Skip to Main Content
 

Global Search Box

 
 
 
 

Files

File List


Nischay Rege Formatted Thesis4.pdf (10.94 MB)

ETD Abstract Container

Abstract Header

THE UN-DESIGN AND DESIGN OF INSULIN: STRUCTURAL EVOLUTION WITH APPLICATION TO THERAPEUTIC DESIGN

Rege, Nischay Kiran
http://rave.ohiolink.edu/etdc/view?acc_num=case1531429783955495

Abstract Details

2018, Doctor of Philosophy, Case Western Reserve University, Biochemistry.
Insulin is a peptide hormone that is the primary regulator of glucose homeostasis in vertebrates. Insulin is secreted by the endocrine pancreas in response to increased interstitial glucose levels; insulin initiates the uptake of glucose by peripheral tissues. Since its first use in 1921, insulin has been the primary treatment for the metabolic condition known as Type I Diabetes Mellitus (T1DM; caused by the absolute lack of insulin), and a component in the treatment of Type II Diabetes Mellitus (T2DM; caused by the relative lack of insulin in relation to peripheral insulin resistance). The ubiquitous clinical use of insulin has led to investigation of its structure-function relationships. Such studies have uncovered the rich evolutionary history of insulin and its usefulness as a model molecule. Indeed, the study of insulin has revealed a number of concepts of protein structure/function relationships and the in vitro and biosynthesis of proteins. This dissertation is a continuation of the nearly century-old field of insulin biochemistry. The first section of the thesis examines the evolutionary constraints responsible for the conservation of several structural features within the insulin B chain as they relate to the biosynthesis, stability, and biological activity of the hormone. Concepts expounded in these studies may be generalized to the evolution and folding xvii process of globular proteins as a class. Furthermore, such studies may be used to inform the design of therapeutic insulin analogs as exemplified in the second part of the dissertation. This section demonstrates how conserved structural features of insulin may be exploited and modified to produce favorable therapeutic effects even if such modifications would be unfavorable in the context of vertebrate physiology. This approach underscores the importance and usefulness of a multidisciplinary approach to the study of insulin both as a model molecule and as a therapeutic agent.
Michael Weiss, MD, PhD (Advisor)
Paul Carey, PhD (Committee Chair)
Faramarz Ismail-Beigi, MD, PhD (Committee Member)
George Dubyak, PhD (Committee Member)
507 p.
Biochemistry; Biophysics; Endocrinology; Medicine
Insulin, Evolution, Diabetes Mellitus, Protein Engineering, Protein Folding, Protein Stability, Self-Association, Amyloid

Recommended Citations

Citations

  • Rege, N. K. (2018). THE UN-DESIGN AND DESIGN OF INSULIN: STRUCTURAL EVOLUTION WITH APPLICATION TO THERAPEUTIC DESIGN [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1531429783955495

    APA Style (7th edition)

  • Rege, Nischay. THE UN-DESIGN AND DESIGN OF INSULIN: STRUCTURAL EVOLUTION WITH APPLICATION TO THERAPEUTIC DESIGN. 2018. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1531429783955495.

    MLA Style (8th edition)

  • Rege, Nischay. "THE UN-DESIGN AND DESIGN OF INSULIN: STRUCTURAL EVOLUTION WITH APPLICATION TO THERAPEUTIC DESIGN." Doctoral dissertation, Case Western Reserve University, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=case1531429783955495

    Chicago Manual of Style (17th edition)

case1531429783955495
369
© 2018, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.