University:
Boston University
Course:
CAS BI 108 | Biology 2
Academic year:

2022
Views:

108

Pages:

1
Author:

Haiden Dudley

Developing a 4OHT Inducible Therapeutic Genetic Circuit for Reversing Tauopathy in Alzheimer Disease Model A growing number of studies have investigated the link between the accumulation of abnormal tau and the progression of Alzheimer’s Disease (AD). Research has shown that as the disease pro-gresses, aggregated Tau forms neurofibrillary tangles that lead to neurodegeneration; a hallmark of the disease. Existing treatment only targets managing symptoms, and at most slowing the progres-sion of the disease in some cases. Thus, a novel therapeutic intervention that targets the pathology before the formation of the neurofibrillary tangles is needed. This project proposed a synthetic bio-logical genetic circuit that targets the initial tau oligomers and reserves the progression of tau ag-gregation at the early stage of the disease. By utilizing existing proteins (FKBP12, FKBP51, Pin1, Hsp70, and Hsp90) with known tau aggregation reversibility, this Zinc Finger coupled- 4OHT induc-ible circuit directly output these proteins in the cytoplasm to reverse oligomeric tau (toxic form) into monomeric tau (non-toxic form). We have accomplished the cloning of all the therapeutic genetic circuits with verified sequences by Quintara. Moreover, to model the early state of tauopathy, this project also built a Doxycycline inducible tau SH-SY5Y cell line for testing system response of the therapeutic circuit. By 1µg/mL Doxycycline induction followed by 500µM sodium arsenite (stress induction), Doxycycline tau SH-SY5Y cell line forms 10µm tau granules in the cytoplasm. The co-localization and exclusion of nucleus calculations were performed by K mean clustering through a machine learning algorithm. This result indicates that under certain environmental conditions the cell line functions as a molecular model for early-stage Alzheimer’s Disease.