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Round 1: 2012-2013 Pilot Projects

Metabolic Effects of Short Term Sugarcane Bagasse Supplementation

Diets high in fiber have been shown to reduce the risk of type 2 diabetes and cardiovascular disease. However, the average American diet contains ~10 to 15 g of fiber per day and is well below the 20-35 g of fiber per day recommended by the Academy of Nutrition and Dietetics (formerly the American Dietetic Association). Therefore, there is a need to study methods of increasing dietary fiber intake as well as novel sources of dietary fiber. Sugarcane bagasse is the remaining fibrous material after sugarcane juice is extracted. Pre-clinical studies have shown attenuated weight gain, enhanced insulin sensitivity via HOMA-IR, lower ghrelin gene expression, and increased GLP-1 levels in mice fed a high fat diet plus sugarcane fiber compared to mice fed the same diet plus cellulose fiber. This 4 week double-blind placebo-controlled pilot study in obese, insulin-resistant adults aims to translate these results into humans. We hypothesize that subjects who consume food supplemented with sugarcane bagasse will have improved glucose tolerance and insulin sensitivity (via OGTT), less weight gain, increased satiety, higher GLP-1 levels, and lower ghrelin levels.

Evaluation of ACE2 as a Biomarker for Neurogenic Hypertension

ACE2 activity is reduced in the central nervous system (CNS) during the development of experimental neurogenic hypertension. This could result from the enzyme being cleaved from the cell membrane through shedding by ADAM 17, also known as TNF convertase. This shedding of ACE2 could lead to increased levels of soluble ACE2 within the CNS which is thought to be associated with hypertension and other cardiovascular diseases. Therefore, measurement of soluble ACE2 in the CNS could be used as a biomarker for developing neurogenic hypertension. We assessed ADAM 17 activity in the brain by measuring soluble ACE2 and TNF in the cerebro spinal fluid of patients by ELISA and mass spectrometry. CSF samples were obtained from 30 patients divided in 3 groups: normotensive (n=15), hypertensive (n=4), and hypertensive controlled with medication (n=11). While Elisa lacked sensitivity, soluble levels of hACE2 could easily be detected by RAS Fingerprint in all patients. Increased ACE2 activity in the CSF was associated with hypertension. On the other hand, patients taking antihypertensive medications appear to show normalization of ACE2 levels in the CSF. In conclusion, soluble ACE2 activity in the CSF is correlated with high blood pressure and could be used as a biomarker of neurogenic hypertension.

Transcriptional Profiling of Gastritis Progression Using High Throughput Sequencing of Tissue MicroRNA

Gastric cancer is one of the most common of all cancers and has one of the highest prevalence and mortality rates worldwide. More than 20,000 new cases of gastric cancer are expected in 2013, and more than 10,000 deaths will be attributed to the disease. Among all the risk factors, which include diet, age and ethnicity, infection with Helicobacter pylori (H. pylori) is the only irrefutable factor associated with the disease, especially in the intestinal form of gastric cancer. Because of this relationship, H. pylori is classified as a Type I carcinogen by the International Agency for Research in Cancer (IARC). A chronic inflammatory cascade from normal epithelia to non-atrophic gastritis (NAG), to multifocal atrophic gastritis (MAG), to intestinal metaplasia, dysplasia and cancer is initiated by the infection and can persist even after the eradication of H. pylori. Thus, determining the ideal therapeutic approach to delay or prevent the progression of inflammatory lesions to gastric cancer remains challenging. We have shown that single nucleotide polymorphisms (SNP) in cytokine genes are differentially associated with risk of advanced gastric lesions in African American and Caucasian individuals. However interesting, these are cross-sectional results and, thus, we are not able to explore gene profiles associated with the evolution of these gastric lesions. microRNA (miRNA) are small 18 - 24 nucleotide molecules known to interfere with both translation and transcription. Several profiles of miRNA have been associated with cancer risk but their role in disease evolution is still unknown. In this application we propose the innovative use of sequential biopsies from individuals with differential outcomes to evaluate the inflammatory lesion-to-malignancy cascade using high throughput sequencing. Our goal is to compare miRNA profiles in gastric biopsies at baseline and 12 years later to determine if there are specific gene sets, which can be associated with progression or regression of the disease.

Using Serum microRNAs as Biomarkers for Cognitive Impairment in HIV Patients

Human Immunodeficiency Virus (HIV)-infected individuals are at increased risk for developing depression and other neurocognitive disorders, but neurobiological mechanisms underlying mental deterioration in HIV-positive individuals remain unknown. Neurocognitive impairment and depression adversely impact HIV treatment adherence. Thus, identification of early markers of neurocognitive impairment could lead to interventions that improve psychosocial functioning and slow disease progression through improved treatment adherence.
MicroRNAs are short non-coding RNAs that regulate gene expression. microRNAs are key regulators of synaptic plasticity and brain development and, as such, could contribute to the etiopathology of neurocognitive disorders. In addition, microRNAs secreted into body fluids can serve as diagnostic and/or prognostic markers for a variety of diseases. Here, we present preliminary results of differentially regulated plasma microRNAs from 21 HIV-1 positive patients grouped on the basis of their neurocognitive status and/or symptoms of depression. Results indicate that plasma miRNAs may serve as useful biomarkers for HIV-associated neurocognitive disorders. 

MicroRNAs as Prognostic Markers of Breast Cancer

Our hypothesis is that miR-27b and miR-23b function as oncogenes by suppressing the function of Nischarin and ST14 tumor suppressors (and possibly other unknown proteins as well), and thus miR-27b and miR-23b are key regulators and good prognostic markers of breast tumor growth and metastasis. We believe these microRNAs have similar prognostic importance as Her2/Neu in breast cancer.  We will test our hypothesis by examining the prognostic importance of miR-27b and miR-23b in breast cancer patients. Here we will examine the expression levels of these two microRNAs in sera of breast cancer patients and controls. It is known that serum microRNAs can be diagnostic and/or prognostic markers for breast cancer. Moreover, blood sampling is minimally invasive and easy to obtain, and thus it is attractive to explore for potential biomarkers in blood.  We will screen blood serum of 103 cancer patients and 103 controls, and this would reveal the prognostic role of these microRNAs in breast cancer.

Discovering the Role of Putative MicroRNAs in Prostate Tumorigenesis

Prostate cancer (PC) is the most frequent cancer among older men. PSA is the most common diagnostic biomarker; however it has well known limitations. Microvesicles (MVs) are cell-derived extracellular bodies, which promote cell-cell communications. The identification of tissue- or disease-specific MVs miRNAs will enable the use of these vesicles as a source of new biomarkers. Our aim is to investigate the differential expression of selected putative onco-miRNAs in normal and PC cells and further establish their clinical utilities as biomarkers for PC. Here, we report the potential role of MVs-associated miRNAs in PC progression and their utility as biomarkers in vitro and in human tissues. The expression of onco-miRNAs was higher in PC patients than normal subjects. High expression of miRNAs suppressed their related targets of tumor suppressor genes, and ectopic expression of some of these onco-miRNAs in benign PC cell lines increased cell growth, migration and invasion.

Urinary Excretion of Renin and Soluble Prorenin Receptor in Hypertension

The prorenin receptor (PRR) increases renin activity and activates prorenin. To test the hypothesis that increased levels of soluble PRR (sPRR) enhances renin activity in the kidneys of hypertensive (HTN) patients, we measured the urine levels of free sPRR and renin activity (uRen) from 56 patients, including normal subjects (CT; n=18) and patients with HTN without (n=18) and with concurrent diabetes mellitus (DM; n=20). Twenty-six (48%) were women (51 13 years-old) and 30 (51%) were men (50 16 years-old). s(P)RR levels did not differ between HTN and HTN+DM patients but were lower compared to CT (HTN: 580 131 and HTN+DM: 500 85 vs. CT: 1,248 346 pg/mg; p0.05). uRen activity was similar between HTN and CT subjects (22 9 vs. 25 10 ngAngI/hr/mL), but higher in HTN+DM patients (164 16 ngAngI/ml/hr; p0.05). These data suggest that PRR bound to cell membrane, but no sPRR, might be responsible for the increases in uRen activity in HTN patients with DM.

Time Restricted Feeding to Improve Insulin Sensitivity and Vascular Function

It is widely believed that grazing improves blood sugar control and overall health. However, recent evidence in rodents suggests that grazing contributes to weight gain, inflammation, and worse glucose tolerance. In comparison, time-restricted feeding (TRF), which involves eating in a narrow time window followed by a daily 15-20 hour fast, reduced metabolic disease and abrogated weight gain in rodents.  We will conduct the first pilot study of TRF in humans.  In this crossover study, 8 obese men will be randomized to either 5 weeks of TRF or grazing, followed by a 7-week washout period, and then 5 weeks of the other feeding condition.  Calories, meal frequency, and diet composition will be matched in each group. Before and after each arm of the study, glucose homeostasis, vascular function, inflammation, and key hormones will be measured. It is hoped that this study will lead to novel insights into how meal timing impacts health and disease risk.

Predicting the Response of Lipoproteins to Exercise using Clinical and Genetic Data

There is large inter-individual variation in the magnitude of changes in plasma lipoprotein traits derived from regular exercise, and genetic factors appear to contribute to this variability. However, the associations of genomic markers with exercise-induced changes in lipoprotein particle traits have not been thoroughly explored. We hypothesize that adding information on genomic markers will significantly improve our ability to predict the responsiveness of lipoprotein particle traits to regular exercise above and beyond the commonly used clinical predictors. We will test this in the following aims:

Aim 1: Examine the response of lipoprotein particle traits to regular exercise in four exercise training studies in order to define significant clinical predictors of response.

Aim 2: Test whether genetic summary scores derived from GWAS improve the prediction of the response of lipoprotein particle traits to regular exercise compared to standard clinical assessment variables, and determine if this enhanced prediction level is clinically meaningful.