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2024 PhD Dissertation-Yijing Tang5.pdf (19.35 MB)

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MOLECULAR UNDERSTANDING AND DESIGN OF AMYLOID CROSS-SEEDING AND AMYLOID PROBES

Tang, Yijing
http://rave.ohiolink.edu/etdc/view?acc_num=akron1712338555516656

Abstract Details

, Doctor of Philosophy, University of Akron, Chemical Engineering.
Accumulating evidence demonstrates that misfolded proteins associated with various amyloid diseases, such as Alzheimer's disease, Parkinson's disease, type 2 diabetes, and cardiovascular disease, can interact across disease boundaries to promote amyloid aggregation through a process known as amyloid cross-seeding. This cross-seeding mechanism is crucial for the spreading of common pathologies across different cells and tissues, thus exacerbating the progression of these diseases. To deepen our comprehension of the amyloid cross-seeding process, we identified and studied a series of amyloid cross-seeding systems of hIAPP (associated with T2D)/TKEQVTNV (associated with PD), Aβ (associated with AD)/ANP (associated with CVD), and Aβ/SEVI (associated with HIV/AIDs). The “Amyloid Cascade Hypothesis” has long been regarded as a primary pathological factor initiating amyloid diseases. However, the complex, multifactorial nature of amyloid diseases has rendered single-target strategies largely ineffective, even in preclinical trials. This ineffectiveness hints at the significant role of an additional factor, the “Microbial Infection Hypothesis”, in the pathology of amyloid diseases. Against this backdrop, we proposed and validated a novel “Anti-Amyloid and Antimicrobial Hypothesis” to identify several antimicrobial peptides containing β-rich structures including intestinal defensins, PG-1, and aurein, with multifunctional and multi-targeting properties. This innovative hypothesis not only demonstrates the cross-seeding process between amyloid and antimicrobial peptides, but also integrate a crucial antimicrobial perspective, which presents a more effective prevention strategy against amyloid diseases by targeting various pathological pathways. The early diagnosis of amyloid diseases represents another significant challenge that has garnered considerable efforts in recent years. Traditional approaches have often been constrained to molecules that offer either a single functionality (such as amyloid imaging or prevention) or target a single protein (like Aβ, hIAPP, or hCT). Here, we have designed and developed a novel series of fluorescent amyloid probes, including GNNQQNY-TBA, BO21, and ROF2 as “conformationally specific, yet sequence-independent” amyloid probes designed to induce a “off-to-on” fluorescence transition upon binding to β-structure-rich amyloid oligomers and fibrils. Intriguingly, molecular interactions between these bio-probes and amyloids also confer them secondary functions.
Jie Zheng (Advisor)
Qixin Zhou (Committee Member)
Xiong Gong (Committee Member)
Ge Zhang (Committee Member)
Linxiao Chen (Committee Member)
405 p.
Biochemistry; Chemical Engineering
Amyloid aggregation; cross-seeding; amyloid probes; protein misfolding diseases; Alzheimer's disease; type 2 diabetes

Recommended Citations

Citations

  • Tang, Y. (2024). MOLECULAR UNDERSTANDING AND DESIGN OF AMYLOID CROSS-SEEDING AND AMYLOID PROBES [Doctoral dissertation, University of Akron]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=akron1712338555516656

    APA Style (7th edition)

  • Tang, Yijing. MOLECULAR UNDERSTANDING AND DESIGN OF AMYLOID CROSS-SEEDING AND AMYLOID PROBES . 2024. University of Akron, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=akron1712338555516656.

    MLA Style (8th edition)

  • Tang, Yijing. "MOLECULAR UNDERSTANDING AND DESIGN OF AMYLOID CROSS-SEEDING AND AMYLOID PROBES ." Doctoral dissertation, University of Akron, 2024. http://rave.ohiolink.edu/etdc/view?acc_num=akron1712338555516656

    Chicago Manual of Style (17th edition)

akron1712338555516656
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This open access ETD is published by University of Akron and OhioLINK.