E2F-2 is a Retinoblastoma (Rb)-regulated transcription factor induced during terminal erythroid maturation. Cyclin E-mediated Rb hyper-phosphorylation induces E2F transcriptional activator functions. E2F-2-loss causes reduced peripheral red blood cell (RBC) counts, without altering relative abundances of erythroblast subpopulations. To determine how E2F-2 regulates RBC production, we comprehensively studied erythropoiesis using knockout...
Gene expression is tightly regulated at the level of transcription through cooperation between cis-regulatory elements and trans-factors that bind to the regulatory elements. Together, these factors regulate the higher order chromatin structure which establishes domains that organize the genome and coordinate gene expression. However, the molecular mechanisms controlling transcription of...
CD1 molecules represent a class of antigen presenting molecules that present lipid antigens to cognate T cells. These molecules have been identified in all mammals examined so far. Unlike MHC molecules, which are highly polymorphic, CD1 molecules exhibit limited polymorphism and are divided in to two groups – 1 and...
The airway epithelium forms an active barrier between the internal and external environments and has multiple roles critical to normal function of the lung. Its development and function are controlled by a network of transcription factors that regulate gene expression in response to varying stimuli. Dysfunction of this tissue plays...
Kainate receptors (KARs) are expressed throughout the central and peripheral nervous systems. One of three subfamilies of ionotropic glutamate receptors, KARs are localized both pre- and post-synaptically and exert important modulatory control over neural circuits. This modulatory role in circuit function makes them a potential actor in wide variety of...
Radiation is a ubiquitous health risk. Contemporary populations are exposed to several hundred milliSieverts per person over their lifetimes from both natural and human made sources such as radon, cosmic rays, CT-scans, etc. Risk estimates based on studies of atomic bomb survivors suggest that these exposures induce excess cancer mortality...
The polypeptide hormone prolactin (PRL) is increasingly recognized as contributing to the development and progression of human breast cancer. This is supported by epidemiologic studies that found women with high levels of serum PRL are at an increased risk for developing breast cancer. Activation of the prolactin receptor (PRLR) by...
FOXA1 is a FKHD family protein that plays pioneering roles in lineage-specific enhancer activation and gene transcription. Through genome-wide location analyses, here we show that FOXA1 expression and occupancy are, in turn, required for the maintenance of these epigenetic signatures, namely DNA hypomethylation and histone 3 lysine 4 methylation. Mechanistically,...
The African trypanosome Trypanosoma brucei is a single-celled eukaryotic protozoan parasite with a single cilium/flagellum. It cycles between its mammalian host (bloodstream cell), in which it scavenges cholesterol, and its tsetse fly host (procyclic cell), in which it both scavenges cholesterol and synthesizes ergosterol. For the first part of the...
SIRT3 is a mitochondrial-localized, NAD+-dependent deacetylase, tumor suppressor protein that functions to direct mitochondrial energy sensing and antioxidant proteins, increasing the efficiency of energy utilization, providing a redox balanced environment, and preventing aging-related diseases. One SIRT3 deacetylation target is NADP+-dependent isocitrate dehydrogenase 2 (IDH2), a key Krebs Cycle enzyme that...
The hormone prolactin (PRL) contributes to breast cancer pathogenesis through various signaling pathways, one of the most notable being the JAK2/signal transducer and activator of transcription 5 (STAT5) pathway. PRL-induced activation of the transcription factor STAT5 results in the upregulation of numerous genes implicated in breast cancer pathogenesis. However, the...
Neisseria gonorrhoeae is the causative agent of the sexually transmitted infection gonorrhea and is adapted to survive in humans, its only host. The N. gonorrhoeae cell wall is critical for maintaining envelope integrity, resisting immune cell killing, and production of cytotoxic peptidoglycan (PG) fragments. Deletion of the N. gonorrhoeae genes...
Metabolic abnormalities of cancers provide opportunities for novel tumor-specific therapies. Isocitrate dehydrogenases (IDHs) catalyze the oxidative decarboxylation of isocitrate to α-ketoglutarate (αKG) and the reduction of NAD(P)+ to NAD(P)H. Oncogenic mutations in two IDH-encoding genes (IDH1 and IDH2) have been identified in acute myelogenous leukemia, low-grade glioma, and secondary glioblastoma...
A number of nonclassical MHC Ib molecules recognizing distinct microbial antigens have been implicated in the immune response to Mycobacterium tuberculosis (Mtb). Due to the low polymorphism of MHC Ib molecules within the human population, these molecules and Mtb antigens are attractive targets for better vaccine development. Among these, HLA-E...
Efferocytosis is the anti-inflammatory removal of dying cells and cellular debris, occurring billions of times per person, per day as a part of homeostatic maintenance during natural cell turnover. Macrophages are major professional phagocytes of the immune system and are responsible for dead cell clearance during infection and injury. During...
Spindle formation in mammalian cells requires precise spatial and temporal regulation of the kinesin-5 motor proteins which generate outward force to establish spindle bipolarity. A growing body of work suggests that phosphorylation of kinesin-5 motor domains is an important regulator of their motor characteristics and function in cells. My thesis...
The development of targeted therapies has revolutionized cancer treatment and markedly increased patient survival time and reduced mortality rates. Yet, some cancers still have few treatment options and remain deadly. In these cases, the development of targeted therapy is critical. Here, we investigated two cancers that lack effective targeted therapies...
Allergic diseases, including asthma, atopic dermatitis, and food allergy, are a widespread health issue. The prevalence of these diseases has been increasing, but the mechanism behind this increase and how allergies develop is not well understood. Although the immune system is central to the pathology of allergy, recent work has...
Tumor progression depends on both tumor-intrinsic processes and interactions with different cell types within tumor microenvironment. Identifying targets that have dual effects on both tumor cells and their interacting surrounding cells, such as tumor-infiltrating immune cells, represent a novel therapeutic approach to treat cancer patients
CD44 is a ubiquitously expressed...
MAPK-interacting kinase (MNK) signaling leads to activation of cap-dependent mRNA translation through phosphorylation of the eukaryotic translation initiation factor 4E (eIF4E). In cancer cells, MNK-eIF4E signaling promotes translation of oncogenic mRNAs. In glioblastoma (GBM), the deadliest malignant brain tumor, MNK-eIF4E signaling is aberrantly activated and represents a promising therapeutic target....
The study of tumor metabolism from the middle of the 20th century through the early 21st almost entirely ignored the mitochondria; instead, the field focused on cancer cells use of glycolysis even when oxygen was not limiting, termed aerobic glycolysis. Due to this observation, it was often speculated that malignant...
The Pseudomonas aeruginosa type III secretion system delivers effector proteins directly into target cells, allowing the bacterium to modulate host cell functions. ExoU is the most cytotoxic of the known effector proteins and has been associated with more severe infections in humans. Previous studies have shown that ExoU is a...
The Bcl-2 family is considered the guardian of the mitochondrial apoptotic pathway. While there are numerous endogenous Bcl-2 antagonists that share similar homology, structure, topology, and expression pattern, only the loss of Bim in mice is sufficient to lead to the development of a systemic autoimmunity. Even loss of both...
Eosinophils are major effector cells in diseases including asthma, rhinitis, certain gastrointestinal disorders and atopic dermatitis. Current treatments include mediator antagonists and anti-inflammatory drugs that reduce allergic cell numbers and inhibit mediator release, but they are not fully effective or curative. On their surface, eosinophils selectively express Siglec-8 (sialic acid-binding...
X-ray Fluorescence Microscopy (XFM) is a useful technique for study of biological samples. XFM was used to map and quantify endogenous biological elements as well as exogenous materials in biological samples, such as the distribution of titanium dioxide (TiO2) nanoparticles. TiO2 nanoparticles are produced for many different purposes, including development...
Spinal cord injury occurs with a worldwide incidence of 13-33 cases per million per year, and more than 2.5 million patients worldwide suffer from spinal cord injury (SCI)-related disability (1, 2). Different methods have been attempted to promote axonal regeneration, including neurotrophin injection, hydrogel injection, olfactory ensheathing cells implantation and...
Mucolipins are lysosomal cation channels, with high permeability to calcium ions, that are thought to regulate endolysosomal trafficking. While mucolipin 1 is expressed in all cells, mucolipin 3 is expressed in a small subset of cells (i.e. neonatal intestinal enterocytes, cochlear hair cells and marginal cells of stria vascularis). This...
Transcription by RNA polymerase II (Pol II) in metazoans is regulated in multiple steps, including preinitiation complex (PIC) formation, initiation, Pol II escape, productive elongation, cotranscriptional RNA processing, and termination. Genome-wide studies have demonstrated that the phenomenon of promoter-bound Pol II pausing is widespread, especially for genes that respond to...
Pseudomonas aeruginosa is a Gram-negative pathogen that frequently causes severe nosocomial infections through expression of virulence factors, evasion of immune clearance and resistance to therapeutic antimicrobial agents. These factors have led the US Centers for Disease Control and Prevention (CDC) and Infectious Disease Society of America (IDSA) to identify P....
Post-transcriptional gene silencing (PTGS) and, more specifically, RNA interference (RNAi) include the processes by which a small double-stranded RNA, 19 to 22 nucleotides (nts) long, negatively regulates the expression and/or translatability of a target RNA, which harbors reverse complementarity to that small RNA, by recruiting the so-called RNA-Induced Silencing Complex...
Polycystic ovary syndrome (PCOS) is a common endocrine disorder affecting approximately 1 in 10 reproductive-age women and remains the leading cause of female factor infertility among women of childbearing age. PCOS presents with features of hyperandrogenism, irregular menses and polycystic ovaries. Twin and family studies have demonstrated high heritability estimates...
There is a shortage of research models that adequately represent the unique mucosal environment of human ectocervical tissue, which has limited the development of new therapies for treating infection or cancer. I hypothesized that engineering the microenvironment of ectocervical tissue with in vivo-like endocrine and paracrine support, would enable squamous...
Immune checkpoint inhibitors have not been effective for immunologically “cold” tumors, such as prostate cancer, which contain scarce tumor infiltrating lymphocytes. We hypothesized that select tissue-specific and immunostimulatory bacteria can potentiate these immunotherapies. Here we show that a patient-derived prostate-specific microbe, CP1, in combination with anti-PD-1 immunotherapy, increased survival and...
Platyrrhines are an enigmatic and intriguing radiation of New World monkeys that currently inhabit the western hemisphere from Argentina to Mexico. Platyrrhini, a taxonomic parvorder within Primates, is their formal taxonomic designation, as they represent the sister group of the Catarrhini or all of the Old World monkeys and apes....
Herpesvirus virions consist of three layers: nucleocapsid, tegument, and envelope. The innermost layer, the nucleocapsid, initially assembles as an immature procapsid precursor built around viral scaffold proteins. The event that initiates procapsid maturation is unknown but it is dependent upon activation of the internal protease. Scaffold cleavage triggers angularization, or...
In 2015, the United States Department of Agriculture (USDA) reported that 1 in 6 Americans fall ill with a foodborne infection annually, resulting in more than 3000 fatalities and an estimated $15 billion in economic burden due to combined medical costs, productivity loss, and death. On a per-case basis, infections...
Ubiquitous in the environment are bacteria that have evolved to adapt to the environmental niches they colonize. To this end, bacteria sensory and signaling molecules are required for processing these extracellular changes within their environment into changes in gene expression. The plague-causing pathogen, Yersinia pestis, contains a repertoire of two-component...
Over the past decade significant advancements have been made across the field of cancer biology resulting in transformative new therapies. Despite these advancements, treatments for metastatic cancer remain relatively ineffective. Metastasis is coordinated by various types of “healthy†stromal cells in addition to the tumor cells themselves. This requires a...
Erythropoietin-producing human hepatocellular (Eph) receptors and their corresponding ephrin ligands are asymmetrically expressed at cell-cell contacts allowing for bidirectional signaling with forward signaling through the receptor expressing cell and reverse signaling through the ligand expressing cell. Eph receptors are the largest family of receptor tyrosine kinases (RTKs) in mammals, which...