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Basic

dorothy sears
Dorothy Sears, Ph.D.

The Basic Science Project aims to elucidate basic, biological mechanisms of sedentary behavior-associated cardiovascular disease (CVD) risk. The Basic Science Project will assess candidate biomarkers by which sedentary behavior (SB) promotes CVD risk and impairs healthy aging. Our model is that extensive time spent sitting causes perturbations in mitochondrial and endothelial dysfunction via sub-optimal blood flow and reduced muscle engagement in the lower extremities. These perturbations influence biomarkers and transducers of CVD risk. The Basic Science Project will leverage biomarker and behavior data generated in the Clinical Project and pre-existing in the Population Project cohort to evaluate known and novel associations of SB with CVD risk in postmenopausal Latina women. The Basic Science Project will facilitate the integration of biomarker and objective SB measures from the Clinical and Population Project. The Clinical Project will randomize 250 sedentary, postmenopausal Latinas who have CVD risk factors, including borderline hypertension and BMI 27.0-45.0 kg/m2, to complete a 3-month study period of either A) control, healthy aging advice or B) intensive intervention aimed to reduce daily sitting time by 25%. The Basic Science Project will conduct analyses of blood samples collected at baseline and follow-up in the Clinical Project.

We hypothesize that biomarkers associated with CVD risk, including biomarkers of glucoregulation and lipid metabolism, mitochondrial and endothelial functioning, will be beneficially changed in the reduced sitting time intervention group but not in the control group.

Only a few randomized controlled studies of sitting time have included health outcomes after a 3- to 6-month intervention and these indicate that CVD risk biomarkers can be improved. Clinical laboratory studies have shown that interruption of prolonged sitting improves glucose regulation. Such studies have also shown that uninterrupted prolonged sitting acutely impairs endothelial function and hemodynamics and increases blood pressure and thrombolytic biomarkers. Importantly, these effects that are blunted by sitting interruptions. Rodent models of SB are translationally limited because of the need to restrain the animals, which confounds outcome interpretation. Our study will extend previous human SB outcome measures by including mitochondrial functioning and epigenetic biomarkers of CVD risk. In a mechanistic sub-study(n=50 per group from the Clinical Project), we will characterize and explore the mechanistic role of candidate microRNAs (miRNAs) as transducers of SB outcomes. Each Basic Science Project aim addresses specific mechanisms by which sitting time increases CVD risk. Physiologic evidence suggests that reducing sitting time, resulting in increased blood flow and muscle engagement in the lower extremities throughout the day, is key to improving cardiovascular and metabolic health outcomes. Evidence generated by the Basic Science Project will compliment and augment the growing clinical and epidemiological evidence linking sitting time with cardiovascular disease risk, including evidence from the Study of Latinos (SOL) cohort (the Population Project sample source). Aims 1 & 2 will compare 3-month outcomes of an intensive 25%-reduced sitting time intervention vs. a control, healthy aging advice condition on the following CVD-related metabolic and functional biomarker categories:

1. Novel biomarkers

1a. Mitochondrial function metabolomics. Approach: We will use state-of-the-art, targeted metabolomic analyses to measure concentrations of ~300 plasma metabolites (e.g., amino acids, acylcarnitines, organic acids) at baseline and follow-up for all Clinical Project participants. We hypothesize that changes in these CVD risk-associated metabolites reflecting improved mitochondrial functioning will be observed in the reduced sitting time intervention group but not observed in the control group.
1b. Epigenetic DNA methylation profiling. Approach: We will conduct targeted DNA methylation profiling of peripheral blood monocytes (PBMC) and determine Apparent Methylomic Aging Rate (AMAR) at baseline and follow-up for all Clinical Project participants. We hypothesize that AMAR will be diminished in the reduced sitting time intervention group and unchanged in the control group.
1c. Epigenetic miRNA expression profiling and identification of candidate cell-cell communication transducers (Sub-study). Approach: We will characterize baseline and follow-up miRNA profiles in plasma and PBMC isolated from 50 control group participants and 50 "best behavioral responder" intervention group participants from the Clinical Project. We will identify SB-associated miRNAs that are specifically altered in the reduced sitting time intervention group and not the control group. We will select and conduct in vitro cell-based, mechanistic studies on 2-4 miRNA candidate transducers of sitting time. We hypothesize that specific miRNAs will be altered after 3 months in the "best responder" intervention group but unchanged in the control group and that these miRNAs can transduce effects on cellular functioning that are related to CVD risk.

2. Standard biomarkers

2a. Vascular environment and endothelial function. Approach: We will measure plasma biomarkers of systemic inflammation (C-reactive protein (CRP)), endothelial cell adhesiveness and activation (vascular adhesion molecule 1 (sVCAM-1), intercellular adhesion molecule 1 (sICAM-1), P- and E-selectins), oxidative stress (F2-isoprostane), and coagulation (fibrinogen) at baseline and follow-up for all Clinical Project participants. We hypothesize that these biomarkers will be diminished in the reduced sitting time intervention group and unchanged in the control group.
2b. Glucose regulation and lipid metabolism. Approach: We will measure fasting plasma insulin, glucose, and lipid panel components and hemoglobin A1c (HbA1c) at baseline and follow-up for all Clinical Project participants. We hypothesize that glucose regulation and lipid metabolism will be improved in the reduced sitting time intervention group and unchanged in the control group.

Summary: The Basic Science Project will concurrently assess novel and standard candidate biomarkers of CVD risk that can shed light on basic, biological mechanisms not evaluated previously in SB research and in a high-risk Latina population that has not been the specific target of any SB intervention study. The Basic Science Project is highly integrated with the Clinical Project. The Basic Science Project team will also contribute to statistical biomarker data analyses conducted by the Shared Resource Core that will integrate behavioral outcomes from both the Clinical and Population Projects. Findings from the Basic Science Project will further our understanding of the effects and effectors of SB on women's cardiovascular health and inform future studies.