Alternate Germinants of C. Difficile, a Leading Hospital Pathogen

Clostridium difficile infections (CDI) are the leading nosocomial infections worldwide. Humans are asymptomatic carriers of C. difficile spores in the intestinal tract. The process known as germination occurs when otherwise harmless C. difficile spores are converted to toxin-producing cells upon recognition of bile salts in humans. This distinctive transition ultimately leads to the onset of disease and recurrent CDI. Germination profiles will be characterized in response to peptidoglycan (PG) fragments isolated from various bacterial species. These specific peptidoglycan fragments contain different amino acid residues that may induce different germination responses. Purification and structural determination of the peptidoglycan fragments will be carried out by HPLC-MS. In this study, C. difficile germination will be tested against exhausted media containing cellular debris, as well as with solutions obtained from post-germination assays. This will reveal if germination of C. difficile induces other spores to germinate as well. If it is shown that there are alternant germinants of C. difficile, further characterization and modeling of C. difficile can be made, and further inhibitors can be tested to ensure complete inactivation of spores, ultimately preventing CDI

Novel Approaches to PET Imaging Neurodegeneration

Early detection of neurodegenerative diseases (NDs) has remained challenging for clinicians. To improve diagnostic confidence across the ND spectrum, there is considerable research devoted to the discovery of potential biomarkers of disease onset and progression. NDs share the common feature of progressive loss of structure and function of neurons resulting from different protein aggregates responsible for the various diseases. Alzheimer’s Disease (AD), the most prevalent ND, is characterized by amyloid plaques (composed of amyloid ß (Aß) protein) and neurofibrillary tangles (composed of tau protein) within the hippocampal and cortex regions of the brain. Parkinson’s Disease (PD), the second most common ND, is caused by dopaminergic neuronal loss within the basal ganglia, which controls voluntary movement, as a result from α-synuclein (α-syn) aggregation within the same region. Biologically relevant transition metals such as iron, copper, and zinc are reportedly accumulating and causing the aggregation of known neurotoxic protein aggregates at sites afflicted by neurodegenerative diseases. Detecting such metal ions may provide a means of early detection of these otherwise hard to diagnose diseases using positron emission tomography (PET) imaging agents. Radiopharmaceuticals available today for imaging of the central nervous system (CNS) are limited to those imaging the mid- to late-stages of CNS disease progression. This imaging modality provides information at the molecular level of living organisms that clinicians can use to confirm a diagnosis or assess the effectiveness of a treatment. Small molecules, peptides, and large proteins can be radiolabeled with a wide range of positron emitting isotopes with various half-lives such as carbon-11 (C-11, 11C, t1/2 = 20 min) and fluorine-18 (F-18, 18F, t1/2 = 109.7 min). The overall objective of the work described in this thesis is to design and analyze novel PET tracers ([11C]deferiprone (Chapter 2) and [18F]FL2-b (Chapter 3)) that bind physiological transition metals (Cu, Zn, and Fe) which are hypothesized to accumulate abnormally in the brain early in NDs. Known metal chelators will be radiolabeled and used in preclinical animal studies to determine brain uptake, binding kinetics, metabolism, biodistribution, and be evaluated in both diseased brains and healthy controls. Additional work described includes development of a novel radiotracer, [11C]AZ683, for neuroinflammation imaging (Chapter 4), where it is thought that inflammation is a result of toxic metal accumulation. Lastly, although several PET tracers are approved by the Food and Drug Administration, some of them are challenging to synthesize for routine production. Efforts to improve the synthesis of such a tracer ([18F]FDOPA) using copper-mediated radiofluorination in accordance with current good manufacturing processes (cGMP) are also discussed (Chapter 5).PHDMedicinal ChemistryUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/167984/1/tanzeys_1.pd

Synthesis and Initial In Vivo Evaluation of [¹¹C]AZ683—A Novel PET Radiotracer for Colony Stimulating Factor 1 Receptor (CSF1R)

Positron emission tomography (PET) imaging of Colony Stimulating Factor 1 Receptor (CSF1R) is a new strategy for quantifying both neuroinflammation and inflammation in the periphery since CSF1R is expressed on microglia and macrophages. AZ683 has high affinity for CSF1R (Ki = 8 nM; IC50 = 6 nM) and >250-fold selectivity over 95 other kinases. In this paper, we report the radiosynthesis of [11C]AZ683 and initial evaluation of its use in CSF1R PET. [11C]AZ683 was synthesized by 11C-methylation of the desmethyl precursor with [11C]MeOTf in 3.0% non-corrected activity yield (based upon [11C]MeOTf), >99% radiochemical purity and high molar activity. Preliminary PET imaging with [11C]AZ683 revealed low brain uptake in rodents and nonhuman primates, suggesting that imaging neuroinflammation could be challenging but that the radiopharmaceutical could still be useful for peripheral imaging of inflammation

UNLV Title III AANAPISI & McNair Scholars Institute Research Journal

Journal articles based on research conducted by undergraduate students in the AANAPISI and McNair Scholars Programs Table of Contents About AANAPISI Biography of Dr. Ronald E. McNair Statements Dr. Len Jessup, UNLV President Dr. Juanita P. Fain, Vice President for Student Affairs Dr. William W. Sullivan, Associate Vice President for Retention and Outreach Mr. Keith Rogers, Deputy Executive Director of the Center for Academic Enrichment and Outreach Title III AANAPISI and McNair Scholars Institute Staff Ms. Terri Bernstein, Director for College Programs Dr. Matthew Della Sala, Assistant Director for Undergraduate Researc