2020 SRF Summer Scholar Profile: Dennis Gong

My name is Dennis Gong. I am a Biomedical Engineering and Applied Math & Statistics major at Johns Hopkins University. At Johns Hopkins, I work in Dr. Jordan Green’s immunoengineering and drug delivery lab, working on improving the potency of artificial antigen presenting cells (aAPCs) to improve immune stimulation with graduate student Savannah Est Witte. This summer, I am working in Dr. Michael Snyder’s multi-omics focused lab with Dr. Lihua Jiang to study the proteomic signatures of aging. In general, the Snyder Lab works to develop and use a variety of approaches to analyze genomes (DNA), transcriptomes (RNA), proteomes (protein), and regulatory networks, applying these approaches to understand human variation and health. My particular project involved understanding upregulated and downregulated protein pathways in aging to develop organ-specific maps of aging regulatory networks.

Aging is a dominant risk factor for many diseases, including cancer, cardiovascular disease, and neurodegeneration, and is associated with a variety of molecular changes including telomere attrition, DNA damage, mitochondrial dysfunction, and immune impairment. While exploratory studies in model animals have demonstrated the possibility of health and life extension with various intervention strategies, a targeted investigation of the molecular signature of aging may provide new insights. High-throughput -omics datasets have provided a more comprehensive map of molecular changes and have shown that aging is distinct at molecular, cellular and tissue levels. My project provides a proteome level characterization of age-related molecular changes in order to identify age-associated proteins and relevant biological pathways.

The Genotype-Tissue Expression (GTEx) project has sequenced human tissue samples from 1000+ people and 56 organ types, with 12,000+ measured proteins. The GTEx cohort contains all age groups, and includes transcriptome, genome, and proteomic data. Using linear regression methods, associations between protein expression and age can be developed. The result of this correlation analysis will be a list of aging-associated proteins that can be cross-referenced with similar analyses of genomic and transcriptomic data to elucidate aging-related pathways and develop aging biomarkers. These biomarkers are essential for developing a quantitative clinical understanding of disease, which can be used to measure the efficacy of therapeutics in clinical trials and give clinicians a quantitative understanding of the ‘molecular age’ of their patients to inform risk of developing disease. Additional uses might include identifying appropriate trial groups to segment the patient population as well as developing therapeutic targets.

2020 SRF Summer Scholar Profile: Gabrielle Klemme

My name is Gabby Klemme, and I am a senior majoring in biochemistry at Iowa State University. At Iowa State, I work in a biochemistry laboratory with Dr. Eric Underbakke, studying scaffolded signaling complexes. Specifically, my project focuses on creating a fluorescence dye that can be used to identify a Halo tag when coupled to it. A Halo tag is a protein that forms a complex when bound to a molecule, and the complex is then used to bind to another protein that is of interest. Through my Halo protein expression system, I re-engineered a gene construct to allow for ample purification, so that I may have a pure source of Halo tag for testing. This summer, I am working at the Sanford Consortium for Regenerative Medicine in Dr. Evan Snyder’s laboratory. With Dr. Snyder and my mentor, Rus Nuryyev, we are focused on studying the biology of stem cells and their roles in the tissues involved in maintaining the body’s stable internal state, developmental biology, and recovery from injury and disease. However, our current research focus has shifted to studying the relationship between stem cells and SARS-CoV-2 with my project looking at neural stem cells and their connection to the SARS-CoV-2 route of entry.

As more COVID-19 cases arise involving patients with neurological symptoms, such as headaches and disturbed consciousness, understanding the relationship between this virus and the central nervous system (CNS) has become vital. The virus responsible for COVID-19, named SARS-CoV-2, enters cells through the binding of the spike (S) protein on the virus to the angiotensin converting enzyme 2 (ACE2) receptor on the host cell. SARS-CoV-2 could cause severe neurological injury, further justifying the need for a better understanding of the virus and the different cell types and body systems it can affect. Thus, my project will look at the relationship between SARS-CoV-2 and cortical interneurons and will establish how the virus enters these neurons to cause infection. Cortical interneurons are a type of neuron found in the brain and are involved in regulating other types of neurons called excitatory neurons. Cortical interneurons regulate or inhibit the number of signals that are sent throughout the brain and nervous system. However, when they malfunction, they are not able to control the excitatory neurons causing overstimulation which is linked to neurological diseases, such as schizophrenia and epilepsy.

Since we are seeing neurological symptoms with COVID-19 infections, I proposed that neurons in the human body express the ACE2 receptor which binds to the S protein on SARS-CoV-2, allowing the virus to enter and infect the cells. To identify how SARS-CoV-2 enters neurons, I grew a cortical interneuron brain organoid, or a simplified brain grown in the laboratory, and later infected it with the virus. Finally, through the use of a confocal microscope, I visualized the neurons, virus, and ACE2 receptor to determine the appropriate SARS-CoV-2 route of entry into neurons. The most significant impact of this project is that the results will allow us to gain a better understanding of SARS-CoV-2 and how it can cause the neurological symptoms that are becoming more common. Furthermore, determining the route of entry SARS-CoV-2 takes into neurons can help develop therapeutics that target and prevent the virus from entering.

2020 SRF Summer Scholar Profile: Allison Bischoff

My name is Allison Bischoff, and I am a rising senior studying Molecular Genetics at The Ohio State University. At Ohio State, I conduct research as part of Dr. Tamar Gur’s research group, aimed at elucidating the mechanisms by which maternal stress during pregnancy impacts neurodevelopmental and behavioral outcomes in children. My research project aims to determine how stress alters maternal immune response and the gut barrier function, potentially having functional consequences for offspring development. With a growing interest in the gut microbiome within the field of neuroscience, we are seeking to identify microbe-dependent mechanisms by which stress alters immune function and neurodevelopment.

As an SRF Summer Scholar, I have been virtually working under the direction of Dr. Julie Andersen and Dr. Chaska Walton to better understand the capacity for neurons and glial cells, non-neuronal cell types residing in the nervous system, to undergo cellular senescence. Senescence is an irreversible state of cell cycle arrest, induced by a variety of cellular stressors that often result in DNA damage. A universal biomarker for detecting senescence has yet to be identified due to the varied nature of the senescent phenotype, being both dependent upon the cell type and form of stress exposure. Additionally, identification of biomarkers that are strictly specific to cellular senescence has been a challenge, with many markers overlapping with biological processes that can exist independently of senescence. Increasing research has documented higher incidence of biomarkers associated with cellular senescence in different central nervous system (CNS) cell types of patients with neurodegenerative diseases, such as Alzheimer’s. This has led researchers to speculate that senescence could play a role in pathogenesis of these diseases—making senescence in the CNS a potential therapeutic target. In particular, the Andersen lab is investigating whether accumulation of amyloid-beta—a peptide that forms aggregates in Alzheimer’s diseases—can induce senescence in cell culture of neurons and glial cells. With emerging interest in the potential role of cellular senescence in age-related neurodegenerative diseases, unique challenges have been presented for studying senescence in cell types inhabiting the CNS.

Establishing distinct biomarker profiles for cellular senescence in different cell types of the CNS as well as identifying triggers that induce senescence in these cells will be crucial to future investigations of senescence in neurons and glia. The Andersen lab has employed a microscopy technique called spectral scanning confocal microscopy with linear unmixing as a method to identify senescence. This technique allows them to simultaneously detect multiple markers of senescence within an individual cell to more accurately identify populations of senescent cells. Already using this technique to investigate the possibility of senescent-like phenotypes in neurons, I helped organize a protocol to induce and detect senescence in astrocytes—a type of glial cell residing in the CNS. This project will help to establish relevant biomarkers for detecting senescence in astrocytes and identify types of cellular stress that could induce senescence in these cells. Establishment of reliable methods for detecting senescence in the CNS will allow for robust, dependable identification of senescence in age-related neurodegenerative diseases—crucial to identifying a potential role of senescence in mediating neurodegenerative pathologies.

2019 SRF Postbaccalaureate Fellow Profile: Emily Parlan

My name is Emily Parlan. I’m a recent graduate of the University of Puget Sound, where I received a degree in Molecular and Cellular Biology and a minor in Business. Through my placement with the SENS Research Foundation Postbaccalaureate Fellowship Program, I have been working in the lab of Dr. Lisa Ellerby at the Buck Institute for Research on Aging, which focuses on understanding the molecular mechanisms underlying Huntington’s disease and other neurodegenerative disorders. Prior to my work in the Ellerby lab, I participated in the University of Washington Neurological Surgery Summer Student Program, where I investigated the effects of chronic intermittent hypoxia on adult neurogenesis in Dr. Nino Ramirez’s lab at Seattle Children’s Research Institute. I also completed a senior thesis project with Dr. Bryan Thines at the University of Puget Sound, characterizing a novel protein family involved in cellular stress responses of the model plant Arabidopsis thaliana.

My project in the Ellerby lab focuses on understanding the effects of apolipoprotein E on longevity pathways. Apolipoprotein E (ApoE) is a protein that helps transport cholesterol and other lipids throughout the body to provide energy to cells. Three versions, or isoforms, of the ApoE protein exist based on an individual’s genetic background – ApoE2, ApoE3, and ApoE4 – and each of these versions has unique roles in health and disease. Specifically, ApoE4 is a major risk factor for Alzheimer’s disease, while ApoE2 is associated with enhanced lifespan and reduced risk of neurodegeneration.

My project aims to understand the differences between these isoforms, particularly how they contribute to aging and neurodegeneration. To do this, I am using a systems biology approach to characterize stem cell lines with ApoE2, ApoE3 and ApoE4 backgrounds. This systems biology approach involves the high-throughput analysis of all genes, proteins, and lipids found within a cell, thus providing a broad overview of cellular status. By applying this systems biology approach to different cell types with different genetic backgrounds, I will be able to identify specific factors that are altered between ApoE isoforms, gaining insight to specific molecular pathways that might be responsible for the observed effects on aging and disease. In doing so, I hope to better understand the role of ApoE in disease and to potentially identify novel therapeutic targets for the treatment of Alzheimer’s and aging.

2019 SRF Postbaccalaureate Fellow Profile: Carolyn Barnes

Hi! My name is Carolyn Barnes. I graduated from the University of Tennessee, Knoxville (UTK) in 2018 with a B.S. in chemistry. As an undergraduate at UTK, I worked in the chemical biology lab of Dr. Michael Best, focusing on identifying peripheral membrane binding proteins that associate with lipids in the cell membrane. After graduating, I worked as a SRF Summer Scholar on a project focused on therapeutic development to treat atherosclerosis with Dr. Matthew ‘Oki’ O’Connor at the SRF Research Center in Mountain View, CA. Following that, I spent a year in Prague, Czech Republic on a Fulbright grant in the chemical biology lab of Dr. Dmytro Yushchenko at the Institute of Organic Chemistry and Biochemistry. I worked on a project synthesizing molecules to help better understand the roles of signaling lipids.

In 2019, I returned to SRF to be a SRF Postbaccalaureate Fellow in Dr. Evan Snyder’s lab at the Sanford Consortium for Regenerative Medicine in La Jolla, California. The Snyder lab studies stem cells and their roles in developmental biology, homeostasis, and injury recovery. My work in the Snyder lab focuses on using stem cells to model and better understand neurodegenerative disorders (ND), such as Alzheimer’s disease and Parkinson’s disease. These disorders currently affect millions of people worldwide, and the World Health Organization has declared neurological disorders as one of the greatest public health risks. Aging is a key factor tied to neurodegeneration, and as the global population continues to age, the number of people suffering from NDs is expected to rise.

Using skin cells taken from patients suffering from various NDs, scientists are able to “reprogram” these cells to revert them back to a stem cell-like state called an induced pluripotent stem cell (iPSC). I am able to direct the iPSCs to become neurons that contain the same genetic code that leads to the ND that the patient has. I study how these neurons communicate by analyzing their chemical and electrical signaling patterns. It is known that the neuronal signaling networks from patients with NDs are aberrant and can lead to cell death. The aberrant signaling profiles are currently being characterized for different NDs, such as Alzheimer’s disease and Parkinson’s disease. Once signaling phenotypes are established for different NDs, we will be able use this data to improve diagnoses, open avenues for possible early intervention, and screen novel therapeutics. During my time in the Snyder lab, I have been collecting the data from diseased neurons for characterization to improve our model and learn more about the phenotypes that are indicative of different neurodegenerative diseases.

2019 SRF Postbaccalaureate Fellow Profile: Elena Fulton

My name is Elena Fulton, and I am a recent graduate from the University of Puget Sound, where I earned a B.S in Molecular Biology. Throughout college, I participated in directed research with Bryan Thines and worked to characterize the role of a core protein degradation pathway (specifically focused on F-box proteins) in plant stress response pathways. I also participated in a summer internship in the Bilousova lab at the Gates Center for Regenerative Medicine in Denver, Colorado where I worked on a project geared towards designing full-thickness skin grafts using induced pluripotent stem cells. As a Postbaccalaureate Fellow, I have had the opportunity to work at the SRF Research Center with Dr. Amit Sharma. The Sharma lab focuses on engineering natural killer (NK) cells to selectively eliminate senescent cells from various tissues.  Currently, we are characterizing age-related changes in NK cell biology in order to design better methods for rejuvenation which would restore NK cell function in older adults. 

Inflammation is an underlying factor that worsens countless diseases. As we age, our bodies undergo a process now called “inflammaging” which results from the chronic circulation of inflammatory molecules that alter the functionality of the immune system. It is unclear exactly where all of the inflammatory signals come from inside the body; however, recent studies have shown that a particular cell type (termed senescent cells) is likely a large contributor to the inflammation which remodels the immune system with age. Senescence occurs when a cell undergoes significant stress or damage which prompts a permanent arrest of cell division. This is largely considered to be a protective mechanism against cancer; however, senescent cells also release many factors into their local environment which cause inflammation. The accumulation of senescent cells with age can contribute to a decrease in immune function and lead to/exacerbate many diseases. Over the past few years, there has been growing interest in designing methods to clear senescent cells throughout the body, so my project is specifically focused on exploring the use of natural killer (NK) cells to achieve this goal. NK cells are known to find and kill senescent cells in the body, but past research has also shown that NK cell function declines with age. I will first characterize specific biological changes in NK cells with age to learn what specific interventions are needed to restore/enhance function, and then I will test different methods of rejuvenation or genetic engineering to see if they can ameliorate the loss of function over time. Donors of various ages will provide blood samples from which I can isolate NK cells, analyze different aspects of function and phenotype across donors, and ultimately test whether our rejuvenation methods result in restored killing capacity against senescent cells. Comparing NK cells across different age groups not only will allow me to assess whether the function of NK cells from older donors has returned to a level comparable to those from young donors but also will set the groundwork for understanding how the local environment impacts NK cell function. Ultimately, I can analyze circulating factors in the blood to identify possible agents/factors that may hinder or support NK cell function over time.

2019 SRF Postbaccalaureate Fellow Profile: Wynnie Nguyen

Wynnie earned her double degree in Neurobiology and Psychology from the University of Wisconsin, Madison. During her undergraduate years, Wynnie worked in Dr. Edwin Chapman’s lab during her undergraduate study, with a focus on the involvement of Synaptotagmin, a family of membrane-trafficking proteins, in neuronal exocytosis. Now, as a part of the SENS Research Foundation post baccalaureate fellowship, she joined Dr. Julie Andersen’s lab at the Buck Institute for Research on Aging under the mentoring of Dr. Josue Ballesteros. The Andersen lab focuses on understanding the underlying age-related processes driving neurodegenerative diseases in order to identify novel therapeutics that slow or prevent them from occurring.  

Alzheimer’s Disease (AD) and Parkinson’s Disease (PD) are the two most clinically encountered neurodegenerative diseases in older populations without known causes or effective prevention and treatment. Although both are age-related, the cause of AD and PD are quite distinguishable from each other. Disruptions in language, memory and reality-to-virtual-reality perception of AD are caused by loss of cells in the basal forebrain, which plays important roles in information processing. In PD, on the other hand, loss of cells in substantia nigra, which is important for movement and reward leads to disturbances in motor function and sometimes mood. Surprisingly, loss of brain cells in both disorders is preceded by the deposit of dysfunctional proteins, although the culprits are different. Is it a coincidence that two age-related diseases share similar developmental mechanism? As organisms age, dynamic metabolic processes inside the body start to fail or become dysregulated, including maintenance of proper protein folding and function. Age-related losses in protein homeostasis result in the increased accumulation of damaged, misfolded, or aggregated proteins which can eventually lead to cell death. Healthy cells can target these non-functional proteins for degradation to their basic components which can then be recycled. Reductions of such waste-cleaning system have been associated with pathological phenotypes associated with both AD and PD, suggesting that enhancing degradation of harmful proteins may constitute a viable therapeutic target for treatment of age-related neurodegenerative diseases. 

Previous works have shown that Urolithin A (UA), a metabolite derived from Ellagic Acid, which is present at high levels in many fruits and nuts, can boost cellular waste-cleaning activities. Unfortunately, the production of UA declines with age due to development of microbial imbalances within the gut. Recent preliminary data from our laboratory has suggested that administration of UA in the diet can have protective effects on brain neurons. We hypothesize that increasing UA production will provide neuroprotective effects against age-related neurodegenerative diseases by preventing and reversing the over-accumulation of proteins within neurons. Using mouse models mimicking phenotypes associated with human AD and PD, we will evaluate the neuroprotective effects of UA and examine if these effects are via its ability to increase removal protein aggregates and maintain healthy cell populations.

2019 SRF Postbaccalaureate Fellow Profile: Sanjana Saravanan

My name is Sanjana Saravanan, and I received my bachelor’s degree in bioengineering from Oregon State University. During my undergrad career, I spent three years studying protein structure and dynamics in Dr. Elisar Barbar’s lab in the biochemistry/biophysics department at Oregon State University. My project involved characterizing the interactions between two cargo transport proteins that are critical for normal biological function. I am currently working with Dr. Amutha Boominathan at SENS Research Foundation. Our lab is focused on introducing engineered copies of mitochondrial protein-encoding genes into the nuclear genome in order to rescue mutations in the mitochondrial DNA. The team has been successful in expressing all thirteen proteins encoded by mitochondrial DNA and is working on optimizing several parameters necessary for successful protein targeting, transport and integration.

Thirteen of the genes in mitochondrial DNA code for proteins in the oxidative phosphorylation (OxPhos) relay, a process that is crucial for metabolism and cellular respiration. Mutations in these genes accumulate with age and can lead to a wide variety of diseases. Recently, a form of gene therapy that directly addresses mitochondrial DNA mutations has emerged as a therapeutic for mitochondrial diseases. This involves inserting the mitochondrial gene coding for the OxPhos protein into the nuclear genome so that it is translated in the cytoplasm. The idea is that introducing a version of the gene without the mutation and synthesizing the proteins using the nuclear translation system will rescue lost function and reverse the symptoms of disease. My project is specifically looking at a mutation in a subunit of the first OxPhos protein complex. This mutation causes a disease called Leber’s Hereditary Optic Neuropathy (LHON) which is characterized by major loss of vision.

Several labs have already shown that this form of gene therapy works in the context of the LHON mutation and is able to reverse vision loss temporarily. The most notable drawbacks to the gene therapy in clinical trial for LHON are that vision loss returns after several months and their method of allotopic expression does not permanently integrate the corrected gene in the patient’s genome. We have been using a version of the gene that is different than the one being using in a clinical trial that will potentially improve the ability of the cell to generate and integrate the protein into the OXPHOS complex. Our lab has also been working on a way to make sure the correct version of the gene is integrated into the nuclear DNA to be copied and translated from the nucleus for a long-term solution.

2019 SRF Postbaccalaureate Fellow Profile: Angelina Malagodi

My name is Angelina Malagodi. I’m a chemistry graduate from Macalester College. My previous research with Dr. Tye Martin was focused on understanding the molecular mechanisms of the active ingredient in turmeric, curcumin, on Alzheimer’s disease.  Dr. Martin and I worked under Dr. Eva Chi at the University of New Mexico Biomedical Engineering department. My SRF Postbaccalaureate position is at Aspen Neuroscience with Dr. Jeanne Loring, under the direct supervision of Dr. Roy Williams. I am working with Dr. William’s bioinformatics team to understand the genetics of dopamine neurons from Parkinson’s patients.

Parkinson’s disease is a neurodegenerative disease that affects elderly populations. The hallmark of Parkinson’s pathology is the loss of dopaminergic neurons, which are specialized to make the neurotransmitter dopamine. The loss of dopamine results in slowed movement, muscle rigidity, tremor, and postural instability. Aspen Neuroscience is devoted to making a patient-derived solution to Parkinson’s disease (PD). Our team has developed a way to make dopamine neurons from a PD patient’s own cells. There are several reasons as to why this is groundbreaking. First, there is no approved cure for PD. The current treatment options are dependent on forms of drugs design to compensate for the low dopamine levels in the body. Although these drugs are effective for a short period of time, long-term usage will cause side effects that lower the patient’s quality of life. Side effects include nausea, low blood pressure, cognitive difficulties, and notably dyskinesia. 

Another treatment, more analogous to Aspen Neuroscience’s therapy, is the usage of fetal brain tissues that contain growing dopamine neurons. These developing neurons are surgically transplanted into the Parkinson patient’s brain. The idea is that the neurons will grow and produce dopamine, which will cure the disease. However, there are drawbacks to this method, which is why Aspen Neuroscience was born. The first drawback is that the patient must take immune system suppressing drugs to prevent the body from rejecting the fetal cells. Since the cells are being sourced from another genetic source, the body has the potential to reject the transplant. Second, the transplant contains a heterogenous mixture of cells. An impure sample can cause medical issues, including transplant-induced dyskinesia.

To advance PD treatment options, Aspen Neuroscience decided to use skin cells from PD patients and transform them into neurons. The process takes skin cells and reverts them back to cells similar to unspecialized fetal cells, known as pluripotent cells. The cells are then fed chemicals to guide them toward becoming dopamine neurons. Sequencing data, including whole genome, bulk-RNA, and single-cell sequencing can help ensure the quality and maturity of the cells. For example, if the cells acquire any oncogenic mutations or mutations in familial PD from the differentiation process, this can be determined by comparing the whole genome sequence of the person’s genome to the day 18 neurons which were produced from the person’s genome but have gone through a reprogramming step. There are several benefits offered by Aspen Neuroscience’s proposed workflow. First, by using the person’s own cells, the patient does not have to undergo any immune suppression. Also, the quality control checkpoints, ensure that the heterogeneity of the transplant samples is kept to a minimum, thereby minimizing the chances of having any induced dyskinesia side effects.  My goal is to help Aspen Neuroscience put their solution to PD on the market by analyzing the sequencing data. I help determine a signature pattern for successful transplantations and make sure that none of the patients have any dangerous mutations. Structural variants, such as CNV’s, insertions, or deletions, are mutations which can be dangerous to cells because they change to protein product. When a section of the DNA is duplicated, deleted, or altered in any way, the transcription and later translation process reads these mutated sections and creates ineffective proteins. This can cause a variety of diseases including cancer. By detecting DNA mutations through whole genome and bulk RNA sequencing, we can lessen the chance of any side effects when the cells are transplanted into a living organism.

2019 SRF Postbaccalaureate Fellow Profile: Nana Anti

My name is Nana Abena Anti, a recent graduate from Michigan State University, where I studied Biochemistry and Molecular Biology. This past year, I have been working at the SENS Research Foundation as a post-baccalaureate scholar. Prior to my fellowship, I worked at Dr. Robert Abramovitch’s lab at MSU.  During my time there, I studied the mechanism by which Mycobacterium tuberculosis, the causative organism for Tuberculosis, infects humans by testing a few compounds with the potential to kill the pathogen. From this experience, I acquired basic knowledge and skills in research, which have been very helpful in my current fellowship.

My current research team at SRF specializes in studying and developing treatments for mitochondrial diseases. These diseases occur when mitochondria, structures in our cells that produce most of the energy for our body, do not function properly.  Mitochondria have their own DNA molecules that constitute a “code language” that tells the mitochondria how to do its job. Most mitochondrial diseases are usually as a result of low numbers of mitochondria in our cells, low levels of DNA in the mitochondria, or errors in the ‘code language’.

For my project, I am developing methods to send in more mitochondria and mitochondrial DNA into cells.  This will help increase their levels in cells and also overcome the effect of dysfunctional mitochondria in the cells. I will achieve this by extracting mitochondria from healthy cells in other parts of the body and coating them with different molecules that will allow them to enter the cell.

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