2018 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.
Mitochondria are the power plants of the cell and are also the only cellular organelle that possess their own DNA in mammals. In humans, mitochondrial DNA (mtDNA) codes for 13 important proteins, which all assemble into the oxidative phosphorylation relay. Mutations in mtDNA occur as a consequence of constant exposure to reactive oxygen species produced by the mitochondrial energy generation process as well as mistakes in mtDNA replication. These mutations accumulate over time due to inefficient repair mechanisms and compromise respiratory chain function. Inherited and acquired mutations in mtDNA result in impaired energy generation and are the cause for several pathologies such as Leber’s hereditary optic neuropathy (LHON), Myoclonic Epilepsy with Ragged Red Fibers (MERRF), Kearns-Sayre syndrome and Leigh syndrome.At SENS Research Foundation, we are in the early stages of creating an exciting and innovative system to repair mitochondrial mutations. Using the allotopic approach, we have identified specific targeting elements/ sequences that can improve expression of these essential genes from the nuclear DNA and their transport to the correct location in mitochondria. The summer intern selected will get the opportunity to design and test a library of constructs in model patient cell lines with specific mutations to mtDNA. The ability of re-engineered genes to rescue function will be evaluated through various techniques, such protein gels, qPCR and activity assays, with the potential of extending the studies to animal models.
One of the most challenging problems in healthcare is the attrition rate during drug development and resultant high costs of bringing new therapies to market. To address this, research in the Brindley lab in collaboration with Professor Chas Bountra over the past two years has resulted in the development of a powerful machine learning model for the prediction of regulatory approval of new small molecule therapeutics. To date, this model has utilised only simple data, accessible via public sources, but it has already demonstrated the potential to improve R&D efficiency significantly.
To improve the model and capture a broader set of predictors, the Bountra/Brindley Summer Scholar will look to incorporate additional, potentially proprietary data, such as in vitro and in vivo results, to improve and evaluate the utility of the model. Furthermore, such analysis may also elucidate trends in the in vitro and in vivo models, which could have widespread impact in life science research and therapeutic development.
The Summer Scholar will develop methods to collate and clean data to be added to the existing dataset and subsequently use computational expertise to apply machine learning algorithms to the updated dataset. Familiarity with statistics and/or machine learning will be useful, and it is essential that the Summer Scholar is able to work independently, drive a project forward, and think through complex problems logically.
Note: this is a non-bench research project.
The ability of stem cells to self-renew and repair damaged tissues decreases with age, which may underlie much of the aging-associated degeneration in mammals. My lab uses hematopoietic stem cells (HSCs) as a model to understand the molecular bases of stem cell aging. We found that SIRT3 is highly enriched in HSCs, where it regulates the oxidative stress response. Importantly, SIRT3 expression declines with age, and SIRT3 overexpression rescues the functional defects of aged HSCs (Brown et al. Cell Reports, 2013). In contrast to the traditional view that reactive oxygen species (ROS) levels increase with age through a random and passive process, our findings suggest that it is a regulated process and that the effect of ROS on aging is acute and reversible. Taking advantage of a defined system, our studies provided the first evidence that aging-associated degeneration can be reversed by a sirtuin.
We have also identified a novel branch of mitochondrial unfolded protein response that is mediated by the interaction between SIRT7 and NRF1 and is coupled to energy metabolism and cell proliferation (Mohrin et al. Science, 2015). We found that this regulatory program is essential for HSC maintenance and its deregulation contributes to HSC aging.
The potential project will involve modeling disease and aging in human induced pluripotent stem models. The Ellerby laboratory has established a number of disease models of Huntington’s disease, Parkinson’s disease and aging. We have developed different methods to identify novel therapeutic targets for HD and aging. The intern will generate models of disease and evaluate therapeutic targets to validate these for treatment of the disease.
The Haghighi lab is interested in understanding how synaptic activity influences and is influenced by aging. We use a combination of genetic, molecular, and electrophysiological techniques in combination with proteomic analysis and imaging to elucidate the molecular mechanisms that underlie the link between synaptic activity and different tissues during the life of the organism. We are interested in a wide range of questions from very basic questions about the regulation of signaling to questions directly related to neurodegenerative diseases.
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.
Our clinical and laboratory research is dedicated to finding new treatments for blindness, particularly in patients with incurable retinal diseases, using stem cell-based approaches, gene therapy or electronic retinas. We are also developing new techniques for cataract and retinal surgery.
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 recently have 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 rational drug design project will involve computational, in vitro, and ex vivo experiments and measurements of the activity of various compounds that we are testing. Our goal is to create a product based on SENS damage repair concepts that can be used in human patients in the near future.
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?
We are presently in an omics revolution in which genomes and other omes can be readily characterized, and new omics technologies can be applied to understand fundamental biology and improve human health. Our laboratory has invented many technologies to analyze genomes, transcriptomes and other omes to:
- Study the relationship between genetic variation, gene expression, and protein in multiple human tissues
- Analyze human variation i.e. what makes people different from one another
- Perform deep omics profiling/big data collection on individuals over time to understand what keeps them healthy and what happens when they become ill or undergo other sorts of changes (e.g. diet, etc)
- Solve mystery diseases and disease prognosis.