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...
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...
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....
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...
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...
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...
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...
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...
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...
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,...
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...
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...
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...
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...
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...
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...
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...
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...
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...
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...
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,...
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,...
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)...
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...
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...
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...
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...
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 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...
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...
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....
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...
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...
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...
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...
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...
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...