The Kiss RNA lab currently focuses on two main areas of research. Namely, developing novel RNA Therapeutics to treat and/or prevent human disease and performing experiments to understand fundamental mechanisms concerning the RNA molecular biology of mammalian cells.
RNA Therapeutics:
As we are housed inside the Houston Methodist Research Institute (HMRI), the lab is committed to the translation of basic science discoveries to benefit human health. Specifically, as a founding lab of the HMRI’s Center for RNA Therapeutics we continue to develop innovative RNA therapy options to transform human health by generating new RNA therapies to treat (or prevent) different conditions. As part of the Center, the lab has developed novel vaccine candidates for COVID-19 and other human diseases. We are currently working with collaborators across the United Sates to test how our candidates compare to other existing vaccine systems. The Center for RNA Therapeutics is an independent program at the HMRI and is currently growing by recruiting multiple new faculty over the next few years. Houston Methodist Research Institute, Department of RNA Therapeutics and Cardiovascular Sciences (academicjobsonline.org)
Shortly after the lab opened, we began working on our first therapeutic candidate, an RNA designed to counter genes driving oncogenic transformation and cell migration in certain breast cancers. That work earned Dr. Kiss a Career Development Award from The American Society for Gene and Cell Therapy (ASGCT). https://www.asgct.org/research/news/october-2019/asgct-career-development-awards. We continue working on this project and recently presented our intermediate findings as a talk titled “Construction of circular RNAs to block miRNA-driven oncogenic transformation” during the Annual Meeting of the ASGCT on May 11, 2021.
In addition to the circular RNA mentioned above, the lab has also been developing a novel RNA vaccine platform for COVID-19 and other diseases. With funding from the HMRI, we’ve been able to develop a customizable second-generation RNA vaccine platform which we are testing in multiple applications. We continue to develop this platform and look for opportunities to expand the applications for our general design. In addition to our COVID-19 vaccine effort, we are developing candidate RNAs designed to treat active coronavirus disease. These RNA therapeutic candidates are designed to slow the course of the infection by interfering with the virus's replication machinery. This RNA therapy approach is in its early stages.
Finally, we are also generating traditional mRNA therapy constructs to target an overexpressed transcription factor in glioblastoma multiforme, the most lethal type of brain cancer. Since transcription factors are often considered ‘undruggable’ with traditional small molecule drugs, they are ideal targets for mRNA-based approaches. We are currently evaluating a handful of different mRNA-based strategies to counteract our targeted transcription factor. This project is showing promise in cultured cancer cells and we are preparing to test the approach in animal models sometime in 2022.
RNA molecular biology:
The basic science research interests of the lab lie in the changes that occur in the RNA and molecular biology of cells when cellular stress responses converge to cause or exacerbate cardiovascular disease or cancer. I am building a two-pronged collaborative basic science group that leverages RNA molecular biology tools with both specialized and traditional RNA sequencing approaches combined with long-read sequencing to elucidate how these RNA-mediated changes occur.
Cytoplasmic RNA capping
The lab's work aims to determine the regulators that determine the conditions under which, and position(s) where, an RNA is capped in the cytoplasm. My lab uses both transcriptome-wide (direct RNA sequencing, RNA-seq, ribosome profiling, and others) in combination with targeted methods (qPCR, polysome gradients, biochemical assays, etc.) to understand how cytoplasmic capping drives some post-transcriptional gene regulatory events such as those in general cellular stress responses and stress responses linked to cardiovascular disease. Ultimately, my lab aims to uncover the evolutionary role of cytoplasmic RNA capping, and to decipher the mechanism(s) controlling the selection, generation, and regulation of capping sites, and to develop cytoplasmic capping-based drug responsiveness screens and/or RNA therapeutics.
The lab is currently in the second year of its 5-year R35 MIRA grant from the National Institute of General Medical Sciences (1R35GM137819) to study the molecular underpinnings of cytoplasmic capping and a 3 year Career Development Award (20CDA35310329) from the American Heart Association to better understand if cytoplasmic capping helps cells respond to stress in the cardiovascular system.
PDGFR-alpha
Another part of my basic science lab focuses on understanding how a single mutation in the platelet-derived growth factor receptor alpha (PDGFRA) gene leads to a genetic defect. This project began as a collaboration with multiple clinical groups and labs based in Houston, TX. The initial observation showed that a single point mutation in the PDGFRA locus tracked with non-syndromic cleft lip and palate in a multi-generational family. We were initially intrigued by the possibility to test a novel PDGFRA mutation as PDGFRA is a receptor tyrosine kinase and is known to initiate a tyrosine kinase signaling cascade. Tyrosine kinase signaling was of particular interest for our cytoplasmic capping work as Nck-1, a key adaptor protein for the cytoplasmic capping complex, contains a Src homology 2 (SH2) domain which may be an input for tyrosine kinase signaling. The initial effort in this work has been completed and a manuscript in the peer review process.
FHIT
Another part of my basic science lab focuses on how the FHIT tumor suppressor modulates the translation of the transcriptome in cancer. My work has shown that expression of the FHIT protein results in translational changes for several known cancer-linked mRNAs. Further, that translational regulation is often driven by the 5’ translation leader sequence of the mRNA. For my future FHIT research, I plan to build upon my published works by expanding ribosome profiling into FHIT negative patient tumor samples and by developing better cell lines where FHIT expression is more tightly regulated.
(updated 9-21-2021)
