pure text version of postdoctoral project research description 06-19-2014d1551


Synopsis of Postdoctoral Project
Kurt Whittemore

	Pathologies associated with the cardiovascular system become major problems as individuals become older and their health declines.  In fact, cardiovascular disease is the number one cause of death 1.  Another pathology which may be associated with cardiovascular health is bone marrow failure.  Recent findings about telomeres have demonstrated that they play a critical role in the health of organisms, and may be related to cardiovascular health as well.  Individuals with mutations in genes involved in the maintenance of telomeres have “telomere syndromes” which result in premature aging and associated pathologies 2.  Telomere shortening, along with genetic and environmental factors, plays a major role in the development of age-associated diseases such as heart disease 3.  Additionally, the quantity of short telomeres has been correlated with heart related diseases and lifespan 4.  Since associations with cardiovascular health and telomeres have been made, these associations now need to be defined more precisely.  This postdoctoral research will identify specific pathways that are associated with the link between telomeres and cardiovascular health.
	Mouse models will be used to study pathways involved in telomere therapy and cardiovascular health.  Many mouse experiments have already been performed.  For example, researchers have demonstrated that transgenic mice with an inducible switch that allows for increased telomerase expression can reverse some tissue degeneration when the switch is activated 5.  I will be performing this research in Dr. Blasco’s lab, and her lab has previously demonstrated that TERT gene therapy with an adeno-associated virus (AAV) virus can also improve the health of the mice, resulting in an increased lifespan 6.  These experiments provided great insight into the roles of telomeres, aging, and health, but they were not designed for the study of cardiovascular diseases specifically.
	There are two mouse models that will be implemented to study the link between telomeres and cardiovascular diseases specifically: one model in which the mice exhibit aplastic anemia, and another model in which the mice have a myocardial infarction.  In the aplastic anaemia model, bone marrow cells are transplanted from a TRF1 knockout mouse to a mouse without the TRF1 modification.    The TRF1 protein is involved in telomere maintenance 7.  The TRF1 knockout is actually under the control of a Cre-recombinase switch that is induced by a response when polyinosinic acid-polycytidylic acid (pI:pC) is added, and this allows the experiment to be more precisely controlled.  Deletion of this gene causes stem cells in the bone marrow to acquire very short telomeres over time which leads to a type of aplastic anemia 8.  Dr. Blasco’s lab has performed TERT gene therapy on these mice.  Sixty days after the treatment, 25% of the control group mice had died, while all of the treated mice were still alive.  The second mouse model uses mice in which arteries have been ligated and myocardial infarction has been induced.  In the past, Dr. Blasco’s lab has found that TERT gene therapy was correlated with lower levels of ANP, a polypeptide hormone secreted by heart muscle cells 9, and Foxo3a, a transcription factor involved in cell survival 9.  Now the lab has recently found that 74% of mice that received TERT gene therapy survived after myocardial infarction, which was a great improvement over the control.
	The plan of my postdoctoral project is to identify pathways that are associated with the better outcome of TERT gene therapy with these two mouse cardiovascular models.  With both types of models, one group of mice will be treated with the TERT gene therapy, and another group will be treated with a control vector.  Then a detailed analysis will be performed to identify which pathways are different between the mice.  This detailed analysis can be performed by analyzing the metabolites present in both groups of mice using methods such as NMR, mass spectrometry, and HPLC.  Since the mice exhibit a very different state of health, these differences should be detectable at the molecular level.  Other types of analysis such as RNA expression could also be performed if this is deemed necessary.  I have acquired experience analyzing large datasets, writing computer programs, and using machine learning techniques during my doctoral study, and this experience could be applied to the large amount of data that may potentially result from this project.
	Telomere research, and the role that biotechnology can play in improving people’s health, is a very exciting area right now.  Researchers have already demonstrated that telomere therapy can improve health and lead to longer lifespans.  They have also demonstrated that such therapy can improve the outcome of age associated diseases such as heart disease, which is the number one cause of death.  My postdoctoral project will take advantage of two mouse models exhibiting cardiovascular related pathologies which have benefited from TERT therapy, and my research will identify the specific pathways that are involved.  Once these pathways are identified, they could be targeted to increase cardiovascular health further, ultimately leading to the maintenance of health for a longer period of time.