Cerebral Microvascular Dysfunction and Neuroinflammation - A Novel Mechanism Mediating Cardiovascular Risk in Chronic Kidney Disease

Louisiana ranks 4^th in the country for deaths from chronic kidney disease (CKD). We hypothesize that this excess mortality is due to increased sympathetic nerve activity (SNA), neuroinflammation, and cerebral microvascular dysfunction. We will test our hypothesis by the following specific aims 1) Investigate the extent to which microglial activation mediates excess SNA in CKD: Our hypothesis predicts that depletion of microglia will attenuate neuroinflammation and excess SNA in mice with CKD. 2) Determine the mechanism by which microglia and neuronal signaling pathways synergize to induce neuroinflammation: We will use scRNA-seq to identify pathogenic interactions between microglia and neurons 3) Determine the molecular mediators of cerebral microvascular dysfunction in CKD We will combine seahorse technology and proteomics to identify defects in brain microvascular cells from mice with CKD. These studies will firmly establish the novel role of neuroinflammation in CKD and pave the way for new drug discovery.

Experimental approach to test predictions of body weight regulation models

The regulation of human body weight and fatness is not fully understood. Although some models of regulation have been proposed (set point, dual-intervention point, others), no studies have been designed to test their predictions. In this pilot and feasibility study, we will implement an experimental approach to test the predictions of models of body weight regulation in humans. Men and women with either underweight or obesity will be exposed to a 2-day fasting followed by a 2-day ad-libitum refeeding. During the entire fasting-refeeding period, energy intake and expenditure will be accurately measured within metabolic chambers. We will therefore determine the compensatory responses to fasting elicited to prevent weight loss. The results will serve to design and power future studies to better understand body weight regulation.