12:00pm Conference Registration

MECHANISM OF ACTION

1:00 Chairpersons' Remarks:
Clark Jeffries, Ph.D., Research Professor, School of Pharmacy, University of North Carolina at Chapel Hill

1:10 Nuclear RNAi Applied to Study Selection of pre-miRNA Biogenesis
Clark Jeffries, Ph.D., Research Professor, School of Pharmacy, University of North Carolina at Chapel Hill
Nature selects sets of pre-miRNAs for excision from pri-miRNAs and hence availability to the miRNA pathway. Novel RNAi in the nucleus employs nanotechnology to deliver ssRNA molecules that selectively bind to certain pri-miRNA subsequences and alter biogenesis. Our presentation will outline progress to date.

1:40 MicroRNA Regulation in Development and Cancer
J. Michael Thomson, Ph.D., Researcher, Hammond Laboratory, Department of Cell and Developmental Biology, University of North Carolina, Chapel Hill

2:10 Deregulation of microRNA Expression and Age-Dependent Diseases
Eugenia Wang, Ph.D., Professor, Gheens Center on Aging & Dept. of Biochemistry and Molecular Biology, University of Louisville
In general, genes identified as associated with either normal aging or age-dependent diseases can be grouped into families regulating the stress response, redox/homeostasis, DNA repair, metabolism, apoptosis, and growth factor signaling. Mapping how these genes are functionally related as signaling networks to control health status, ranging from that of individual cells to their host organs and then to individuals, has been a tremendous challenge, since most age-dependent degeneration is an accumulation of complex interactions between gene and environmental functions over an individual’s entire life span. Moreover, the changes in expression of most, if not all, individual aging-related genes may be controlled by underlying "hubs", which serve as the underlying factors governing the wholesale programmatic shift of gene expression seen in cells of tissues from older individuals. Our last few years’ work has led us to investigate microRNAs as candidate "hubs", hidden molecular master switches; dysregulation of their expression may precipitate the observable, age-dependent gene expression changes. We have used two different systems to study changes of microRNA expression during aging: mouse liver aging, and peripheral lymphocytes from victims of sporadic Alzheimer’s disease. Screening with microRNA microarrays allows us to identify microRNAs unique to the older mouse liver, and those unique to sporadic Alzheimer’s disease peripheral lymphocytes. Interestingly, some of the microRNAs identified are shared between these two diverse systems; and their target genes are located in families regulating oxidative response, cell signaling, and genomic maintenance, etc. These findings led us to suggest that selected microRNAs may control genetic networks common to most, if not all, cell types in response to life-long cellular insults; their deregulation of expression may be then the molecular roots for age-dependent disease. Obviously, these selected microRNAs are the pivotal leads for advance diagnosis and therapeutic countermeasures to curtail, reduce and slow down age-dependent diseases.

2:40 Role of microRNA Pathway in Mental Retardations
Peng Jin, Ph.D., Assistant Professor, Department of Human Genetics, Emory University School of Medicine
Small noncoding RNA guides, including microRNAs (miRNAs), small interfering RNAs (siRNAs), and repeat-associated small interfering RNAs, 21 to 30 nucleotides in length, could shape diverse cellular pathways, from chromosome architecture, development, and growth control, apoptosis to stem cell maintenance. In fact, it has been estimated that miRNAs could regulate as many as one-third of human genes. MiRNAs and the components of the RNAi pathway have been implicated in diverse human diseases. In my presentation, I will discuss our most recent work on both Fragile X syndrome and Rett syndrome, and how the misregulation of the miRNA pathway could contribute to the pathogenesis of these two diseases.

3:10 microRNA Profiling Using a High Performance, Flexible µParafloTM Biochip Platform Christoph Eicken, Ph.D., Head of Technical Services, Microarrays, LC Sciences, LLC An advanced microfluidic biochip system designed to produce high quality data, stay current with the rapidly evolving microRNA field, and perform diverse small RNA discovery experiments is presented. This technology’s unique flexibility allows for miRBase synchronicity and design of customized biochips adapted to each researcher s specific needs. Applications featuring disease marker discovery, drug treatment, microRNA target screening, and small RNA discovery are highlighted.

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3:30 Refreshment Break with Exhibit and Poster Viewing

microRNA IN CARDIOLOGY

4:15 Chairpersons' Remarks
Thomas Thum, M.D., Head, Research Group Cardiac Wounding/Healing,
Julius-Maximilians-University

4:20 microRNAs in the Broken Heart
Thomas Thum, M.D., Head, Research Group Cardiac Wounding/Healing,
Julius-Maximilians-University
MicroRNAs are recently discovered natural, single-stranded molecules consisting of ~22 noncoding nucleotides that negatively regulate gene expression. Recent findings suggest that microRNAs exert their function in a cell-type and organ-specific manner and can be aberrantly expressed in human disease, adding further complexity to microRNA-mediated control of eukaryotic gene expression. We and others previously have presented evidence for the involvement of microRNAs in the regulation of cardiac structure and function. Cardiac disease is characterized by reactivation of a fetal gene program, finally leading to left ventricular remodeling and progressive dysfunction. Indeed, cardiac microRNAs critically determine the transcriptional changes observed in heart failure. Cardiac transcriptome analyses revealed striking similarities between fetal (gestation age 12-14 weeks) and failing human heart tissue. Using microRNA-arrays we discovered profound alterations of microRNA expression in failing hearts. These changes closely mimicked the microRNA expression pattern observed in fetal cardiac tissue. A prerequisite for an understanding of microRNA function and potential therapeutic use in heart disease is the search, identification and validation of miRNA targets. Bioinformatic analysis demonstrated a striking concordance between deregulated messenger RNA expression in heart failure and the presence of microRNA binding sites in the respective 3´untranslated regions. Messenger RNAs upregulated in the failing heart contained preferentially binding sites for downregulated microRNAs and vice versa. Mechanistically, transfection of cardiomyocytes with a set of fetal microRNAs induced cellular hypertrophy and disarray as well as changes in gene expression comparable to the failing heart. Based on our initial findings, we now analyzed selected cardiac microRNAs in detail by loss- and gain-of function experiments and identified miRNA-regulated disease-specific cardiac growth control pathways leading to cardiac hypertrophy and dysfunction. Application of synthetic miRNA inhibitors in vivo in cardiac disease models prevented development of cardiac hypertrophy and dysfunction. The recently discovered miRNAs confer increasing levels of complexity in the control of cardiac gene expression, and unraveling the regulatory circuits is challenging. MicroRNAs now have emerged as pivotal regulators in regulating gene expression in the heart, thus presenting attractive targets for treating heart disease. The identification of microRNA targets relevant in cardiac biology has just begun and potentially will guide us into a new era of molecular-mechanism based development of innovative therapeutic approaches.

4:50 Altered Expression of microRNAs Contributes to Heart Failure
William Pu, M.D., Assistant Professor, Cardiology, Children’s Hospital, Boston
We profiled ~430 microRNAs in 68 myocardial samples from controls, ischemic cardiomyopathy, dilated cardiomyopathy, and aortic stenosis. This showed disease-specific altered expression of about 40 microRNAs, among them the cardiac-specific microRNA miR-1. We have identified calcium-signaling molecules as targets for miR-1. Upregulation and inhibition of miR-1 in vitro alters calcium signaling downstream of these molecules. Data from in vivo studies will also be discussed.

5:20 The Myriad Roles of microRNAs in Heart Disease
Eva van Rooij, Ph.D., Eric Olson Lab, Department of Molecular Biology, University of Texas Southwestern Medical Center
The myriad roles of stress responsive microRNAs in the control of cardiac function and dysfunction and therapeutic opportunities for manipulating microRNA biology in the settings of muscle disease will be discussed.

5:50 RNAi Screens for miRNAs involved in Human Mesenchymal Stem Cell Differentiation Anita Seto, Scientist, Thermo Fisher Scientific Inc. microRNAs (miRNAs) are small RNAs that modulate gene expression and are implicated in normal development, differentiation, and disease. Here we will describe the power of combining RNAi-based silencing and high content analysis technologies to characterize the cell fates of adult pluripotent human mesenchymal progenitor stem cells (hMSCs).

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6:10 Reception in the Exhibit Hall

7:10 Close of Day