The SRF Summer Scholars Program offers undergraduate students the opportunity to conduct biomedical research to combat diseases of aging, such as cancer, Alzheimer’s, and Parkinson’s Disease. Under the guidance of a scientific mentor, each Summer Scholar is responsible for his or her own research project in such areas as genetic engineering and stem cell research. The Summer Scholars Program emphasizes development of both laboratory and communication skills to develop well-rounded future scientists, healthcare professionals, and policy makers. Students participating in the program will hone their writing skills via periodic reports, which are designed to emulate text scientists commonly must produce. At the end of the summer, students will have the opportunity to put all of their newly developed communication skills into practice at a student symposium.
SRF Education undergraduate programs primarily are designed to address two pressing needs in STEM education: the availability of novel, inquiry-based research opportunities and scientific communication skills. Whether a student plans to pursue postgraduate studies or apply for a research position at a pharmaceutical company, practical experience is key. However, research opportunities are limited at some colleges, and specific fields of research, such as tissue engineering, may be completely absent.
SRF Education sets itself apart from many other training programs with its focus on the development of scientific communication skills in addition to enhancing laboratory and critical thinking skills. Over the course of its educational programs, participants are guided through practical writing assignments that simulate documents scientists are often asked to produce, such as grant proposals. The communication training culminates in a formal presentation at a symposium where participants present the results of their work to their peers and mentors.
Review the following to confirm your eligibility to participate in the program:
If you have any questions regarding your eligibility for the program, you may contact SRF Director of Education Gregory Chin at [email protected].
Below is an alphabetical list of the Principal Investigators (PIs) and their 2020 Summer Scholar research projects.
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.
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 Scholar selected will use a computational approach 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 as protein gels, qPCR, and activity assays, with the potential of extending the studies to animal models.
Senescence is a state where cells irreversibly arrest their growth against damage response. Accumulation of senescent cells (SnCs) with age contributes to age-associated phenotypes and diseases by altering the tissue microenvironment through secretion of cytokines, growth factors and metalloproteases, called the senescence-associated secretory phenotype (SASP). Our lab found that mitochondrial dysfunction induces a senescence state termed mitochondrial dysfunction-associated senescence (MiDAS), causing a distinct secretion profile and mitotic arrest. Progeroid mice that rapidly increase mtDNA mutations accumulated senescent cells in skin with a MiDAS SASP in vivo, which stimulated keratinocyte differentiation in cell culture. Recently, I established 3D skin organoid culture system to mimic human skin. The Summer Scholar will work on a project to characterize the differentiation of keratinocytes in 3D skin organoids formed by MiDAS fibroblasts compared to them formed by non-senescent fibroblasts. The scholar will further characterize keratinocyte differentiation and skin aging phenotype in the progeroid mouse model. The final goal of this study is to determine whether SASPs secreted from MiDAS cells play a key role in keratinocyte differentiation and imbalance in skin homeostasis, leading to skin aging.
SENS Research Foundation has spun out a project on atherosclerosis into a startup company called Underdog Pharmaceuticals. Underdog is engineering drugs that can bind and reverse the pathological effects of certain oxidized forms of cholesterol implicated in atherosclerosis and several other diseases of aging. The laboratory techniques involved include isolation of PBMCs and macrophages from human blood; flow cytometry to characterize macrophages in various states of differentiation, polarization, and disease; semi-automated (robotic liquid handler) biochemical binding and toxicity assays; ELISA; and other common molecular biology and biochemistry techniques. The choice of a specific project will depend on the skillset and preferences of the trainee. As an example, one project involves developing a new assay to accurately measure 7-keto cholesterol levels in tissue samples. Interested applicants do not need to know all the techniques required to run these assays but should be familiar with routine lab protocols and should not be uncomfortable working with human or animal blood and tissues.
Cancer is a complex disease caused by uncontrolled cell proliferation and it is the second leading cause of death globally. There is a dire need for rapid and cost effective screening platforms that also provide a physiologically relevant background that include host immunity and a complex tumor microenvironment. We will implement a high-throughput screening strategy using the multicellular organism C. elegans to identify anticancer compounds. Many of the pathways that when deregulated lead to tumor formation are conserved between humans and C. elegans. We found that a constitutively active mutant in the FGFR3 (Fibroblast Growth Factor Receptor 3) ortholog old-2 in C. elegans causes late-onset germ cell tumors and sterility similar to the ovarian tumors and late-onset testicular tumors observed due to a constitutively activating mutation in FGFR3 in humans. Utilizing a strain carrying a fluorescent reporter to track mitotic germ cells/tumors, animal viability and fertility in the old-2 constitutively active mutant we will perform a high-throughput screen to identify compounds that suppress tumor formation and rescue fertility while also controlling for drug toxicity.
The Summer Scholar 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 Summer Scholar will generate models of disease and evaluate therapeutic targets to validate them for treatment of the disease.
As animals age they exhibit correlated recognizable and predictable changes to their physiology. These changes occur nearly synchronously across multiple tissues. Alterations in neuromodulatory signaling that lead to disruption of homeostasis may be one mechanism by which these concerted changes occur during aging. We want to understand how neuromodulators influence behavior and aging. Our lab develops new methods to monitor and manipulate signaling in living animals and to identify the fundamental enzymes that regulate inter-tissue communication. The goal of this project will be to characterize the role of intermediate filaments during aging in a C. elegans model.
Human neurodegenerative diseases are characterized by progressive loss of neurons in the nervous system with aging being the major risk factor for disease onset. Studies have revealed an involvement of a class of non-coding RNAs, known as microRNAs (miRNAs), in aging and neurodegenerative diseases.
MicroRNAs have been shown to influence neuronal survival and accumulation of toxic proteins that are associated with neurodegeneration and brain senescence. Evidence from animal models as well as in vitro studies has indicated that energy metabolism and nutrient-sensing pathways function as critical determinants of neuronal processes that may be required for brain repair or adult neurogenesis. Since, dietary factors can modulate expression levels of miRNAs, it is likely that miRNA pathways that are regulated by dietary interventions can be targeted for development of therapeutic strategies to prevent or delay neurodegenerative diseases. Dietary restriction (DR) is an evolutionarily conserved intervention that has been shown to extend healthy lifespan by eliciting cell protective effects in diverse tissues including brain. In this project, we will utilize a Drosophila neurodegenerative/Alzheimer’s disease model to provide mechanistic insights into the role of DR-modulated miRNAs and their downstream effectors in neurodegenerative disease pathogenesis as well as neuroprotection. We will utilize genetic, molecular and cell biology approaches to assess the efficacy of miRNAs in promoting brain health and preventing disease onset and progression.
Dr. Lithgow’s lab is focused on understanding the role of aging in the origins of age-related chronic disease. Specifically, his lab has led the field in the identification of pharmacological interventions in aging. The Lithgow lab utilizes molecular genetics, biochemistry and a range of leading edge technologies, including proteomics and metabolomics. His team utilizes the microscopic worm, C. elegans, which ages rapidly but exhibits many characteristics of human aging.
This Summer Scholar project will use C. elegans and mammalian cell culture to explore how the mitochondrial unfolded protein response may initiate cell death cascades, such as necrosis, which has widespread implications for understanding aging and age-related diseases such as neurodegeneration and ischemia-reperfusion injury (stroke and heart attack). Prior experience with the nematode is desirable but not required. A strong interest in genetics and mitochondrial biology is also preferable.
Turn Biotechnologies is a new rejuvenation therapeutics company spun out of Stanford University. The focus of the company is to develop epigenetic reprogramming technologies to reset aged cells back to a more youthful state. This represents a dramatic new form of anti-aging intervention, rather than just modulating a specific set of aging pathways these technologies remodel the entire gene expression landscape to a more youthful configuration. This approach has been shown to drive a more holistic reversion of aging phenotypes that is generalizable to a variety of different cells and tissues. Furthermore, these benefits extend to pathological states as well, and as such the company has developed these technologies for multiple age-related disease applications. Opportunities over the summer will provide a taste of these applications. An example project will be designing age reprogramming protocols to improve muscle stem cell therapy platforms. This will involve techniques like biopsy processing, cell sorting, cell transfection and transduction, live animal injection and imaging (may be done offsite), histology and analysis. Projects can evolve and positions can transition into a more full time basis.
Cell-based therapies are emerging as a promising strategy to tackle cancer. We have developed tumor cell surface receptor targeted T cells and adult stem cells expressing novel bi-functional pro-apoptotic and immunomodulatory proteins and oncolytic viruses. Using different primary and metastatic tumor models that mimic clinical settings, we show that engineered stem cells expressing novel bi-functional proteins or loaded with oncolytic viruses target both the primary and the invasive tumor deposits and have profound anti-tumor effects. Recently, we have reverse engineered cancer cells using CRISPR/Cas9 technology and demonstrated self-tumor tropism and therapeutic potential of receptor self-targeted engineered cancer cells. These studies demonstrate the strength of employing engineered cells and real-time imaging of multiple events in preclinical-therapeutic tumor models and form the basis for developing novel cell based therapies for cancer.
Senescent cells are characterized by an irreversible arrest of the cell cycle and secrete a unique milieu of pro-inflammatory cytokines, chemokines, and growth factors collectively referred to as the senescence-associated secretory phenotype (SASP) due to which these cells have been implicated in a large number of age-related diseases, and recent efforts to develop therapeutic interventions are centered around selectively eliminating senescent cells (senolytics). While these approaches present two possible avenues for reducing the impact of senescent cells, they still lack specificity for their intended target.
We are focusing on developing therapeutic interventions to selectively eliminate senescent cells by utilizing innate immune cells like Natural Killer (NK) cells. These innate immune cells have evolved mechanisms to selectively induce apoptosis in target cells based on the expression of ligands on the target cells. In addition, recent publications suggest that (a) senescent cells have evolved mechanisms to escape NK cells or (b) NK cells lose their ability to eliminate senescent cells with aging. We will utilize approaches to isolate and enrich NK cells from human blood and investigate the mechanism by which they can selectively target and kill senescent cells. The main aim of the project is to test these hypotheses using in vitro and ex vivo cell co-culture experiments.
This approach will afford better understanding of mechanisms involved in NK cell interaction with senescent cells, which will be critical in designing targeted therapeutic approaches to age-related diseases caused by the accumulation of senescent cells.
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:
The Genotype-Tissue Expression (GTEx) project funded by NIH common fund has sequenced thousands of human tissue samples from around 1000 people and 56 different types of organs. One of the main aims is to understand the association of genetic variations to phenotypes. However, the massive data generated by GTEx not only can provide information to explain the variations but also can be used to study aging. The GTEx cohort contains all age groups, and the data provides molecular profiles from multi-omics. Most of the previous aging studies were done using animal models or with very limited clinic data. For a few large-scale studies, they are mainly based on genomic information in general. As part of the GTEx project, our lab has sequenced the proteome of multiple organs from many individuals. Compared to genomics, proteomics is closer to phenotype and can provide direct evidence. Integrating proteomics information with other omics can provide a more comprehensive molecular profile for the study of aging at organ level. However, integrating information from multi-omics is a daunting task. It requires knowledge from both domains and also needs sophisticated mathematical models. We believe results from this study will greatly advance the understanding of aging.
– The 2020 SRF Summer Scholars Program application period will open on Tuesday, October 15, 2019. –
The 2020 SRF Summer Scholars Program application period is now closed.
Applications will be accepted until noon PST Wednesday, January 15, 2020 (12pm PST 1/15/20).
Please be sure to download the recommendation instructions and give your
recommender(s) ample time to submit your letter of recommendation by the deadline.
Offering recent graduates the opportunity to conduct biomedical research to combat diseases of aging under the guidance of a scientific mentor, with the goal of preparing participants for a career in regenerative medicine research.