published_or_final_version / abstract / Microbiology / Doctoral / Doctor of Philosophy

ABSTRACT WAYLON MOORE'S THEOLOGY AND METHODOLOGY OF DISCIPLE-MAKING IN LIGHT OF NEW TESTAMENT DISCIPLESHIP PRINCIPLES Calvin Johnson Carr, Ph.D. The Southern Baptist Theological Seminary, 2014 Chair: Dr. Timothy K. Beougher This dissertation evaluates Waylon Moore's discipleship strategy to determine whether it conforms to the principles that are taught in the New Testament scriptures. Chapter 1 presents the case to study Moore on the subject and how the research was carried out. Chapter 2 gives a brief biography of Moore's background, with a view to his development as a disciple-maker. Chapter 3 examines Moore's core theological beliefs that can be seen from his scriptural interpretation and other key theological influences. Chapter 4 lays out Moore's methods, which are the result of his theological beliefs and become his "how to's" in disciplemaking. Chapter 5 examines the New Testament teachings on disciple-making. Chapter 6 takes what was learned in chapter 5 and critiques Moore's approach, showing his strengths and weaknesses. Chapter 7 gives the conclusions of this study and provides suggestions for future study.

Today, current drug discovery and lead generation efforts focus on high throughput screening of large chemical libraries as the primary source of lead candidates. A lack of investment in novel chemotype development by pharmaceutical companies over the last 15 years coupled with the concurrent merger of screening collections and the availability of generic compound libraries commercially have resulted in many discovery efforts that lack uniqueness and do not offer a strong patent position to operate. The need for better, more diverse, and more drug-like libraries is essential in order to feed high throughput screening efforts with molecules that probe new dimensions of chemical space and allow for the discovery of untapped intellectual property.This dissertation details a complete structure based study to design novel inhibitors of B-Raf and p38a MAP Kinase. A structural evaluation of the important and similar interactions necessary for DFG-out allosteric inhibitors to bind their respective targets was accomplished through the synthesis and evaluation of three known allosteric kinase inhibitors, Gleevec®, Nexavar®, and BIRB-796, and 8 additional DFG-out allosteric inhibitors that were developed directly from fragments of these successful scaffolds. The structural insight that was gained from the evaluation of known DFG-out allosteric inhibitors was then utilized to design novel inhibitors that incorporated two unique scaffolds based on two new [3+2] cycloaddition reactions.A pyrrolo-3,4-dicarboximide scaffold has been developed through the utilization of a novel tandem [3+2] cycloaddition then elimination reaction scheme. This scaffold, which contains three sites for variation, was then rationally incorporated into lead molecules using structure-based methods and in silico feedback for the production of dual DFG-out allosteric kinase inhibitors of p38a and B-Raf kinase. These inhibitors display micromolar to submicromolar enzymatic IC50's for both p38a and B-Raf kinase and low micromolar inhibition of cell growth in 4 separate cancer cell lines.We also explored new chemistry that utilizes a key one pot, [3+2] cycloaddition reaction to obtain highly substituted imidazoles and their application in the design of specific allosteric B-Raf inhibitors. Inhibitors based on this scaffold display subnanomolar potency and a favorable kinase profile.

This work explores bacterial motility from the mechanisms of propulsion of an individual cell to the complex behavior of collective motility. The shear modulus of bacterial flagella was measured by stretching isolated flagella with an optical trap and by measuring force extension curves of the stretched flagella shedding light onto the me-chanics involved in the motility of single micro-organisms. Experiments in concentrated suspensions of bacteria show collective behavior with large scale mixing on a time and length scale greater than can be understood from the standard model of "run and tumble" motility of a single organism are reported. To further understand the transition from individual to collective motility a novel form of motility where an individual bacterium can reverse direction without changing cell orientation is reported here. These experiments further the understanding of bacterial motility.

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The NF kappa B family of heterodimeric transcription factors is activated by many stimuli, and lead to the upregulation of countless genes. Not surprisingly, NF kappa B plays a critical role in many aspects of cellular function. In T and B lymphocytes, antigen receptor stimulation leads to the activation of NF kappa B through a signal transduction cascade involving the Bcl10-MALT1 complex. We hypothesized that this complex may be critical to signalling cascades other than those emanating from antigen receptors. B cell activation factor of the TNF family (BAFF) activates non-canonical NF kappa B heterodimers that promote B cell survival. Here, we show that MALT1 is required for BAFF-induced phosphorylation of NF kappa B2 (p100), p100 degradation and RelB nuclear translocation in B220+ B cells. TRAF3, a known negative regulator of BAFF-R mediated signaling, interacts with MALT1 in a manner which is negatively regulated by BAFF, and TRAF3 levels are enhanced in MALT1-/- B cells. MALT1-/- CD21highCD23low (MZ) B cells show a defect in BAFF-induced survival and MALT1-/- x BAFF-transgenic (Tg) mice have decreased MZ and B1 B cell levels compared to BAFF-Tg mice. In agreement with this in vitro data, phenotypes associated with over-expression of BAFF including increased serum immunoglobulin titres, spontaneous germinal center (GC) formation, and immune complex deposition in the kidney were found to be dependent on B cell-intrinsic MALT1 expression. Our results demonstrate a novel role for MALT1 in biological outcomes induced by BAFF-mediated signal transduction. The mechanism by which the Bcl10-MALT1 complex regulates antigen induced NF kappa B activation in T cells remains controversial. To shed light on this regulatory network, we conducted biochemical purification of Bcl10, and identified Uev1a, a known regulator of antigen receptor mediated NF kappa B activation. We hypothesized that mms2, and structurally similar molecule to Uev1a, may also impinge on NF kappa B activation. Mms2 overexpression in 293T cells inhibited the Bcl10-induced activation of an NF kappa B sensitive luciferase. Lymphocyte development and antigen receptor induced activation occurs normally mms2-/- mice. However, class switched serum immunoglobulins, and survival responses to DNA damage inducing gamma-irradiation, are decreased in mms2-/- mice. Therefore, mms2 is dispensible in vivo for lymphocyte function and development, but is required for DNA damage responses.