2017 Research Project Descriptions
Below is an alphabetical list of Principal Investigators (PIs) and a description of the Summer Scholars research project they will be supervising. Please use the list to guide your selection of research projects in your application. Recall you can apply to as many as three projects but ONLY apply to locations to which you are willing (and eligible) to travel. During the final matching process, selected candidates will be offered an SRF Scholar position in a specific lab from among the list provided in the application. Do not forget to mention your specific interest in your choice(s) in your personal statement as well as an explanation of any relevant skills in your scientific statement.
The exceptionally high cost and time of developing new drugs is a critical challenge of modern translational research. The ability to predict the eventual success of early drug candidates with greater accuracy could help to reduce this cost and ensure that drugs that are likely to be successful are prioritised. Computational methods to facilitate this prediction have been attempted; however, this project will develop a novel machine learning based approach using variables that have largely been ignored but that we believe may have considerable predictive value. Currently, a pilot study model has been completed which focusses on small molecule therapies; this student will expand the model to further indications and explore the possibility of increasing the scope of the model to other therapeutics such as biologics and potentially regressive medicines. Furthermore, developing such a predictive approach may allow identification of variables which are important predictors of eventual drug success and which may warrant further in depth investigation.
The student will be expected to, largely independently, develop expertise in machine learning approaches using statistical software such as R. They will develop a keen understanding of the drug development process and potential drivers of its success while developing skills that are applicable in almost any big data scenario. Some experience in statistics is essential, and experience using R or similar software is preferred.
Note: this is a non-bench research project.
The potential project will be to identify additional candidate genes involved in regulating what we termed as a 'proteostasis checkpoint' in the Drosophila intestinal stem cells (ISCs). Young ISCs carrying protein aggregates activate the proteostasis checkpoint and this activation leads to a transient cell cycle arrest and the elimination of aggregates. However, old ISCs are unable to clear protein aggregates due to failure in the activation of the checkpoint. Aggregate clearance can be improved in old ISCs by feeding the flies the drug Oltipraz, a Nrf2 activator. Nrf2 is a transcription factor known as the master regulator of the antioxidant response and it has been shown to also regulate the expression of the proteasomal subunits. Currently, Nrf2 is our top candidate regulating the proteostatic checkpoint. Nevertheless, we suspect that there are more candidates involved in the proteostasis checkpoint and this is the part where an intern could help.
Autophagy has emerged as a central regulator of lifespan given its process for cellular homeostasis through the degradation of long-lived proteins and damaged intracellular organelles. Reduced autophagic activity may promote aging, while evidence suggests that enhanced autophagy promotes longevity and delays age-related phenotypes. The natural polyamine, spermidine, a pharmacological activator of autophagy that increases lifespan via autophagy-dependent mechanism. In this project, the Summer Scholar will exploit the use of spermidine to determine whether enhanced autophagy underlies beneficial cardiac effects in the context of a disease, dilated cardiomyopathy, and normal heart aging.
Treatment with rapamycin, an inhibitor of the mammalian/mechanistic target of rapamycin (mTOR), has also been shown to improve survival in multiple model organisms. Additionally, treating mice with rapamycin improves cardiac function in both cardiac disease models and normally aged mice. Rapamycin rescues cardiac function and extends survival by suppressing elevated mTORC1 signaling and increasing autophagy in the Lmna-/- model of dilated cardiomyopathy. The goal of this project is to determine whether induction of autophagy alone can improve cardiac function in a cardiac disease model and in aging mice. The Summer Scholar will examine the role of autophagy using spermidine as an activator of autophagy in the Lmna-/- model as well as during normal aging using models where rapamycin is efficacious. This Summer Scholar project will contribute to a better understanding of cardiac tissue during aging and disease and will provide mechanistic insights into the efficacy of two anti-aging small molecules with clinical potential.
The Loring lab is focused on harnessing the power of pluripotent stem cells for regenerative medicine. We believe that cells derived from pluripotent stem cells will revolutionize medicine and lead to longer and healthier lives. We are looking for an intern to work on our cell therapy project for Parkinson’s disease in which induced pluripotent stem cells from Parkinson’s patients are used to derive dopaminergic neurons, the same neurons which are lost in the brains of Parkinson’s patients. The aim of this Summer Scholar project is to evaluate whole-genome gene expression profiles from dopaminergic neurons derived from 10 different patient lines helping to build a model by which future cell lines can be evaluated prior to clinical use. The intern will generate the neurons from the patient stem cell lines and analyze the resulting gene expression data.
Mutations in mitochondrial genes occur as we age, and the human body does not have a good system to repair them. At SENS Research Foundation, we are in the early stages of creating an exciting and innovative system to repair mitochondrial mutations. Mitochondria are the power plants of the cell and are also the only cellular organelle that possesses their own DNA, mitochondrial DNA (mtDNA). Mutations in mitochondrial genes occur as a consequence of constant exposure to reactive oxygen species resulting from the mitochondrial energy generation process as well as mistakes in mtDNA replication. Because mitochondria lack an efficient repair mechanism, these mutations accumulate over time and compromise respiratory chain function and hence energy generation.
In this project, engineered mitochondrial genes will be used to restore function to cells that have defective mitochondrial genes. We have identified specific sequences that improve expressed RNA and protein targeting to and import into mitochondria. We then test the ability of our engineered mitochondria genes to rescue mitochondrial mutations in cells derived from patients suffering from mitochondrial genetic diseases. The SRF Scholar will test a library of targeting sequences that we have designed to target a gene, ATP6, to the mitochondria. Our intern will test the ability of these engineered genes to rescue ATP6 mutant cells derived from a patient with a mutation in this gene. These project goals will be achieved through imaging, mitochondrial purifications, various kinds of protein gels and blots, and assays designed to measure the activity of our engineered proteins.
This project seeks to employ a small molecule approach to remove a toxic form of cholesterol from human blood in order to combat the development of atherosclerosis. Oxysterols are non-enzymatic cholesterol oxidation products that have recently become of interest in the pathology of several diseases, including atherosclerosis. The human body has difficulty processing such cholesterols and thus they accumulate in certain types of cells and tissues over time. We are testing the ability of various drugs to remove such toxic cholesterols from human cells. This project will involve in-vitro and ex-vivo (human blood) experiments and measurements of the activity of various compounds that we are testing. Our goal is to create a product that can be used in human patients in the near future.
The damage caused by a heart attack cannot be repaired in humans, leading to a permanent loss of cardiac tissue. Several attempts have been made over the past decade to overcome this difficulty, mainly using stem cells differentiated into cardiomyocytes in the lab and then transplanted into the injured heart. However problems like inefficient delivery, survival and homing of these cells to the site of injury have contributed to a disappointingly modest therapeutic outcome. Therefore, novel strategies targeting cells already present in the adult heart as potential sources for cardiac repair could bypass this hurdle and deliver a more effective treatment.
The epicardium has a unique developmental plasticity and contributes to most of the cell types that form the heart, at the same time epicardial signals nurture muscle and vascular growth. The retention of the epicardium into adulthood, albeit in a state of relative dormancy, establishes this lineage as a potential target for reactivation towards regenerating the injured heart. In the adult zebrafish, which can fully repair cardiac tissue lost by injury, activation of the epicardial layer is observed as an immediate response to damage. For this project, we aim to investigate regulatory sequences that are differentially accessible in the regenerating adult epicardium, based on ATAC-Seq data recently generated in our lab. The Summer Scholar will investigate selected open chromatin regions at different stages of the regenerative process and will perform perturbations experiments in the zebrafish to further elucidate the epicardial contribution to the regenerating heart.
Metastatic brain tumors are the most commonly observed intracranial tumors frequently occurring in patients with metastatic cancers, particularly from cancers of lung, breast, and skin (melanoma). In an effort to effectively treat multiple highly aggressive breast metastatic foci in the brain, there is an urgent need to develop tumor specific multi-targeting agents that simultaneously target aberrant signaling pathways in breast to brain metastatic cells and utilize vehicles which specifically seek metastatic foci in the brain. In an ongoing study, we have created an in vivo imageable mouse model of breast to brain metastasis and shown that human neural stem cells (NSC) and mesenchymal stem cells (MSC) home specifically to metastatic-foci in the brain. In this study we will explore the mechanism based therapeutic efficacy of human MSC expressing immunoconjugates that simultaneously target multiple specifically expressed cell surface receptors and their downstream signaling pathways in a mouse model of breast-to-brain metastasis.
We believe the study of stem cell biology will provide insights into many areas: developmental biology, homeostasis in the normal adult, and recovery from injury. Indeed, past and current research has already produced data in these areas that would have been difficult or impossible via any other vehicle. We have engaged in a multidisciplinary approach, simultaneously exploring the basic biology of stem cells, their role throughout the lifetime of an individual, as well as their therapeutic potential. Taken together, these bodies of knowledge will glean the greatest benefit for scientists and, most importantly, for patients. All of our research to date has been performed in animal models with the ultimate goal of bringing them to clinical trials as soon as possible.
Possible research project options include:
- Model Parkinson’s Disease (PD) using human induced pluripotent stem cells (hiPSCs)
- Search for molecules that confer a resistance to age-related degeneration
- What directs the homing of neural stem cells to areas of pathology?