2019 Fellowship Project Descriptions
Below is an alphabetical list of Principal Investigators (PIs) and a description of the Postbaccalaureate Fellowship research project they will be supervising. Please use the list to guide your selection of research projects in your application. ONLY apply to locations to which you are willing to travel. During the final matching process, selected candidates will be offered a Postbaccalaureate Fellowship 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.
Neurofibrillary tangles are a defining hallmark of both Alzheimer's and Parkinson's disease and they or similar aggregates also appear in the neuronal cytoplasm in other neurodegenerative diseases of old age. One possibility for their formation is that these tangles arise from an autophagic "traffic jam" caused by lysosomal inactivation. Lysosomal autophagy is an important mechanism by which cells rid themselves of such proteotoxic aggregates. Restoration of lysosomal function therefore constitutes an attractive candidate target for these disorders. As part of funded research from the SENS Research Foundation, we have established human tau P30L mutant versus wildtype-expressing neurons as an in vitro model of disease to test whether restoration of lysosomal function can prevent or reverse the formation of toxic tau aggregates. We determined using this model that low-dose (0.1 microM) application of a pharmacological accelerator of autophagic flux, K604, decreases levels of phosphorylated tau and protects against neurite retraction associated with the P30L model, even following their formation. We now propose to use this model to test newly identified lysosomal rejuvenating factors recently identified by our laboratory as part of a compound library screen for such compounds. These could potentially serve as novel therapeutics for the treatment of Alzheimer's and Parkinson's disease.
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.
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 Fellow selected will get the opportunity to design a library of constructs to attempt to rescue specific mtDNA mutations in model patient cell lines. 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. Time permitting, the Fellow will validate these constructs for expression from a safe harbor locus using the CRISPR/Cas9 and dual integrase mediated cassette exchange (DICE). Candidates with an interest in mitochondrial biology and with exposure to cell culture, molecular biology and protein biochemistry are encouraged to apply.
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 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 Postbaccalaureate Fellow 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 Fellow will generate the neurons from the patient stem cell lines and analyze the resulting gene expression data.
This research project is geared toward performing translational research studying aging as it relates to the immune system and senescent cells. More specifically, the Summer Scholar will study how the immune system interacts with senescent cells. Research will include testing of candidate signaling protein blockers to try to induce killing of senescent cells. Another aspect of this project will involve identifying and characterizing new types of senescent cells from among the many tissue and cell types in the body. This will involve high-throughput microscopy on our robotic microscope. The research project will be a collaborative effort between SRF and the Buck Institute for Research on Aging, located in Novato, CA.
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?