targets of therapeutic value for diabetes and obesity treatment.
Project Methods
The novel findings or science-based knowledge from this project will be delivered and disseminated to communities of science, healthcare, and clinical practice through peer-reviewed journals, websites, conferences, workshop, and symposia. Meanwhile, students and trainees will lean the skills and knowledge in the classroom and laboratory. As a plan to evaluate the success of the project, the project director and or the research team will present the research findings at national/international conference, or at research universities/colleges/hospitals, at least once a year, and publish 1-2 articles/year in peer-reviewed journals.