Lee Ryan - US grants

[unreadable] DESCRIPTION (provided by applicant): The primary goal of the proposed research is to explore the functional roles in memory retrieval of structures within the medial temporal lobe, including the hippocampus and adjacent structures. The proposal builds on recent work by the investigators positing a new view of medial temporal lobe involvement in memory consolidation, storage, and retrieval, referred to as Multiple Trace Theory (MTT). Tradition holds that the role of medial temporal lobe structures in memory is time-limited, lasting only until consolidation of the memory trace in neocortex is complete, after which memories can be retained and retrieved without hippocampal involvement. MTT, in contrast, argues that the hippocampus plays a lasting role in the storage and retrieval of memory, and that the central role of the hippocampus reflects its essential role in the processing of various types of spatial information. The proposed studies will ask whether the hippocampus plays a special role in the retrieval of three kinds of spatial information important to personal memories: spatial context, spatial location, and spatial relations. The studies will also explore the various forms of personal or episodic memory, comparing personal memory to world knowledge or semantic memory. Healthy adults will participate in a series of experiments, using functional magnetic resonance imaging fMRI). While in the scanner, they will be asked to recollect personal experiences, recently learned information, and well-established world knowledge, in order to compare activation within medial temporal and neocortical brain structures during retrieval of these varied types of memories. Some memories will include spatial information or spatial relations, while others will not. The study will not only directly test some of the assertions from MTT, but it will also provide important information regarding the neural mechanisms underlying long-term storage and retrieval in humans. [unreadable] [unreadable]

PROJECT SUMMARY Every year, more than 500,000 patients in the US have coronary artery bypass surgery (CABG) to treat coronary artery disease. However, postoperative outcomes are complicated by a significant incidence of stroke and cognitive impairment. Postoperative cognitive impairment results in decreased quality of life for these individuals and higher hospital readmission rates. There is a clear unmet medical need to find treatments to attenuate or prevent cardiac disease and CABG induced cognitive impairment. Although the precise triggers are debated, CABG increases brain hypoxia and circulating cytokines. Increases in circulating inflammatory cytokines and brain hypoxia result in increased brain reactive oxygen species (ROS) production, activation of brain inflammatory pathways leading to neuronal dysfunction and cognitive impairment. Recent work by our group and others have shown in animals that Angiotensin-(1-7) (Ang-(1-7) can inhibit ROS production, increase nitric oxide production and reduce inflammatory cytokines in the brain, microvasculature and peripheral tissue via activation of the Mas receptor. The ideal therapeutic candidate to treat CABG induced cognitive impairment would be designed to interrupt this cascade by working at both sides of the blood-brain barrier, the brain vascular endothelium and neuronal cells. Ang-(1-7) meets these criteria because Ang-(1-7), acting at the Mas receptor, is known to have anti-inflammatory effects at both endothelial cells and neurons. In Q2 2014, we received regulatory support from the NHLBI SMARTT program to submit an IND to the FDA for the use of Ang-(1-7) to treat cognitive impairment in CABG patients and this IND was approved in August 2015. The present UO1 application is designed to evaluate the safety and efficacy of Ang-(1-7) to enhance cognitive function in participants undergoing CABG surgery. Further, by teaming with the unique capabilities of the NIH Clinical Center, these studies will measure, for the first time, post CABG surgery brain inflammation and microglia activation as measured by PET imaging of [11C]PBR28 and the test the hypothesis that Ang-(1- 7) will result in a decrease in brain inflammation and microglia activation in CABG patients. When completed, this clinical study will have advanced development of a new therapy with potential to treat cognitive impairment in CABG patients.