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Biological Responses to Therapeutic Treatments of Human Vascular Diseases


Shao, Zixuan (2019) Biological Responses to Therapeutic Treatments of Human Vascular Diseases. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/P2S4-AY40.


Diseases of the retina affect hundreds of millions of patients worldwide, with limited treatment options available. ALG-1001 is an investigational drug that showed success in mitigating disease symptoms in animal models and improved patient vision in multiple clinical trials. To gain a better understanding of the drug’s mechanism of action, RNA sequencing (RNA-seq) and shotgun proteomics were employed to study the drug-induced transcriptome change in retinal tissue and cell culture models. Chapter 2 focuses on application of this approach in an animal model of the disease that showed the drug can reversely modulate hypoxia-activated angiogenesis and inflammation gene expression changes. Chapter 3 discusses the study of drug-induced transcriptome response in two cell culture models relevant to pathophysiology of the retinal diseases. Chapter 4 explores retinal cell transcriptome after short and long-term exposure to disease-relevant hypoxia condition and after hypoxia recovery. Appendix A documents our shotgun proteomics protocol and includes results from the application of this method in the study of drug mechanism.

Typical RNA-seq studies use few biological replicates for differential expression analysis, mainly due to the high cost of generating sequencing data. As a result, not all comparisons have the proper statistical power, which result in false positives and false negatives that can lead the researcher to the wrong conclusion. Chapter 5 discusses a novel algorithm and software that help users perform quality control of their dataset to identify whether the appropriate sample size was used for differential gene discovery. The chapter covers demonstration of the software with four publicly available RNA-seq datasets to illustrate its utility.

Bioresorbable vascular scaffolds (BVSs) are the application of biocompatible polymer in the treatment of coronary heart disease, one of the leading causes of death worldwide. BVSs are designed to replace metal stents, which stay permanently in the body after surgery and can lead to various complications, such as lethal thrombosis. In contrast, BVSs provide the necessary support and are resorbed by the body to leave behind a healthy artery after 2-3 years. Improving on the existing BVS material, chapter 6 explores a new polymer nanocomposite that increases the structure’s radial strength in a thinner profile and provides radio-opacity to enhance surgery success.

Item Type:Thesis (Dissertation (Ph.D.))
Subject Keywords:Transcriptome, proteomics, drug, RNA-seq, vascular disease, eye, software, biomaterial
Degree Grantor:California Institute of Technology
Division:Biology and Biological Engineering
Major Option:Bioengineering
Thesis Availability:Public (worldwide access)
Research Advisor(s):
  • Kornfield, Julia A.
Thesis Committee:
  • Wold, Barbara J.
  • Elowitz, Michael B.
  • Tirrell, David A. (chair)
  • Kornfield, Julia A.
Defense Date:21 December 2018
Non-Caltech Author Email:zach.shao (AT)
Funding AgencyGrant Number
Rosen Center for Bioengineering at CaltechUNSPECIFIED
Allegro OphthalmicUNSPECIFIED
Record Number:CaltechTHESIS:05302019-145256322
Persistent URL:
Related URLs:
URLURL TypeDescription data for Chapters 2, 3, 4 and Appendix. Empirical RNA-seq Sample Size Analysis Software Package, described in Chapter 5
Shao, Zixuan0000-0002-4676-6023
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:11570
Deposited By: Zixuan Shao
Deposited On:10 Jun 2019 22:47
Last Modified:12 Dec 2019 21:37

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