Electronic Theses and Dissertations

Identifier

971

Date

2013

Date of Award

11-25-2013

Document Type

Dissertation (Access Restricted)

Degree Name

Doctor of Philosophy

Major

Biology

Committee Chair

Ramin Homayouni

Committee Member

Andrew Liu

Committee Member

Judith Cole

Committee Member

David Freeman

Abstract

NIPSNAP1 (4-nitrophenyl phosphatase domain and non-neuronal SNAP25-like protein homolog1) is an evolutionarily conserved protein found in a wide range of species including human. The molecular, cellular and physiological function(s) of this protein is not known. Previously, we found NIPSNAP1 as an APP (amyloid precursor protein) interacting protein. Mutations in APP are associated with early onset Alzheimer’s Disease (AD). The long-term goal of our lab is to determine the molecular and cellular functions of NIPSNAP1 and investigate its potential role in pathogenesis of AD. The goal of my studies was to investigate the physiological function of NIPSNAP1 using two approaches. First, I utilized an integrated systems genetics and bioinformatics approach to identify Nipsnap1 co-regulated gene networks and performed functional analysis to gain insights into the molecular role of NIPSNAP1 in the brain. These results suggest that Nipsnap1 transcript is co-regulated with a number of mitochondrial proteins and appears to play a role in glycolysis and oxidative respiration. In the second approach, we performed high-throughput metabolomic profiling of brain and liver tissues from mice in which the Nipsnap1 gene was disrupted by a retroviral targeting strategy. Though the NIPSNAP1 deficient brains did not exhibit any obvious morphological defects, the brain metabolomic profile showed a striking difference in adenosine 5´diphosphoribose accumulation in the absence of NIPSNAP1. In contrast to brain, absence of NIPSNAP1 in the liver resulted in significant oxidative stress. Moreover, amino acid and lipid metabolism was altered in both NIPSNAP1 deficient brain and liver. Taken together, my studies suggest that NIPSNAP1 is involved in mitochondrial metabolism and that NIPSNAP1 deficiency disrupts amino acid, lipid and nucleotide homeostasis in both liver and brain and produces oxidative stress in liver.

Comments

Data is provided by the student.

Library Comment

Dissertation or thesis originally submitted to the local University of Memphis Electronic Theses & dissertation (ETD) Repository.

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