Grants and Contracts Details


The main goal of our research project is to develop a tool that will enable understanding and controlling conditions that underlie accumulation of the pancreatic hormone amylin in the brain and its relationship with the altered plasticity of neural networks in aging and chronic metabolic stress. The scientific premise of our proposed studies is based on i) prior studies showing that the pancreatic hormone amylin crosses the blood-brain barrier and plays a role in regulating satiety, ii) a growing body of evidence of amylin deposition in brains of aged individuals, particularly those presenting cognitive decline, iii) the structural difference between human amylin (amyloidogenic) and rodent amylin (non-amyloidogenic), which renders murine models “humanized” for amylin expression as a basis for mechanistic studies, iv) our published data from human amylin-expressing rats indicating that the brain amylin accumulation impairs the exploratory drive, long-term recognition memory and vestibulomotor function, v) recent reports that amylin accumulation in the brain drastically reduces synthesis of catecholamines, and vi) our preliminary results indicating signs of premature aging (hunched posture, altered gait and unkempt fur) in human amylin-expressing rats. Based on these facts, our overall hypothesis is that dyshomeostasis of amylin accelerates brain aging by altering neural networks. So, manipulation of amylin secretion in a “humanized” mouse carrying human amylin gene may reveal currently unknown contributing mechanisms to aging. To test these ideas, we will generate a new mouse model in which regulated expression of the human amylin transgene will be achieved in pancreatic â-cells. The new mouse model will enable specific activation of the transgene at defined developmental ages to understand changes in the interactions of circulating amylin with neural component of the brain during the mouse lifetime. This versatile tool will enable interrogation and monitoring of neuron activity under amylin-mediated stress and its subsequent effects on specific neural networks (self-motivation and long-term recognition memory). Furthermore, the newly engineered mouse model will enable turning off transgene expression at defined points during aging to ascertain whether changes in behavior and cognitive performance can be reversed. We anticipate that phenotypic changes in behavior and cognition are reversible upon silencing the transgene expression indicating amylin as a potential modulator of the plasticity of neural networks. To generate the new mouse model, our laboratory will collaborate with Dr. Gopal Thinakaran of the University of Chicago, who will serve as a co-PI.
Effective start/end date9/15/174/30/24


  • National Institute on Aging: $3,275,524.00


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