The 2014-2015 Pilot Project award recipients are T. Cooper Woods, Ph.D., Shaowei Chen, M.D., Ph.D., and Prerna Kumar, Ph.D.
T. Cooper Woods, PhD
Research Assistant Professor,
Department of Physiology
Phone: (504) 988-2588
Room #: 4008
Email: twoods3@tulane.edu
Non-coding RNA in Diabetes mediated Enhanced Intimal Thickening during Early Atherosclerotic Plaque Development.
Dr. Woods completed his PhD from the Birmingham, Alabama in 1998 and his Postdoctoral fellowship from the Harvard-MIT Division in 2000 and Columbia University Medical Center in 2005. His pilot project study will compare the RNA in artery tissue obtained from patients with cardiovascular disease with and without diabetes mellitus to determine new targets for preventing the cardiovascular complications of diabetes.
PILOT PROJECT RESEARCH: Intimal thickening, a component of both the initiation of atherosclerotic lesion formation and subsequent plaque development, is increased in diabetic subjects. Dr. Woods data suggest this is driven by changes in the levels of one form of non-coding RNA (ncRNA), microRNAs (miRNAs). Recently it has become clear that another form of ncRNA, circular RNAs (circRNAs) that can negatively regulate miRNAs, has the potential to play a major role in disease processes via negatively regulating miRNAs. He hypothesize that diabetes induces alterations in miRNA and circRNA levels in the vasculature that promote acceleration of intimal thickening through decreases in apoptosis and increases in proliferation and migration. The hypothesis will be tested via three specific aims: 1) Link changes in miRNA expression in carotid arteries induced by diabetes mellitus to an increase in intimal thickening; 2) Link changes in circRNA expression in carotid arteries induced by diabetes mellitus to changes in miRNA activity that promote increased intimal thickening; and 3) Integrate changes in ncRNA expression with changes in mRNA levels in carotid arteries induced by diabetes. This study will use next generation sequencing of RNA to identify differences in the miRNAs and circRNAs in early stage human carotid artery plaques obtained from diabetic and non-diabetic subjects. Aim 1 will characterize how changes in miRNA associated with diabetes lead to an increase in intimal thickening. Aim 2 will examine how changes in circRNA expression induced by diabetes alter the activity of miRNA in the vasculature to further promote intimal thickening. In vitro methods will be used in each aim to establish a functional connection between the non-coding RNA of interest and intimal thickening. Aim 3 will combine the data obtained in the first two aims with mRNA expression data to connect ncRNA to mRNA regulation. Together the expected outcome of this project is a first of its kind dataset that connects expression of circRNAs and miRNAs to mRNA regulation in the cardiovascular complications of diabetes. These data will have a significant positive impact as they will link changes in ncRNA expression induced by diabetes with accelerated atherosclerotic plaque development, providing future targets for therapeutic interventions.
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Shaowei Chen, MD, PhD Research Assistant Professor |
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Hongbing Liu, PhD Research Assistant Professor |
Histone Deacetylases 1 and 2 in Kidney Development
Dr. Shaowei Chen earned his MD from Nanjing Medical University in China in 2001, his PhD from Tulane University in 2010 and his Post-doctoral fellowship from Tulane in 2012. His proposed pilot project study will provide new insights into the potential epigenetic mechanisms of CAKUT, and open new avenues to novel strategies for the prevention and treatment of CAKUT and its associated kidney & cardiovascular diseases in both children and adults.
PILOT PROJECT RESEARCH: Congenital Anomalies of the Kidney and Urinary Tract (CAKUT) are a major cause of morbidity in children, constituting approximately 20~30% of all anomalies identified in the prenatal period. CAKUT plays a causative role in 30~50% of cases of end stage renal disease (ESRD) in children, and predisposes to the development of hypertension and other renal-cardiovascular diseases in patients that survive to adolescence and adulthood. Therefore, CAKUT poses a significant economic burden on health care systems related to the patients' lifelong costly therapeutic needs. The long-term goal of Dr. Chen’s study is to uncover the epigenetic mechanisms accounting for CAKUT. His study propose to investigate the nephric lineage-specific functions of class I histone deacetylases (HDACs), HDAC1 and HDAC2, in kidney development. HDACs are an evolutionarily conserved group of enzymes that remove acetyl groups from histones as well as non-histone proteins. His preliminary data indicate that HDAC1 and HDAC2 play redundant yet essential functions in the renal progenitor cells: double deletion of HDAC 1 and HDAC2 in the renal progenitor cells disrupts nephron formation, due to defective cell proliferation and differentiation. To build on his previous studies showing that HDAC activity is required for expression of key renal developmental pathways, he will use a variety of genetic, biochemical and bioinformatic approaches to accomplish the following specific aims: (1) To determine the role of HDAC1 and 2 in regulation of Wnt4 expression during nephrogenesis; and (2) To elucidate the HDAC1/2-gene regulatory network in nephron progenitor cells. The results will provide new insights into the epigenetics of kidney development and will open new avenues to novel strategies for the prevention and treatment of CAKUT and its associated renal-cardiovascular diseases, through pharmaceutical agents that target epigenetic modifiers. Such epigenetic drugs are already in clinical use or under investigation for the treatment of cancer as well as other diseases.
Prerna Kumar, PhD
Research Instructor,
Department of Physiology,
Phone: (504) 988-6599
Room #: 4168/4018
Email: pkumar@tulane.edu
Estrogen-dependent activation of guanylyl cyclase /natriuretic peptide receptor A gene expression via estrogen receptors ERα and ERβ.
Dr. Prerna Kumar earned her PhD in 2004 from the Jawaharlal Nehru University, School for Biotechnology, in New Delhi, India. She completed her post-doctoral training from Tulane University in 2010. Her proposed pilot project study will help in understanding the gender-based differential regulation involved in cardio-protection as observed in young females and will provide a basis for designing strategies for prevention of CVD in aging females besides developing therapeutic strategies for treating women with CVD.
PILOT PROJECT RESEARCH: Estrogen (E2) and its receptors (ERs) have been shown to protect the heart and vasculature and have important effects on vascular physiology and pathophysiology with potential therapeutic implications. Guanylyl cyclase/natriuretic peptide receptor-A (GC-A/NPRA) is the primary receptor for the cardiac hormones atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) and plays a central role in the pathophysiology of hypertension and cardiovascular disorders. Few studies have reported that treatment with estradiol (E2) increases ANP and GC-A/NPRA signaling but the critical molecular mechanisms involved in this process and E2 effect on Npr1 gene (coding for GC-A/NPRA) expression in target cells is not understood. The long-term goal of this study is to define the molecular mechanisms involved in estrogen-mediated Npr1 gene regulation involving its receptors and chromatin modulation. The preliminary results in human cardiomyocytes (HCM) show that E2-mediates upregulation of Npr1 promoter activity and presence of estrogen response element(s) (EREs) in Npr1 gene promoter. These observations led Dr. Kumar to propose that E2 regulates Npr1 expression with yet to be defined signaling pathway in cardiomyocytes. The proposed project will test the central hypothesis that estrogen regulates Npr1 gene transcription and expression via its receptor and response elements present on the Npr1 promoter. To test that hypothesis we propose (1) To define the effects of estrogen and functional role of estrogen response element(s) (EREs) in mediating Npr1 gene transcription and expression (2) To determine the role of estrogen receptors (ERα and ERβ) in mediating estrogen effect on Npr1 gene expression. Her experimental approach consists of a well established in vitro model system, using mainly HCM isolated from age-matched male and female heart ventricular tissue. She will address each of the specific aims by using molecular biology techniques to analyze effect on E2 on Npr1 promoter activity and expression at mRNA and protein levels and its downstream signaling by cGMP assay. The experimental approach proposed should define the molecular interaction of ERs and EREs involved in E2-mediated upregulation of Npr1 gene transcription. Results should provide significant insight into role of E2 in Npr1 gene regulation and its downstream signaling, in a gender-specific manner, which is yet to be defined.
