Massey Documents by Type

Permanent URI for this communityhttps://mro.massey.ac.nz/handle/10179/294

Browse

Subject: search.filters.subject.Blood-brain barrier

Search Results

Now showing 1 - 2 of 2
  • Thumbnail Image
    Item
    Serum biomarkers of neuroinflammation and blood-brain barrier leakage in amyotrophic lateral sclerosis
    (BioMed Central Ltd, 2022-12) Cao MC; Cawston EE; Chen G; Brooks C; Douwes J; McLean D; Graham ES; Dragunow M; Scotter EL
    Amyotrophic lateral sclerosis (ALS) is an incurable and rapidly progressive neurological disorder. Biomarkers are critical to understanding disease causation, monitoring disease progression and assessing the efficacy of treatments. However, robust peripheral biomarkers are yet to be identified. Neuroinflammation and breakdown of the blood-brain barrier (BBB) are common to familial and sporadic ALS and may produce a unique biomarker signature in peripheral blood. Using cytometric bead array (n = 15 participants per group (ALS or control)) and proteome profiling (n = 6 participants per group (ALS or control)), we assessed a total of 106 serum cytokines, growth factors, and BBB breakdown markers in the serum of control and ALS participants. Further, primary human brain pericytes, which maintain the BBB, were used as a biosensor of inflammation following pre-treatment with ALS serum. Principal components analysis of all proteome profile data showed no clustering of control or ALS sera, and no individual serum proteins met the threshold for statistical difference between ALS and controls (adjusted P values). However, the 20 most changed proteins between control and ALS sera showed a medium effect size (Cohen's d = 0.67) and cluster analysis of their levels together identified three sample subsets; control-only, mixed control-ALS, and ALS-only. These 20 proteins were predominantly pro-angiogenic and growth factors, including fractalkine, BDNF, EGF, PDGF, Dkk-1, MIF and angiopoietin-2. S100β, a protein highly concentrated in glial cells and therefore a marker of BBB leakage when found in blood, was unchanged in ALS serum, suggesting that serum protein profiles were reflective of peripheral rather than CNS biofluids. Finally, primary human brain pericytes remained proliferative and their secretome was unchanged by chronic exposure to ALS serum. Our exploratory study suggests that individual serum cytokine levels may not be robust biomarkers in small studies of ALS, but that larger studies using multiplexed analysis of pro-angiogenic and growth factors may identify a peripheral signature of ALS pathogenesis.
  • Thumbnail Image
    Item
    Testing of parameters for a biologically accurate brain membrane and molecular dynamics simulations exploration of membrane interactions and conformational changes exhibited by p110α and its oncogenic mutants : a dissertation submitted in fulfilment of the requirements for the degree of Masters of Science in Biochemistry, Massey University, March 2014
    (Massey University, 2014) Irvine, William A
    Phosphatidylinositide 3-kinases are a family of enzymes which are involved in the regulation of cell growth and proliferation via signalling pathways. This, in turn, means they are linked with cancer development through mutations borne by the genes which encode them. One of these oncogenes, PIK3CA, encodes the catalytic subunit of p110a. This study will focus on p110a’s interaction with a phospholipid bilayer, using computational techniques, in an effort to better understand this protein and the effect the cancer-related mutations have on its activity. In order to model the phospholipid bilayer in a biologically and physiologically accurate manner, with all key components present in their correct proportions, model parameters for the components had to be produced and tested in small binary systems. The components of the membrane used include the phospholipids POPC, POPE, POPS and PIP2, as well as sphingomyelin and cholesterol. Using these new parameters for the components of a phospholipid bilayer, molecular dynamics simulations were run of the activated p110a subunit and two of its oncogenic mutants (E545K, H1047R) in the presence of a realistic brain lipid membrane. The results will pave the way to the development of drugs which will serve to inhibit the pathway when necessary, in an effort to control and reduce the incidence of cancer.