Wednesday, March 30
7:30-8:15 am Breakfast Presentation (Sponsorship Opportunity Available) or
Morning Coffee
Contact Jon Stroup at jstroup@healthtech.com or 781-972-5483
microRNA in Human Development
and Disease
8:30-8:35 Chairperson’s Opening Remarks
8:35-9:00 Inverse Modifications in microRNAs -132 and -211 Contribute to Synapse and Cholinergic Malfunctioning in Alzheimer’s Disease
Hermona Soreq, Ph.D., Professor, Molecular Neuroscience, Biological Chemistry, The Hebrew University of Jerusalem
Alzheimer’s disease (AD) notably involves failed synaptic functioning and premature death of cholinergic neurons, but the underlying mechanism(s) and possible interrelationships between these two phenomena are yet incompletely understood. Using a global high-throughput screening, we discovered increased exon inclusion events and corresponding decreases in the exon exclusion regulators, heteronuclear ribonucleoprotein particles (hnRNPs) in the entorhinal cortex from AD patients compared to non-demented controls. This was accompanied by increased microRNA (miR-211) which co-targets three different hnRNP mRNAs; and lentiviral-mediated knockdown of these hnRNPs caused synapse loss in cultured neurons and learning and memory impairments in brain-injected mice. Furthermore, in vivo destruction of cholinergic neurons, but not APP or TAU mutations, reduced brain hnRNP levels, and the synaptogenesis regulating and acetylcholinesterase (AChE)-targeted miR-132 was drastically reduced in the AD entorhinal cortex, possibly attributing part of the loss of cholinergic input to this change. Together, our findings suggest that AD involves a feed-forward loop of miR-211 increases which mediate hnRNP depletion, leading to synapse loss; and parallel miR-132 decreases which cause AChE elevation, impair cholinergic signaling and enhance neuroinflammation while exacerbating hnRNPs loss.
9:00-9:25 microRNAs that Regulate Adipocyte Differentiation and Function
Harvey F. Lodish, Ph.D., Professor, Biology and Biological Engineering, Whitehead Institute for Biomedical Research, MIT
Brown adipocytes are specialized for heat generation and energy expenditure. To investigate the role of miRNAs in the lineage determination of brown adipocytes, we compared the global miRNA expression profiles of brown fat, white fat and skeletal muscle. We identified a brown fat-enriched miRNA cluster that was upregulated during brown fat adipogenesis and induced by ectopic expression of PRDM16 in both primary white preadipocytes and myoblasts. This miRNA cluster serves as an important downstream effector of PRDM16 and contributes to brown adipocyte lineage determination primarily by repressing white fat adipogenesis and myogenesis.
9:25-9:50 Opposing Functions and Differential Regulation of the Bicistronic Cardiac miRNAs, miR-1 and miR-133a
Kathryn N. Ivey, Ph.D., Staff Research Investigator, Gladstone Institute of Cardiovascular Disease, University of California, San Francisco
miR-1 and miR-133a are bicistronic muscle-specific miRNAs that are essential for heart development and function. Although they are co-transcribed, they have opposing effects on differentiation and accumulate to dramatically different levels. Therefore, we hypothesized that interaction of miR-1 or miR-133a with distinct proteins may differentially control their biogenesis or stability. Using a biochemical approach, we identified several proteins that uniquely interact with miR-1, but not miR-133a, and specifically affect the accumulation of miR-1. This represents the first description of differential regulation of bicistronic miRNA accumulation and is likely to have broader implications for miRNA control.
9:50-10:15 Speaker to be Announced
10:15-10:50 Networking Coffee Break
microRNA in Therapeutic Development
Chairperson's Opening Remarks
Fazlul H. Sarkar, Ph.D., Professor of Pathology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine
10:50-11:15 A microRNA Screen to Identify Modulators of Sensitivity to BCL2 Inhibitor ABT-263 (Navitoclax)
Lloyd T. Lam, Ph.D., Senior Scientist II, Global Pharmaceutical R&D, Tumor Genomics, Abbott Oncology
ABT-263 is a first-in-class BCL2 family inhibitor that restores the ability of cancer cells to undergo apoptosis. However, many cancer cells are resistant to ABT-263 due to high expression of a BCL2 family member MCL1. A functional genomics approach was used to explore the role of microRNAs in determining ABT-263 sensitivity. All the identified microRNAs restore apoptosis in the presence of ABT-263 by reducing MCL1 protein expression. This approach can facilitate the identification of microRNA modulators to other cancer agents and the design of microRNA replacement therapies.
11:15-11:40 Novel Approach for Targeted Deregulation of miRNAs for Cancer Therapy
Fazlul H. Sarkar, Ph.D., Professor of Pathology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine
Emerging evidence suggests the acquisition of epithelial-to-mesenchymal transition (EMT), a transient process that is typically found during tumor progression in vivo, which is reminiscent of cancer stem-like cell (CSC) characteristics, contributes to tumor progression and metastasis. Moreover, these cells within a tumor mass are also highly resistant to conventional therapeutics, suggesting that novel targeted strategies must be discovered so that these resistant cells could be eliminated in order to make improvement in the treatment of most solid tumors because the EMT (CSC) phenotypic cells are believed to be the root cause of tumor recurrence and metastasis. We have discovered a novel compound that is very effective in eliminating EMT (CSC) phenotypic cells both in vitro and in vivo, which was found to be due to specific deregulation of miRNAs. This subject will be discussed during the presentation.
11:40 am-12:05 pm miR-21 Overexpression in Breast Cancer Confers Herceptin Resistance by Downregulation of PTEN
Dihua Yu, M.D., Ph.D., Professor and Deputy Chair, Department of Molecular and Cellular Oncology; Hubert L. and Olive Stringer Distinguished Chair in Basic Science; Director, Cancer Biology Program, The University of Texas MD Anderson Cancer Center
Aberrant expression of certain microRNAs can lead to therapeutic drug resistance. Our lab previously found that PTEN loss confers Herceptin resistance in ErbB2-overexpressing breast cancers. Other studies in hepatocellular carcinoma have shown that miR-21 targets the 3’UTR of PTEN mRNA leading to downregulation of PTEN protein levels. Based on these findings, we hypothesized that overexpression of miR-21 may confer Herceptin resistance in breast cancer patients by downregulation of PTEN. I will discuss our exciting data from cell culture, animal model, and human breast cancer patients demonstrating miR21 overexpression can be found in almost 60% of ErbB2 positive breast cancers, and miR21 overexpression in breast cancer cells confers Herceptin resistance by down-regulation of PTEN and modulation of apoptotic pathways. Furthermore, targeting miR21 can sensitize ErbB2 positive breast cancers to Herceptin treatment in vivo. These data clearly indicated a new direction and strategy of overcoming Herceptin resistance to further improve the clinical management of breast cancer patients.
12:05-12:30 microRNA-Based Therapeutics
Eric G. Marcusson, Ph.D., Director, Drug Discovery, Regulus Therapeutics
microRNAs are endogenous non-coding RNAs that post-transcriptionally regulate gene expression. Each microRNA can regulate hundreds of genes that have been evolutionarily selected to regulate biological pathways. The pathways involved are central to many areas of biology, including development, cancer, metabolism, and immunity. The ability of microRNAs to modulate disease pathways by influencing multiple, functionally-linked genes makes targeting or augmenting them an exciting new approach for drug discovery. Recent genetic and pharmacologic studies have suggested opportunities for microRNA therapeutics in multiple disease areas. However, the nontraditional nature of these drug targets presents unique challenges in the process of developing targeted therapeutics. In this talk I will discuss some of these challenges as well as give examples within the areas of fibrosis and cancer where exciting new data demonstrate the potential power of microRNA-based therapeutics.
12:30 Close of Conference