Previous studies have strongly linked lipids and lipoproteins with neurovascular inflammation and dementia. However, the mechanisms and impact of lipid-induced or lipotoxic injury on neurovascular inflammation, microvascular cell death, blood-brain barrier permeability, and cognitive function is not known. This proposal aims to address two important questions about lipotoxic neurovascular injury: 1) What are the cell signaling pathways induced by lipotoxic injury in the brain microvasculature? 2) What are the pathophysiological outcomes of lipotoxic injury to the brain? We will examine cell signaling pathways using brain microvascular endothelial cells and mouse and human brain microvessels. Pathophysiological outcomes will be assessed by measuring brain microvascular cell death, blood brain permeability, and cognitive function. Answering these questions will enable us to develop a better understanding of the development of neurovascular inflammation and point the way to potential therapies for prevention and treatment of vascular dementia. This proposal is innovative because it will investigate the microvascular determinates of neuroinflammation, rather than concentrating only on the neuropathological causes. Also, we plan to use state-of-the-art and novel techniques in this project to examine neurovascular pathophysiology at a level not previously possible. This proposal has a strong translational component in that we will test the concepts developed in cell culture in mouse and human brain microvessels, and mouse models of cognitive impairment. The results of this project could result in a reassessment of blood lipids and lipoproteins in terms of their potential to induce microvascular neuroinflammation and determine if diets that modulate blood fatty acids, rather than lipoproteins, reduce vascular dementia.

Public Health Relevance

Lipotoxicity is a metabolic disorder that results from accumulation of lipids, particularly fatty acids, in non- adipose tissue leading to cellular dysfunction, lipid droplet formation, and cell death. Our studies indicate for the first time that he neurovascular circulation also can manifest lipotoxicity, which is the major focus of this proposal. Previous studies have shown that therapies aimed at attenuation and prevention of macrovascular diseases are not necessarily beneficial in microvascular disease. Further, brain microvascular pathologies are a difficult area of investigation to explore at both the cellular levl and clinically. This proposal offers the opportunity to not only investigate basic mechanisms of microvascular injury, but also to identify and test potential therapies for brain microvascular disease.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG045541-04
Application #
9280822
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
Opanashuk, Lisa A
Project Start
2014-09-15
Project End
2019-05-31
Budget Start
2017-07-01
Budget End
2018-05-31
Support Year
4
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of California Davis
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
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Ng, Kit Fai; Anderson, Steve; Mayo, Patrice et al. (2016) Characterizing blood-brain barrier perturbations after exposure to human triglyceride-rich lipoprotein lipolysis products using MRI in a rat model. Magn Reson Med 76:1246-51
Syed, Raisa; Shibata, Noreene M; Kharbanda, Kusum K et al. (2016) Effects of Nonpurified and Choline Supplemented or Nonsupplemented Purified Diets on Hepatic Steatosis and Methionine Metabolism in C3H Mice. Metab Syndr Relat Disord 14:202-9
Walton, Jeffrey H; Ng, Kit Fai; Anderson, Steven E et al. (2015) MRI measurement of blood-brain barrier transport with a rapid acquisition refocused echo (RARE) method. Biochem Biophys Res Commun 463:479-82
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