Graduation Date

Fall 12-16-2016

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Biochemistry & Molecular Biology

First Advisor

Surinder K. Batra

Abstract

Although the etiology of a particular disease will vary, there are genetic and epigenetic bottlenecks that frequently converge resulting in dysregulation of mitogenic and morphogenetic signaling. This propensity is acutely experienced in malignancy and neurodegenerative disease.

Here, we have first investigated the role of dysregulated signaling in the context of pancreatic cancer (PC). Morphogenetic signaling has been regarded as a pleiotropic pathway with the potential to promote and inhibit metastatic features. Our investigation of bone morphogenetic protein 2 (BMP-2), an archetypical member of the BMP superfamily, has revealed the presence of extracellular, intracellular, and long non-coding RNA products. Our findings implicate the individual product activity as significant determining factors in the functional output. Although our observations suggest a novel explanation for these pleiotropic properties, futures studies will be necessary to understand how these variants may behave from an in vivo perspective.

Next, we have examined how this axis is exploited in Alzheimer’s disease (AD). AD is characterized by progressive neurodegeneration. The most frequently implicated feature associated with AD is the pathological accumulation of the amyloid beta (Aβ) peptide. While the extracellular deposition of Aβ is thought to be the pathophysiological form, recent findings have shown that intracellular expression of Aβ precedes the extracellular deposition. This observation suggests the intracellular localization of the Aβ peptide may harbor important and unknown pathophysiological properties. To address the influence of intracellular Aβ on neurotrophin mediated mitogen signaling and BMP-2 mediated morphogen signaling we have employed a cell line model (HEK293 and primary rat hippocampal neurons). Interestingly, our investigation has revealed an intracellular Aβ dependent decrease in mitogen signaling intensity and increase in BMP-2 signaling. Combined, this pattern of dysregulation is closely mirrored during embryonic and postnatal programmed cell death. Further studies will need to be performed to assess how these finding may behave in an in vivo setting.

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