Chaluvally Lab

Chaluvally Lab

Copy number variations (CNVs) such as deletions or amplifications of chromosomal loci are common events during the initiation and progression of cancer. While the role of coding genes and proteins are well characterized in the CNVs, non-coding RNAs such as microRNAs and long noncoding RNAs (lncRNAs) part of the CNVs are understudied in the context of tumor initiation and progression. Recently we have characterized the role of two microRNAs miR569 and miR551b in the progression of cancer. Our studies identified that miR569 downregulates the expression of tumor suppressor gene TP53INP1 (Chaluvally-Raghavan et al., Cancer Cell, 2014), and miR551b activates the transcription of master regulator STAT3 in ovarian cancer (Chaluvally-Raghavan et al., Cell Reports, 2014). While CNVs altered expression of microRNAs (miRs) in tumors, the mechanism of action of miRNAs deregulated by CNVs and how they intersect with neoplastic progression remains unclear. The long-term goal of our research is to characterize the critical factors that regulate the expression of non- coding genes, novel actions of non-coding RNAs and the sequential changes in downstream signaling associated with non-coding RNA expression in women’s cancer. Projects in the lab cover each of these avenues of research. We are expecting that our studies will lead to a greater understanding of the versatile role of both coding and noncoding RNAs, their mechanism of action and novel therapeutic targets.

The lab has three major scientific focus areas:

1. Characterize the role of microRNAs on the transcriptional activation and translational up-regulation.
miRNAs are thought to primarily downregulate the gene expression by binding 3’UTR of target genes. Currently we are extending our research to study novel actions of microRNAs as critical modulators that can directly activate gene expression. Our recent results demonstrate that microRNA can bind the promoter, in turn facilitates the recruitment of transcription factors and activate gene expression through the process called RNA activation (RNAa). We are employing biochemical and molecular biology approaches integrated with computational biology and bioinformatics tools to characterize the process of RNA activation.

2. Characterize the role of Copy Number Variations (CNVs) on the competent endogenous RNA effect in Cancer in Women.
Although much progress has been made in our understanding on the effect of microRNAs on the target genes, the reverse effect of mRNAs on binding and degrade microRNAs is not well understood. The competitive mechanism of 3’UTR of genes to downregulate the endogenous microRNAs is called competent endogenous RNA (ceRNA) effect. A minimum number of transcripts are required for any RNA to function as a ceRNA in order to decoy the expressions of microRNAs. These competitive endogenous RNAs act as molecular sponges for a microRNA through their miRNA binding sites (also referred to as miRNA response elements, MRE), thereby de-repressing all target genes of the respective miRNA family. Herein, our studies will unwind the collective effect of ceRNAs located in the 3q26.2 amplicon and characterize the change in the expression of microRNAs and subsequent signaling cascades regulated by ceRNAs.

3. Exploit RNA interference (RNAi) as a therapeutic tool to target oncogenes.
Over the last six years, we have made major scientific contributions in the RNAi field using anti-microRNAs target and inhibit the oncogenic microRNAs to treat the tumor cell proliferation and metastasis in vitro and in vivo. We are using small RNAs encapsulated in biocompatible nanoparticle platforms (e.g., DOPC, chitosan) for the in vivo delivery. These studies were summarized in several publications (Cancer Cell 2014, Cell Reports 2016 and Oncoscience 2016). Our current research characterizing several novel genes could be used as potential targets to inhibit the tumor growth and metastasis in vivo using the small RNAs encapsulated in nanoliposomes.

Meet Dr. Chaluvally-Raghavan

Chaluvally-Raghavan, Pradeep, PhD

Chaluvally-Raghavan, Pradeep, PhD

Assistant Professor
(414) 955-2573

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