Splicing out Cancer: Implicating Novel Splicing Factors in Metastatic Breast Cancer

University of Toronto Libraries Undergraduate Research Prize Winner 2017. The University of Toronto Libraries Undergraduate Research Prize awards undergraduate students in any first-entry faculty across the University of Toronto’s three campuses based on their effective and innovative use of information sources. This prize provides students with an opportunity to reflect on their information-seeking experience, showcase their research to an audience beyond the classroom, and promote scholarship excellence at the undergraduate level at University of Toronto. Please visit the Undergraduate Research Prize website https://onesearch.library.utoronto.ca/undergrad-research-prize/criteria for more information about the award, including submission guidelines.Breast cancer is among the leading causes of mortality among Canadian women; yet a clear therapeutic target remains elusive. This project sought to investigate the role of 2 splicing factors: SFX and SF3X as a potential driver of metastatic breast cancer. Upon revision of the literature and extensive associative bioinformatics study, we noted several potential correlations by which splicing may modulate carcinogenesis. We subsequently demonstrated that multiple oncogenic systems are involved in the regulation of SFX and SF3X, and loss of these factors induces dynamic morphological changes; thus identifying a hitherto undiscerned role of SFX and SF3X in metastatic cancer

Alzheimer's disease as an autoimmune disorder of innate immunity endogenously modulated by tryptophan metabolites

Abstract Introduction Alzheimer's disease (AD) is characterized by neurotoxic immuno‐inflammation concomitant with cytotoxic oligomerization of amyloid beta (Aβ) and tau, culminating in concurrent, interdependent immunopathic and proteopathic pathogeneses. Methods We performed a comprehensive series of in silico, in vitro, and in vivo studies explicitly evaluating the atomistic–molecular mechanisms of cytokine‐mediated and Aβ‐mediated neurotoxicities in AD.  Next, 471 new chemical entities were designed and synthesized to probe the pathways identified by these molecular mechanism studies and to provide prototypic starting points in the development of small‐molecule therapeutics for AD.   Results In response to various stimuli (e.g., infection, trauma, ischemia, air pollution, depression), Aβ is released as an early responder immunopeptide triggering an innate immunity cascade in which Aβ exhibits both immunomodulatory and antimicrobial properties (whether bacteria are present, or not), resulting in a misdirected attack upon “self” neurons, arising from analogous electronegative surface topologies between neurons and bacteria, and rendering them similarly susceptible to membrane‐penetrating attack by antimicrobial peptides (AMPs) such as Aβ. After this self‐attack, the resulting necrotic (but not apoptotic) neuronal breakdown products diffuse to adjacent neurons eliciting further release of Aβ, leading to a chronic self‐perpetuating autoimmune cycle.  AD thus emerges as a brain‐centric autoimmune disorder of innate immunity. Based upon the hypothesis that autoimmune processes are susceptible to endogenous regulatory processes, a subsequent comprehensive screening program of 1137 small molecules normally present in human brain identified tryptophan metabolism as a regulator of brain innate immunity and a source of potential endogenous anti‐AD molecules capable of chemical modification into multi‐site therapeutic modulators targeting AD's complex immunopathic–proteopathic pathogenesis.  Discussion  Conceptualizing AD as an autoimmune disease, identifying endogenous regulators of this autoimmunity, and designing small molecule drug‐like analogues of these endogenous regulators represents a novel therapeutic approach for AD