Biochemistry, Biophysics, and Structural Biology Commons^™

Dynamics Of Nucleosome Assembly Characterized By Atomic Force Microscopy, Tommy Stormberg

Theses & Dissertations

Nucleosomes are the basic repeating unit defining the assembly and function of chromatin. Understanding the fundamental mechanisms of nucleosome structure and dynamics is critical to elucidating the chromatin assembly process. This dissertation describes my work in elucidating the role of different factors that drive the nucleosome dynamics.

In my first study, we characterized, for the first time, the effect of sequence on nucleosome assembly. We then characterized the role of internucleosomal interactions, discovering a critical role internucleosomal interactions in the assembly of higher order structures.

Based on the previous study and literature regarding histone tails, we hypothesized the histone H4 …

The Role Of Parkin In Mitochondrial Dna, Eliezer Lichter

Theses & Dissertations

Mitochondria are at the center of biological phenomena such as aging and diseases, especially neurodegenerative diseases. While the discovery of mitochondria only came approximately 200 years after the cell was discovered, a lot of progress has been made since. The mitochondrial genome encodes proteins vital for mitochondrial function. These proteins are only a subset of the proteins present in mitochondria; the rest are nuclear encoded. The nucleus also encodes cytosolic proteins vital for mitochondrial maintenance. One of these is Parkin, an E3 ubiquitin ligase that ubiquitinates mitochondrial proteins as mitochondria become depolarized. Its activity has been shown to be involved …

Metoprolol Disrupts Sterol Biosynthesis Through Inhibition Of 7-Dehydrocholesterol Reductase (Dhcr7), Luke B. Allen

Theses & Dissertations

Cholesterol is essential for life. It is particularly important in the brain as it relies on de novo synthesis of cholesterol following the formation of the blood brain barrier (BBB). As such, disrupting sterol biosynthesis during neurodevelopment can have devastating outcomes. The most common post-lanosterol sterol biosynthesis disorder, Smith-Lemli-Opitz Syndrome, arises from a faulty DHCR7 enzyme. DHCR7 has also been shown to be inhibited by several psychotropic medications. Here we assess six beta-blockers and their effects on sterol biosynthesis in vitro. Two beta-blockers, metoprolol and nebivolol strongly inhibit DHCR7 in four separate in vitro models of both mouse and …

Novel Mechanisms Of Protein Kinase C Α Regulation And Function, Xinyue Li

Theses & Dissertations

Protein kinase Cα (PKCα) is a member of the PKC family of serine/threonine kinases, which have been implicated in regulation of many cellular processes, including cell proliferation, differentiation, survival, and transformation. A large body of evidence from the Black laboratory and others support an anti-proliferative function of PKCα in normal epithelial tissues, including the intestinal mucosa and endometrial epithelium. PKCα is also tumor suppressive in epithelial cancers, such as colorectal cancer (CRC) and endometrial cancer (EC). However, a major obstacle to harnessing the tumor suppressive functions of PKCα to benefit patients is the widespread loss of PKCα expression in tumors. …

Dysregulation Of Mir-10a Promotes Cancer Features In Cholangiocarcinoma, Matthieu Spriet

Theses & Dissertations

Cholangiocarcinoma is a primary liver cancer of the bile duct epithelium that exhibits microRNA-mediated control of tumor cell signaling. Strides toward new treatment rest on a better defining of cholangiocarcinoma tumor biology including the RNA-based layer of regulation. Additionally, there is a gap in knowledge on microRNA expression in human tissue. While there is RNA-seq data of microRNA expression in tissue, it does not differentiate between cell types, thus leaving unanswered questions about cell specific microRNA biology and expression.

Here, we identify miR-10a as an oncogenic microRNA acting through MAPK signaling. Using cholangiocarcinoma cell lines, we determined miR-10a is an …

Mechanisms Of Sorting And Fission At The Endosomes, Kanika Dhawan

Theses & Dissertations

Endocytic trafficking is a fundamental cellular process that regulates the transport of lipids and proteins. Our lab focuses on the intracellular trafficking of receptors involved in cellular processes such as cell division, migration, and proliferation. Accordingly, the regulation of these trafficking pathways is tightly controlled, involving a complex series of events, of which a key step is the endosomal fission. Perturbations in the endosomal network can eventually lead to impaired receptor recycling to the plasma membrane (PM) and, therefore, have pathological consequences like Alzheimer’s disease and multiple cancers. Upon internalization, cargo-laden vesicles released from the PM fuse with the sorting …

Innate Immunity In The Pathobiology And Treatment Of Infectious And Neurodegenerative Diseases, Mai Mostafa

Theses & Dissertations

Mononuclear phagocytes (MPs; monocytes, macrophages, and dendritic cells) are the governors of innate immunity which is the body’s first line of defense against microbial pathogens. They act beneficial or detrimental. They are crucial for an effective non-specific immune response to invading pathogens by engulfing, destroying, then eliciting an adaptive specific immune response. Given their pivotal functions in the host immune defense, studying MP immune responses in disease is paramount important for understanding disease pathobiology and uncovering therapeutic strategies.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the driver of acute respiratory distress syndrome (ARDS) in coronavirus disease 2019 (COVID-19) amongst …

Paf1/Pd2 Augments Pancreatic Cancer Progression And Mediates Radiation And Chemoresistance, Sanchita Rauth

Theses & Dissertations

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Extracellular Mechanotransduction In Marfan Syndrome: An Equivalence Principle, Stephen Haller

Theses & Dissertations

Biological tissues continuously experience mechanical stress and have evolved sophisticated mechanisms to sense mechanical stimuli. While traditional viewpoints regard cells as the ultimate sensors and processors of mechanical information, compounding evidence demonstrates that extracellular matrix, the structural component of tissues, also exhibits evolved molecular responses to force. This led us to propose a new paradigm termed extracellular mechanotransduction, in which matrix orchestrates a complementary form of force integration distinct from traditional cellular and extracellular viewpoints. We thus propose that force-sensitive signaling mechanisms evolved within the extracellular space to help cells maintain mechanical homeostasis in tissues. In this dissertation, we apply …

Novel Molecular Mechanisms Of C-Terminal Eps15 Homology Domain (Ehd) Proteins In Endocytic Trafficking And Primary Ciliogenesis, Tyler M. Jones

Theses & Dissertations

Endocytic membrane trafficking is a key cellular process that is critical for regulating the transport of internalized cargoes such as lipids and receptors. Our lab focuses on understanding the mechanisms and cellular functions of the proteins that regulate this pathway. One family of proteins that has seen significant interest over recent years is the C-terminal Eps15 Homology Domain (EHD) family of proteins. Mammalians have four EHD paralogs (EHD1-4) that are expressed ubiquitously in tissues. These proteins have distinct yet overlapping functions in regulating endocytic pathways. EHD1 has been shown to induce constriction and is recruited to induce fission of tubular …