Cell-based therapies are an exciting frontier in medicine. This field is built on a simple premise—cells can be engineered to recognize and treat various human diseases. The paradigm of cell-based therapy uses biosensors to interrogate a cell’s environment and distinguish disease from health, intracellular signaling pathways and genetic circuitry to...
Bumble bees are ecologically and economically important pollinators but have experienced rapid declines in recent decades. Yet, we know little about the lives of most wild bumble bee species. Where do they live? When are they active? What do they eat? What does all this mean for the future of...
Plasminogen activator inhibitor-1 (PAI-1) is an essential mediator of senescence and a potential therapeutic target for preventing aging-related pathologies. Cellular Senescence is associated with organismal aging and related pathologies. In our study, we investigate the efficacies of PAI-1 inhibitors in both in vitro and in vivo models of homocysteine...
The goal of this project was to better understand the pathogenesis behind rheumatoid arthritis(RA), an autoimmune disorder that primarily affects the joints. Despite affecting around 1.3 million people in the United States, its causes are not well-understood. Previous research at Pope Lab indicated that when compared to the healthy controls,...
With concerns about how to feed an exponentially growing, increasingly obese population, humanity’s relationship with food is a pressing concern. Evaluating the evolutionary changes in the composition of gut microbiota (GM), defined as the microorganisms that live in the digestive tract, may offer insight into how human bodies have adapted...
Physiological linkage (i.e., the covariation of moment-to-moment physiology between individuals) is thought to play an important role in relationship functioning. The present study examined physiological linkage across interbeat interval (IBI) and skin conductance levels (SCL) in a sample of married spouses (N=106) during both a pleasant and a conflict conversation...
The formation of neuronal inclusions is one of the hallmarks of neurodegenerative diseases. These structures are composed of aggregated proteins, molecular chaperones, and components of the ubiquitin-proteasome system (UPS). Co-localization of aggregated proteins with cell-homeostasis maintaining machinery indicates that the cell may be failing in an attempt to clear these...
Prostate cancer (PCa) is the most common non-cutaneous cancer among U.S. men. Lack of effective treatments for advanced disease make it a significant public health concern. However, PCa’s long natural history makes it an excellent target for prevention approaches that reduce overtreatment of indolent disease, treatment related morbidity, and mortality....
Ionizing radiation is known for being dangerous at high doses, beneficial for diagnosis and treatment of diseases, and expensive for hazardous waste disposal and other protection policies governments put in place. Balancing the benefits and risks is key to maximizing public health, reducing public fears, and reducing extraneous costs that...
Glioblastoma (GBM) is the most common aggressive primary malignant brain tumorin adults with a median age of onset of 65 years of age. Although advanced age is often associated with worse GBM patient survival, the predominant source(s) of maladaptive aging
effects remains to be established. Here we studied intra-tumoral and...
Some of the oldest drugs targeting metabolism are the antifolates such as aminopterin and methotrexate (MTX). MTX started being used in the 1950s to treat rheumatoid arthritis. Aminopterin and MTX both target one carbon metabolism and inhibit proliferation of cells. MTX was a potent inhibitor of inflammation, because it prevented...
Proteins represent a critical class of biomolecules, universally employed by all living organisms to fulfill essential structural, functional, and enzymatic roles necessary to support life. In nature, these polymers are composed generally of twenty natural amino acid (AA) building blocks, which can be modified with covalent adducts known as post-translational...
Down syndrome occurs in approximately 1 in 700 births annually in the United States. It is caused by trisomy of chromosome 21, and is characterized by dysmorphic features and congenital abnormalities. Although children with DS have a decreased risk of developing solid tumors, they have an increased risk of acquiring...
Mitochondrial complex I is the primary entry point for electrons into the mitochondrial electron transport chain that is composed of 45 individual protein subunits that are encoded in both the nuclear and mitochondrial genomes. Mitochondrial complex I sits at an important nexus in the essential bioenergetic, biosynthetic, and signaling functions...
The treatment of AML remains to be a challenge due to the high rates of resistance and relapse experienced by patients after initial therapy. The MAPK-interacting kinases 1 and 2 (MNK1/2) have generated increasing interest as therapeutic targets for AML due to their critical role in malignant hematopoietic transformation via...
Kaposi’ sarcoma-associated herpesvirus (KSHV) causes primary effusion lymphoma (PEL). PEL cell lines require expression of the cellular FLICE inhibitory protein (cFLIP) for survival, although KSHV encodes a viral homolog of this protein (vFLIP). Cellular and viral FLIP proteins have several functions, including, most importantly, the inhibition of pro-apoptotic caspase 8...
Tumor-initiating cells with reprogramming plasticity are thought to be essential for cancer development and metastatic regeneration in many cancers; however, the molecular mechanisms are not fully understood. We have previously identified that CD44, a breast tumor-initiating cell marker, drives mammosphere self-renewal and multicellular aggregation of circulating tumor cell (CTC) clusters,...
Phenotypic variation is the functional unit that evolution acts upon and is the main contributor to the diversity of species. The phenotype of an individual is shaped by genetic and environmental factors. These genetic and environmental factors contribute to biomedically relevant traits such as an individual’s susceptibility to disease and...
Biological systems comprise diverse collections of cellular and non-cellular components with intricate relationships and dynamic interactions. To gain system-level understanding, we must be able to accurately model these systems, both experimentally and computationally. Agent-based models (ABMs) in particular are a uniquely intuitive, modular, and flexible framework capable of supporting multi-scale,...
With the ability to rapidly screen and manipulate genomes, the in depth study of the functional actors of biology—metabolites and proteins—is necessary to understand complex biochemistry in developmental and disease states. The analytical processes by which biological information is gained from metabolomics and proteomics experiments must also evolve with our...
The last decade has witnessed a rapid transformation in our understanding of the structure of chromatin, the nuclear complex of DNA and its structural proteins. While, barring mutations, the DNA sequence in each cell of the human body is the same, it is the structure of the chromatin complex that...
Stimulation of the cGAS-STING (cycle GMP-AMP synthase-Stimulator of Interferon Genes) pathway increases T cell activation and tracking into the tumor and reverses the immunosuppressive phenotype of myeloid cells. Direct targeting of the STING receptor using synthetic cyclic dinucleotide (CDN) ligands represents an attractive immunotherapeutic strategy for the treatment of lymphocyte-depleted...
Store-operated Ca2+ entry (SOCE) is a principal mechanism for generating cellular Ca2+ signals. Store-operated Ca2+ release-activated Ca2+ (CRAC) channels serve an essential role in generating Ca2+ elevations needed for transcriptional, enzymatic, and secretory effector cascades in many cell types. CRAC channels, comprised of the ER Ca2+ sensor STIM and the...
Platelets are circulating anucleate discs derived from megakaryocytes, and play major roles in hemostasis, inflammation, thrombosis, and vascular biology. Multi-phase culture systems for inducing in vitro platelet production from mature megakaryocytes have been explored to allow progenitor expansion, megakaryocyte maturation, and promotion of platelet formation and shedding. In this thesis,...
Transcription is tightly regulated to ensure genes are appropriately expressed both temporally and spatially. This tight regulation governs various processes within the cell, such as differentiation and cell identity, cellular maintenance, and dynamic responses to external signals. Transcription factors (TFs) coordinate these various gene programs and in particular, are key...
Cancer is a complex and heterogeneous disease characterized by aberrant gene regulation. Gene regulation is fundamentally orchestrated by the 3D genome organization which involves chromatin looping, compartmentalization, and the formation of topologically associating domains (TADs). Structural variations (SVs), such as genomic rearrangements, deletions, inversions, and duplications, are commonly observed in...
The interaction of amyloid-β (Aβ) with endogenous metal ions is thought to play a role in the pathogenesis of Alzheimer’s disease (AD). However, limited tools exist to study and modulate Aβ-metal binding. The Meade lab has developed cobalt(III) Schiff base (Co(III)-sb) complexes as protein inhibitors that competitively displace metals from...
Nearly all animals exhibit behaviors that can be classified as sleep. The distinctly disadvantageous nature of the asleep state, evolutionarily speaking, accentuates its role as a critical physiological process, yet chronic inadequate sleep is prevalent in today’s society. Among the multitude of health problems that have been linked to chronic...
ABSTRACTFor several decades, dams have played an essential role in human development. In many low-and middle-income countries (LMICs), the construction of dams remains an integral part of industrialization and modernization. However, dam construction and associated infrastructure have significantly contributed to socioecological destruction and population displacement. For example, the construction of...
Microfluidic technologies enable multi-tissue culture and precise control of media exchange and therefore have significant potential to create more complex in vitro models of reproductive systems, including endocrine cycles. However, microfluidic technologies have largely been applied to gamete-level culture in reproductive biology, with very little progress in organ-level culture. Herein...
Pathogenic bacteria scavenge essential nutrients including metals, amino acids and peptides to survive within the hostile host environment. Bacteria utilize ATP-binding cassette (ABC) transporters, powered by the energy of ATP hydrolysis, to move substrates across cellular membranes. The substrate-binding protein (SBP) shuttles substrate in the periplasm and directs the substrate...
The ribosome, the cell’s machine for synthesizing proteins, can be thought of as the chef of the cell. Just as a chef reads a recipe and combines ingredients to create a dish, the ribosome reads cellular instructions and connects building block molecules (amino acids) to construct proteins. Like the final...
Burkitt lymphoma (BL) is a B cell cancer that develops primarily in children and is associated with Epstein-Barr virus (EBV). The EBV latent membrane protein 2A (LMP2A) drives BL in part by providing constitutively active pro-survival signaling. A double transgenic mouse model of BL expressing LMP2A and the oncogene MYC...
Store-operated Ca2+ entry through Orai1 channels mediate transcriptional, proliferative, and effector cell programs in many cells and are activated through a unique inside-out mechanism involving binding of the endoplasmic reticulum Ca2+ sensor, STIM1, to cytoplasmic sites on Orai1. Mutations in Orai1 that block channel activation or evoke constitutive channel activity...
The critical importance of alternative mRNA splicing and the RNA binding proteins that orchestrate this essential layer of post-transcriptional gene regulation is increasingly recognized in gene regulatory programs. We and others have shown that alternative splicing plays a causal role during the Epithelial-Mesenchymal transition, a cell-developmental program that is hijacked...
The NLRP3 inflammasome is a multi-protein complex that drives sterile and pathogen-dependent inflammation. Activation of the NLRP3 inflammasome occurs in two steps: priming and activation. Priming occurs in response to an inflammatory stimulus, such as LPS. LPS-primed macrophages are subsequently activated by a second stimuli, most of which require K+...
Nanocarriers are nanometer-sized (1-1000 nm) structures capable of encapsulating cargo. This encapsulation can drastically alter the pharmacokinetic properties of the cargo, while also allowing for the rational design and engineering of the nanocarrier itself. Poly(ethylene glycol)-block-poly(propylene sulfide) is an amphiphilic diblock copolymer capable of self-assembling into diverse nanocarriers. The purpose...
A central question in biology is how the flow of genetic information—from DNA to RNA to protein—is regulated. Regulatory mechanisms exerted at the level of DNA and protein have been described in detail but by contrast, little is known regarding the regulation of RNA. Methylation on N6-adenosine (m6A) is the...
A variety of human diseases and pregnancy related disorders reflect endometrial dysfunction. However, rodent models do not share fundamental biological processes with the human endometrium, such as cyclic menstruation, and no existing human cell cultures recapitulate the cyclic interactions between endometrial stromal and epithelial compartments necessary for decidualization and implantation....
Proper size control of organs and tissues is critical to their function, and it is necessary for the millions of precisely sized tubes that make up those organs— for example, excessive cell growth can lead to devastating diseases such as Polycystic Kidney Disease. The regulation of tube growth is therefore...
Individuals within a species vary in complex phenotypes, such as responses to toxins. This drug-response variation causes patients who are treated with the same medicine to experience a range of side effects, ultimately decreasing the efficacy of some drugs. Particular genetic variants among individuals might contribute to differential drug responses,...
A central theme in biological anthropology is investigating how the human body responds to interactions with the surrounding environment. The microbiome—the collection of microorganisms (and their genes) that live in and on the human body— represents one such pathway that mediates the environment’s influence on human biology, physiology, and health....
Uterine leiomyoma (LM), the most common tumor of women, causes severe morbidity. LM cells can be separated into three molecularly and functionally distinct cell populations based on the expression pattern of CD34 and CD49b: stem (LSC, CD34+/CD49b+), intermediate (LIC, CD34+/CD49b-), and differentiated cells (LDC, CD34-/CD49b-). Progesterone via progesterone receptor (PR/PGR)...
Nuclear receptors (NRs) are an important family of transcription factors that often regulate genes in response to ligands and by way of direct interactions with coactivator proteins. Many NR-coactivator pairs have been identified that cooperate to regulate transcription but fully understanding how NRs recruit specific coactivators involves learning which of...
In the United States, allergic disease affects approximately 60 million people and impacts more people every year. While prevalence of allergic disease has steadily increased, there has concurrently been an increase in rates of metabolic syndrome—characterized by increased abdominal girth, decreased sensitivity to insulin, and higher levels of circulating blood...
Meiosis is a highly regulated process necessary for proper chromosome division. Zincfluxes regulate mammalian meiosis; between prophase I and metaphase II, total intracellular zinc
increases by 50%, while 20% of zinc is released in “zinc sparks” following fertilization. Although
zinc fluxes had been shown to be conserved in mammals, it...
Transcription plays a pivotal role in the transfer of genetic information within living organisms. It serves as the initial step in gene expression, allowing cells to convert the instructions encoded in their DNA into functional molecules. Eukaryotic transcription initiation is a complex and dynamic process that requires joint efforts from...
Natural Killer (NK) cell dysfunction is associated with poorer clinical outcome in cancer patients. What regulates NK cell dysfunction in tumor microenvironment is not well understood. NKG2D/NKG2DL pathway is very well recognized as an effective immune axis in tumor immunosurveillance. Abundant evidence from experimental preclinical animal models as well as...
The epidemic of obesity and associated metabolic diseases have led to increased scrutiny of adipose tissue and its primary cell type, the adipocyte. However, studies show that regional adipose tissue distribution rather than obesity per se is a major determinant of metabolic disease risk. Despite having an obese body mass...
Inter-organelle contacts facilitate communication between organelles and impact fundamental cellular functions. Investigations into the molecular mechanisms of inter-organelle tethering are still in the early stages, and we are just beginning to appreciate the number and variety of inter-organelle tethers that exist. We have used budding yeast as a model polarized...
Pediatric high-grade gliomas (pHGGs) are aggressive pediatric CNS tumors and an important subset are characterized by mutations in H3F3A, the gene that encodes Histone H3.3 (H3.3). Substitution of Glycine at position 34 of H3.3 with either Arginine or Valine (H3.3G34R/V), was recently described and characterized in a large cohort...
A prominent cause of premature ovarian insufficiency (POI) is gonadotoxic cancer therapies, which deplete the ovarian reserve of follicles, oocytes, and hormone-producing cells. Current fertility preservation methods include the removal and cryopreservation of ovarian tissue prior to gonadotoxic treatment. This cryopreserved tissue can be transplanted back and has been found...
When a cell divides, it must assemble a microtubule-based structure called a spindle, which provides the forces that physically segregate the chromosomes. In most cell types the microtubules that comprise the spindle are nucleated and organized by centriole-containing centrosomes. In many species, however, oocyte meiosis is carried out in the...
Skeletal muscle is a highly sexually dimorphic tissue, with males and females exhibiting differences in muscle size, gene transcription, and metabolism. This thesis describes two models wherein males and females responded to an intervention with the same physiological adaptation but through two distinct mechanisms. In the first model, mice of...
The protein homeostasis (proteostasis) network, a critical cytoprotective system that restores homeostasis in response to molecular stress, comprises distinct pathways, including the heat-shock response, unfolded protein response, oxidative stress response, and autophagy. These distinct pathways are all co-opted by tumor cells to cope with cancer-associated stress, and their activation in...
This dissertation focuses on quantifying protein folding stability determinants and presenting initial experiments that can guide the development of a novel assay that identifies cell-penetrating miniproteins. First, despite over a century of scholarship on protein folding stability, applying this knowledge to design proteins computationally remains limited. Usually, protein designers generate...
The eukaryotic genome is packaged into chromatin. The nucleosome, the basic unit of chromatin, is composed of DNA coiled around a histone octamer. Histones are among the longest-lived protein species in mammalian cells, due to their thermodynamic stability and their associations with DNA and histone chaperones. Histone metabolism plays an...
Uterine leiomyomas (fibroids) are a major source of gynaecologic morbidity in reproductive age women and are characterised by the excessive deposition of a disorganised extracellular matrix, resulting in rigid benign tumours. Clinically, leiomyoma patients usually present with pelvic pain, urinary incontinence, as well as heavy cyclic and non-cyclic bleeding. Curative...
To combat the rise of antibiotic-resistant pathogens in clinical settings, it is necessary to understand which environments and conditions select for antibiotic resistance. Analysis of environments hypothesized to select for antibiotic resistance has been revolutionized by metagenomic sequencing. The metagenomic pool of DNA sequences can be probed in silico using...
Over the past fifty years, techniques for synthesizing and manipulating matter on the 1-100 nanometer scale have led to the development of nanoparticle-based approaches to both disease diagnosis and treatment. The modification of nanoparticles with biological macromolecules such as proteins and nucleic acids has led to the development of highly...
Current biomaterials-based methods for in vitro ovarian follicle culture enable individual follicles or follicle classes to survive and carry out basic functions of the ovary, including hormone and release of mature oocytes upon gonadotropin stimulation. However, these current strategies do not support the survival and maturation of isolated primordial and...
Inflammasomes are intracellular multiprotein signaling complexes that link Pathogen Associated and Danger Associated Molecular Patterns (PAMPs and DAMPs) by Pattern Recognition Receptors (PRRs) to the activation of Caspase-1, leading to the secretion of pro-inflammatory cytokines interleukin (IL)-1β and IL-18, and the induction of pyroptosis. Nucleotide-binding oligomerization domain (NOD)-like containing a...
Macrophages are innate immune cells that are traditionally thought to be specialists in phagocytosis. More recent evidence suggest that macrophages reside in nearly every organ and readily adapt to local microenvironmental signals, leading to highly plastic phenotypes across and within tissues. Therefore, rather than treating it as a homogenous cell...
One of the fundamental questions in developmental biology is how a single cell gives rise to a complex organism. More specifically, how a totipotent egg divides into cells that become increasingly restricted in their potential. Development is a process of increasingly restricted cellular potential, and here I home in on...
Ovulation is the process by which an ovulatory follicle releases a mature egg and is essential for fertility and maintaining female reproductive cycle. Understanding the mechanisms of ovulation have implications for the development of non-hormonal contraceptives and treatments of anovulatory diseases. We developed a 3D alginate encapsulated in vitro follicle...
Proper spatiotemporal expression of genes is essential during development. One method of regulation of signaling-responsive genes is at the level of transcription. In this work, I present the adaptation of single molecule fluorescent in situ hybridization for use in Drosophila imaginal disc tissues in order to more precisely quantify transcript...
The literature has established glucokinase (GCK) to be the principal hexokinase (HK) in the liver, operating as a glucose sensor to regulate glucose metabolism and lipid homeostasis. We have recently proposed Hexokinase Domain Containing-1 (HKDC1) to be a novel 5th HK with expression in the liver. Here, we reveal HKDC1...
Biological tubes are essential for animal survival, and their functions are highly dependent on tube shape. Analyzing the contributions of cell shape and organization to the morphogenesis of small tubes has been hampered by the limitations of existing programs in quantifying cell geometry on highly curved tubular surfaces and calculating...
This dissertation focuses on quantifying protein folding stability determinants and presenting initial experiments that can guide the development of a novel assay that identifies cell-penetrating miniproteins. First, despite over a century of scholarship on protein folding stability, applying this knowledge to design proteins computationally remains limited. Usually, protein designers generate...
Processing of sensory information in the brain is a pervasive and fundamental phenomenon across animal species and is involved in both "hard-wired" innate responses as well as learned and adaptive behaviors. Here, I show that the avoidance of hot temperature, a simple innate behavior, contains unexpected plasticity and complex processing...
Many human diseases are chronic and ultimately fatal because they damage organs and tissues beyond the body’s normal repair mechanisms. Therefore, there is significant medical interest in developing pharmaceuticals that enhance the body’s natural injury repair mechanisms and engineering organs in the lab for transplantation. However, comparatively little is known...
Evolutionary theory predicts that reproduction entails energetic costs that detract from somatic maintenance, accelerating biological aging. In women, such ‘costs of reproduction’ (CoR) are thought to arise predominantly during pregnancy and lactation, while in men the physiological effects of the steroid hormone testosterone (T) are believed to be a major...
Meiosis is a specialized form of cell division that occurs to generate sperm and eggs with unique sets of paternal or maternal DNA; this process shuffles genetic information to promote the amazing variation that we observe in living organisms. In order to carry out two rounds of DNA separation with...
Eukaryotic genomes are organized into chromatin, which acts to regulate access to the organism’s genetic material. A large and diverse class of proteins, known as chromatin modifiers and remodelers, are responsible for regulating the composition and structure of chromatin by monitoring nucleosomes. Chromatin remodelers are involved in multiple cellular processes,...
Gold nanoparticles (AuNPs) display unique characteristics compared to their macro-counterparts that are dependent on shape, size, and attached surface molecules. Methods have been developed to precisely control both size and shape of AuNPs for specific applications. The biocompatibility, plasmonic properties, and ease of functionalization with thiolated molecules, make gold nanoparticles...
The product of hexokinase (HK) enzymes, glucose-6-phosphate, can be metabolized through glycolysis or directed to alternative pathways, such as the pentose phosphate pathway (PPP) to generate anabolic intermediates. HK1 contains an N-terminal domain that permits mitochondrial binding, but its physiologic significance remains unclear. We generated mice lacking the HK1 mitochondrial-binding...
Inter-organelle contact sites have become increasingly appreciated as important regulators of cellular homeostasis, and disruption of inter-organelle contact site dynamics and function has been observed in various pathologies. Recently, inter-organelle contact sites between mitochondria and lysosomes were discovered, offering a new mechanism by which these two organelles may directly interact,...
Regulatory T (Treg) cells are required to control immune responses and maintain homeostasis, but are a significant barrier to antitumor immunity. Conversely, Treg instability, characterized by loss of the master transcription factor Foxp3 and acquisition of proinflammatory properties, can promote autoimmunity and/or facilitate more effective tumor immunity. A comprehensive understanding...
Uterine leiomyomas (fibroids) are a major source of gynaecologic morbidity in reproductive age women and are characterised by the excessive deposition of a disorganised extracellular matrix, resulting in rigid benign tumours. Clinically, leiomyoma patients usually present with pelvic pain, urinary incontinence, as well as heavy cyclic and non-cyclic bleeding. Curative...
The engineering of human reproduction is one of the defining scientific advances of the past century. Methods to specifically engineer the testis have an equally long and rich history, and have experienced significant progress over the past two decades, leading to current-day breakthroughs which are shifting the paradigms by which...
Androgen receptor pathway inhibitors are the mainstay treatment for advanced prostate cancer, but resistance is common. Here, we used a CRISPR activation screen to identify genes that promote enzalutamide resistance in the metastatic castration-sensitive prostate cancer cell line LNCaP. We found that activation of the TGF-β target gene, PRRX2, promoted...
Cells are complex, autonomous machines that integrate many environmental cues to execute a desired response. Though this property makes cells versatile, it presents significant design challenges when, to treat diseases, we must alter cellular responses. To understand changes to the complex regulatory pathways that cause diseases, studies often investigate the...
Mitochondria-derived reactive oxygen species (mROS) are required for the survival, proliferation, and metastasis of cancer cells. The mechanism by which mitochondrial metabolism regulates mROS levels to support cancer cells is not fully understood. To address this, we conducted a metabolism-focused CRISPR/Cas9 genetic screen and uncovered that loss of genes encoding...
Pattern formation of biological structures involves the arrangement of different types of cells in an ordered spatial configuration. Patterning is thought to involve the spatial organization of molecular pre-patterns that precede and drive subsequent cell differentiation and coinciding morphogenesis. These molecular prepatterns are often, although not exclusively, organized through Turing...
Involuntary motor activities such as spasms arise from hyperreflexia in about 70% of individuals with spinal cord injuries (SCI). Despite this prevalence and the negative impact on health and safety, it is unclear what determines the severity of the spasms that develop. This study investigated the impact of injury severity...
Neurodegenerative diseases (NDs) commonly involve the accumulation and aggregation of neurotoxic proteins that impair and ultimately destroy specific neurons. Considerable evidence from human and animal studies indicates that many NDs show disrupted circadian and sleep as symptoms. Yet little is known about the molecular mechanisms by which genes cause NDs...
Spinal cord injury (SCI) is a devastating injury, which can be caused by motor vehicle accidents, violence, and non-traumatic causes. These injuries can leave patients with lifelong paralysis, as well as incontinence and life threatening autonomic dysreflexia. There is currently no FDA approved treatment for SCI. Spinal injury disrupts the...
Prostate cancer (PCa) is the second most common cancer in American men and has led to approximately 29K deaths in 2018. The androgen signaling pathway plays a pivotal role in the pathogenesis of PCa, and androgen deprivation therapy (ADT) has been the main therapeutic approach for PCa. However, almost all...
The worldwide community of patients affected by Basal Cell Carcinoma of the skin (BCC) is larger than that of any other cancer. While BCC is rarely lethal, currently available treatment strategies often leave patients with disfiguring scars on their faces, heads, and necks. Moreover, the high recurrence rates of BCC...
One of the fundamental observations in oncology is that the rate of cancer malignancy increases with age, which applies to most human malignancies including breast cancer. Therefore, it is crucial to elucidate the mechanistic connection between aging and carcinogenesis. The NAD+-dependent sirtuin family, specifically SIRT3, the primary mitochondrial deacetylase, which...
The BCR-ABL negative Myeloproliferative Neoplasms (MPNs) are clonal hematopoietic stem-cell disorders characterized by abnormal proliferation of differentiated myeloid lineages. MPNs include 3 clinically distinct disorders: Polycythemia Vera (PV), Essential Thrombocythemia (ET) and Primary Myelofibrosis (PMF). 95% of MPNs are characterized by driver mutations in Janus Kinase 2 (JAK2), Thrombopoietin receptor...
This thesis proposes a robust multi-pronged approach to study the effect of nanoparticles on cells. In the first place, this work is focused on investigation of the protein corona that accumulates on the surface of nanoparticles internalized by the cells and their poly-pathway effects on protein availability and messenger RNA...
The planarian flatworm Schmidtea mediterranea is capable of recovery from nearly any injury, including regenerating an entire brain after decapitation, made possible by a pool of pluripotent stem cells which maintain all of the worm’s tissues into adulthood. However, the signals that control the production of new neurons in these...
The negative early and late health consequences from exposure to artificial sources of radiation are particularly apparent in victims of radiological emergencies who were diagnosed with cancer, radiation pneumonitis, among other conditions. The renaissance of nuclear energy, increased use of ionizing radiation in the medical field, and nuclear threats from...
The reprogramming of somatic cells to a spontaneously contracting cardiomyocyte-like state using defined transcription factors has proven successful in mouse fibroblasts. However, this process has been less successful in human cells, thus limiting the potential clinical applicability of this technology in regenerative medicine. We hypothesized that this issue is due...