Hydrogen peroxide in endothelial function and dysfunction

The parent R01 grant for this Administrative Supplement is supporting studies of an experimental program that uses chemogenetic approaches to define the roles of reactive oxygen species (ROS) and oxidative stress in the vascular endothelium. Supplemental funds are now requested to directly extend these studies from the characterization of the

peripheral vascular phenotype to perform studies of mouse behavior in order to define the roles of vascular oxidative stress in the pathophysiology of Alzheimer’s Disease and Alzheimer’s Disease-Related Dementias (AD/ADRD). Oxidative stress has been observed in nearly all animal models of AD/ADRD and also in brain tissues from

human AD/ADRD patients. We plan to exploit novel chemogenetic approaches to generate a new model of AD/ADRD, with a focus on vascular dementias caused by oxidative stress in the vascular wall. The parent R01 proposed studies to develop and characterize the vascular phenotype of a new DAAO- TGendo transgenic/chemogenetic mouse line that exploits the chemogenetic yeast enzyme D-amino acid oxidase

(DAAO) to generate ROS in vascular endothelium. Here we request an Administrative Supplement that will extend these studies to test the hypothesis that cerebrovascular oxidative stress causes AD/ADRD. The proposed studies address one of the target research topic areas that are explicitly listed for this Administrative

Supplement: “Vascular Contributions to Cognitive Impairment and Dementia (VCID)”. The proposed work is likely to lead to the development of new experimental models for AD/ADRD and to the development of novel therapeutic targets both within VCID as well as in other AD/ADRD disease states. It is important to note that the new DAAO-TGendo transgenic mouse line that we plan to study has already

been generated and characterized, and the scope of the proposed studies has been tightly focused in order to yield informative results within the one-year time frame supported by the Administrative Supplement. Results from these studies will set the stage for future experiments to extend chemogenetic approaches into extant

mouse models of AD/ADRD in which oxidative stress has been implicated in disease pathophysiology. My laboratory has a long record of basic/translational discovery in cardiovascular disease states, yet we have limited expertise in study of neurological diseases. We have engaged a key collaborator for these studies:

Professor Dennis Selkoe, MD. Dr. Selkoe is a close colleague at BWH who is an acknowledged world leader in Alzheimer’s Disease basic/translational research. Dr. Selkoe’s laboratory at BWH is located nearby my own lab, as is the Anne Romney Center for Neurological Disease (which Dr. Selkoe co-directs)– which includes advanced

neuropathology imaging facilities as well as a sophisticated Mouse Behavior Core Lab. The proposed studies will pursue experiments using DAAO-TGendo transgenic mice following the generation of chronic in vivo chemogenetic oxidative stress in the vasculature. We will determine the resulting behavioral phenotype as well as the neuropathological phenotype that follows generation of oxidative stress.