The doctoral dissertation in the field of Molecular Medicine will be examined at the Faculty of Health Sciences at Kuopio campus.
What is the topic of your doctoral research? Why is it important to study the topic?
Ischemic diseases are a group of diseases that are caused by the lack of oxygen and nutrients in the tissue. This condition occurs due to the malfunctional blood flow, often caused by a blockage in the blood vessels. Ischemic diseases contain diseases like coronary artery disease which occurs in the heart when the coronary artery is blocked. If the blockage is total, heart cells start to die and this may lead to a myocardial infarction i.e., heart attack. Similarly, ischemic condition in the brain leads to stroke.
Ischemic diseases are usually treated with balloon surgery or with blood thinning medication. Many times, these treatments bring ease to the patient. However, they are not always effective, and they do not erase the issue at the molecular level in the tissue. In this thesis I studied how microRNAs that are found in the nuclei of the cells are taking part in the regulation of the gene expression. The aim of the studies in the thesis is to find new treatments for ischemic diseases.
What are the key findings or observations of your doctoral research?
MicroRNAs are small RNA molecules that do not lead to the formation of protein, but they participate in the regulation of gene expression. MicroRNAs have been studied for decades, and they are most known for their role in the silencing of gene expression in the cytoplasm. This RNA interference is a widely known phenomenon where microRNAs can act as fine tuners of the cells’ function. With microRNAs, cells can quickly react to the changing circumstances occurring in the body.
In this thesis, microRNAs and their less known activity in the cells’ nuclei were studied. Genes are encoded in the DNA that is located in the nucleus of the cells. Genes are transcribed into RNA in the nucleus, and they are further translated into proteins in the cytoplasm. Nuclear microRNAs can affect gene regulation already when gene is transcribed. This allows cells to rapidly response to the changing conditions.
In this thesis, mouse endothelial cells were studied in hypoxic i.e., low-oxygen conditions. The study shows that there are specific microRNA populations found enriched in the cytoplasm or in the nucleus. In addition, it was observed that the number of some microRNAs expressed in the cytoplasm or in the nucleus increased when cells were treated with hypoxia. Therefore, it is possible that microRNAs are important regulators in hypoxic conditions, such as in ischemic diseases.
The main cause for ischemic diseases is the lack of adequate blood circulation into the damaged tissue. Vascular endothelial growth factor A (Vegfa) is one of the main factors contributing to the new blood capillary formation. Increasing Vegfa protein alone induces new capillary formation in the damaged tissue. In this doctoral research, mouse microRNA miR-466c was found to increase Vegfa transcription in the cell nucleus. In addition to cell culture models, induction of miR-466c in mouse hindlimbs after ischemia was found to increase blood capillary formation in the ischemic tissue.
How can the results of your doctoral research be utilised in practice?
The observed mouse microRNA miR-466c is very similar to a human microRNA. Therefore, miR-466c may function also in humans to upregulate VEGFA expression. Intellectual property rights have been applied for concerning the function of miR-466, and research continues in the start-up company RNatives which was founded to commercialise this novel microRNA function. In the future, it is perhaps possible to use microRNAs in the treatment of heart attack and ischemic stroke to help the tissue to grow new capillaries and to gain back its normal function. Therefore miR-466c has future potential to help patients suffering from ischemic diseases.
What are the key research methods and materials used in your doctoral research?
The research was performed at A. I. Virtanen Institute for Molecular Sciences and finalised at RNatives. A wide range of different molecular biology methods, as well as bioinformatics and mouse models were used in this PhD thesis. The main features in this thesis are the widely used sequencing techniques, as both small and long RNA molecules were sequenced in the different conditions. In addition, advanced methods such as CRISPR and RNA pulldown techniques were used.
The doctoral dissertation of Pia Laitinen, MSc, entitled Nuclear microRNAs: The role of miR-466c in transcriptional gene activation will be examined at the Faculty of Health Sciences. The Opponent in the public examination will be Associate Professor Olof Gidlöf of the University of Lund, and the Custos will be Docent Mikko Turunen of RNatives.
Doctoral defence
Dissertation (link available later)
For further information, please contact: Pia Laitinen, MSc, pialai(a)student.uef.fi
