This proposal describes a 5 year training project that will allow me to achieve my goal of becoming an independent investigator in diabetes research. The training and career development plan includes a research project with potential implications for public health, training in laboratory techniques, and didactic scientific and career development seminars and courses. Dr. C. Ronald Kahn, a leader in the field of insulin signaling and diabetes, will serve as my mentor. He has trained over 150 postdoctoral fellows, many of whom are now department heads. In addition, an advisory committee will provide me with scientific and career advice. The research will take place at the Joslin Diabetes Center;a Harvard affiliated institution, providing me access to all of the resources the Harvard Community has to offer. There is an increased risk of cognitive decline and Alzheimer's disease in patients with diabetes. The mechanism connecting these diseases is unclear. Recent data in mice demonstrate a decrease in the rate of cholesterol synthesis in the brains of diabetic mice. This is particularly significant given that the greatest risk factor for late onset Alzheimer's disease s a variant in a cholesterol transporter (ApoE). My preliminary data demonstrate that decreasing cholesterol synthesis by knocking out one copy of the sterol sensing protein SCAP in the brain produces mice with an impaired rate of cerebral cholesterol synthesis, impairment in synaptic transmission, and cognitive impairment. The overall goal of the project is to understand how insulin regulates SREBP-2, a more specific regulator of cholesterol synthesis than SCAP.
In Aim 1 I will define the molecular pathway used by insulin to stimulate insulin signaling in the brain.
Aim 2 will determine the biochemical consequences of deleting SREBP-2 from neurons and glia in mice.
Aim 3 will delineate the changes in brain function produced by knocking SREBP-2 out from neurons or glia. In addition, these knockout mice will be made diabetic or crossed with a model of Alzheimer's disease to determine how a background of reduced cholesterol exacerbates these diseases.

Public Health Relevance

Dementia and cognitive impairment occur more frequently in diabetic patients than in the general population. We recently observed that diabetes leads to decreased cholesterol synthesis in the brains of mice. I will determine how the regulator of cholesterol synthesis, SREBP-2, is controlled by insulin in the brain, how loss of SREBP-2 impacts cognitive function and how decreased cholesterol interacts with diabetes and dementia to impair cognitive function.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Clinical Investigator Award (CIA) (K08)
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Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
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Hyde, James F
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Joslin Diabetes Center
United States
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Ferris, Heather A; Perry, Rachel J; Moreira, Gabriela V et al. (2017) Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism. Proc Natl Acad Sci U S A 114:1189-1194
Fukui, Kenji; Ferris, Heather A; Kahn, C Ronald (2015) Effect of cholesterol reduction on receptor signaling in neurons. J Biol Chem 290:26383-92
Kleinridders, André; Ferris, Heather A; Cai, Weikang et al. (2014) Insulin action in brain regulates systemic metabolism and brain function. Diabetes 63:2232-43