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Systems Pharmacology Approach to Mechanism-Based Drug Discovery Reveals New Class of Small-Molecule Therapies to Prevent Vision Loss and Neurodegeneration in the Retina
Systems Pharmacology Approach to Mechanism-Based Drug Discovery Reveals New Class of Small-Molecule Therapies to Prevent Vision Loss and Neurodegeneration in the Retina
상세정보
- 자료유형
- 학위논문 서양
- 최종처리일시
- 20260202104729
- ISBN
- 9798315781974
- DDC
- 610
- 저자명
- Luu, Jennings C.
- 서명/저자
- Systems Pharmacology Approach to Mechanism-Based Drug Discovery Reveals New Class of Small-Molecule Therapies to Prevent Vision Loss and Neurodegeneration in the Retina
- 발행사항
- [Sl] : Case Western Reserve University, 2024
- 발행사항
- Ann Arbor : ProQuest Dissertations & Theses, 2024
- 형태사항
- 160 p
- 주기사항
- Source: Dissertations Abstracts International, Volume: 86-12, Section: B.
- 주기사항
- Advisor: Palczewski, Krzysztof;Kiser, Philip D.
- 학위논문주기
- Thesis (Ph.D.)--Case Western Reserve University, 2024.
- 초록/해제
- 요약Globally, an estimated 420 million people today suffer from debilitating vision loss caused by age-related macular degeneration (AMD), diabetic retinopathy (DR), retinitis pigmentosa (RP), or glaucoma; a large majority of these cases (up to 90%) have only minimally effective or no treatment options available. These chronic, progressive retinal diseases arise from a complex interplay of genetic and environmental factors that disrupt, and eventually compromise, cellular and tissue stability. Such disruptions accumulate with repeated exposures to stress over time, leading to progressive visual impairment and, in many cases, legal blindness. Despite decades of research, effective treatments to preserve eyesight have remained elusive for the millions of patients suffering from these debilitating disorders, especially in the vast majority of cases that are in early stages of disease progression, wherein lies the greatest opportunity to slow or halt vision loss. In the coming decades, population aging will exacerbate the increase in global prevalence of vision impairment and blindness, thus underscoring a critical, unmet need for innovative, new ophthalmic medications.In pre-clinical studies, we demonstrated the efficacy of prototypical `stress resilience-enhancing drugs' (SREDs) that preserved both retinal morphology and function across a variety of genetic and environmental animal models of AMD, DR, RP, and glaucoma. These small-molecule therapies can be subdivided according to primary mechanism of action, resulting in two distinct subclasses of SREDs: 1) epigenetic modulators that include inhibitors of select histone deacetylases (HDACi) or methyltransferases (SUVi); and 2) selective inhibitors of cyclic nucleotide phosphodiesterases (PDEi). With pharmacological inhibition of histone deacetylase 11 (HDAC11) or suppressor of variegation 3-9 homolog 2 (SUV39H2), key histone-modifying enzymes involved in promoting reduced chromatin accessibility, stress-induced retinal degeneration was ameliorated in a photosensitive mouse model that recapitulates epigenetic and pathological hallmarks of AMD. Similarly, across multiple models of AMD, DR, RP, and glaucoma, pharmacological inhibition of select phosphodiesterases enhanced resilience to stress in the degenerating retina and preserved retinal structure as well as visual function. Taken together, these findings validate the systems pharmacology framework for drug discovery, serving as proof-of-concept for a new class of therapeutics to combat the leading global causes of blindness.
- 일반주제명
- Medicine
- 일반주제명
- Ophthalmology
- 일반주제명
- Pharmacology
- 일반주제명
- Pharmaceutical sciences
- 키워드
- Vision
- 키워드
- Retina
- 키워드
- Eye
- 키워드
- Aging
- 기타저자
- Case Western Reserve University Pharmacology
- 기본자료저록
- Dissertations Abstracts International. 86-12B.
- 전자적 위치 및 접속
- 로그인 후 원문을 볼 수 있습니다.
MARC
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■24510▼aSystems Pharmacology Approach to Mechanism-Based Drug Discovery Reveals New Class of Small-Molecule Therapies to Prevent Vision Loss and Neurodegeneration in the Retina
■260 ▼a[Sl]▼bCase Western Reserve University▼c2024
■260 1▼aAnn Arbor▼bProQuest Dissertations & Theses▼c2024
■300 ▼a160 p
■500 ▼aSource: Dissertations Abstracts International, Volume: 86-12, Section: B.
■500 ▼aAdvisor: Palczewski, Krzysztof;Kiser, Philip D.
■5021 ▼aThesis (Ph.D.)--Case Western Reserve University, 2024.
■520 ▼aGlobally, an estimated 420 million people today suffer from debilitating vision loss caused by age-related macular degeneration (AMD), diabetic retinopathy (DR), retinitis pigmentosa (RP), or glaucoma; a large majority of these cases (up to 90%) have only minimally effective or no treatment options available. These chronic, progressive retinal diseases arise from a complex interplay of genetic and environmental factors that disrupt, and eventually compromise, cellular and tissue stability. Such disruptions accumulate with repeated exposures to stress over time, leading to progressive visual impairment and, in many cases, legal blindness. Despite decades of research, effective treatments to preserve eyesight have remained elusive for the millions of patients suffering from these debilitating disorders, especially in the vast majority of cases that are in early stages of disease progression, wherein lies the greatest opportunity to slow or halt vision loss. In the coming decades, population aging will exacerbate the increase in global prevalence of vision impairment and blindness, thus underscoring a critical, unmet need for innovative, new ophthalmic medications.In pre-clinical studies, we demonstrated the efficacy of prototypical `stress resilience-enhancing drugs' (SREDs) that preserved both retinal morphology and function across a variety of genetic and environmental animal models of AMD, DR, RP, and glaucoma. These small-molecule therapies can be subdivided according to primary mechanism of action, resulting in two distinct subclasses of SREDs: 1) epigenetic modulators that include inhibitors of select histone deacetylases (HDACi) or methyltransferases (SUVi); and 2) selective inhibitors of cyclic nucleotide phosphodiesterases (PDEi). With pharmacological inhibition of histone deacetylase 11 (HDAC11) or suppressor of variegation 3-9 homolog 2 (SUV39H2), key histone-modifying enzymes involved in promoting reduced chromatin accessibility, stress-induced retinal degeneration was ameliorated in a photosensitive mouse model that recapitulates epigenetic and pathological hallmarks of AMD. Similarly, across multiple models of AMD, DR, RP, and glaucoma, pharmacological inhibition of select phosphodiesterases enhanced resilience to stress in the degenerating retina and preserved retinal structure as well as visual function. Taken together, these findings validate the systems pharmacology framework for drug discovery, serving as proof-of-concept for a new class of therapeutics to combat the leading global causes of blindness.
■590 ▼aSchool code: 0042.
■650 4▼aMedicine
■650 4▼aOphthalmology
■650 4▼aPharmacology
■650 4▼aPharmaceutical sciences
■653 ▼aSystems pharmacology
■653 ▼aVision
■653 ▼aRetina
■653 ▼aEye
■653 ▼aAging
■653 ▼aNeurodegeneration
■690 ▼a0564
■690 ▼a0381
■690 ▼a0572
■690 ▼a0419
■71020▼aCase Western Reserve University▼bPharmacology.
■7730 ▼tDissertations Abstracts International▼g86-12B.
■790 ▼a0042
■791 ▼aPh.D.
■792 ▼a2024
■793 ▼aEnglish
■85640▼uhttp://www.riss.kr/pdu/ddodLink.do?id=T17358634▼nKERIS▼z이 자료의 원문은 한국교육학술정보원에서 제공합니다.
