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Polymer Scaffold Approaches to Enhance Monitoring and Treatment of Type 1 Diabetes
Polymer Scaffold Approaches to Enhance Monitoring and Treatment of Type 1 Diabetes
상세정보
- 자료유형
- 학위논문 서양
- 최종처리일시
- 20260202103643
- ISBN
- 9798314874295
- DDC
- 610
- 서명/저자
- Polymer Scaffold Approaches to Enhance Monitoring and Treatment of Type 1 Diabetes
- 발행사항
- [Sl] : University of Michigan, 2025
- 발행사항
- Ann Arbor : ProQuest Dissertations & Theses, 2025
- 형태사항
- 179 p
- 주기사항
- Source: Dissertations Abstracts International, Volume: 86-11, Section: B.
- 주기사항
- Advisor: Shea, Lonnie D.
- 학위논문주기
- Thesis (Ph.D.)--University of Michigan, 2025.
- 초록/해제
- 요약Type 1 diabetes (T1D) is an autoimmune disease with a prevalence of over 8 million people globally. Following autoimmune destruction of their pancreatic islets, T1D patients rely on exogenous insulin therapy to regulate their blood glucose levels. This lifelong therapy is associated with high burden of disease, and long-term risks for complications. As a result, the T1D research field has pursued cell replacement therapies as a treatment for patients with active disease, and preventive immunotherapies for recent onset patients who maintain a functional islet mass. This dissertation investigates the use of microporous polymer scaffolds as tools to address existing challenges in the development of cell replacement therapy and disease monitoring. We identify deficiencies in current cell replacement approaches and develop methods to improve cell quality and delivery. We also develop a monitoring platform for T1D progression that has the potential to inform immunotherapy treatment timing to sustain the greatest functional islet mass.In order to address the challenge of disease monitoring in a glucose agnostic manner, we implemented PCL scaffolds as immunological niches (IN) at a subcutaneous site. We first established that sequencing analysis of the IN distinguishes healthy from diabetic conditions in two murine models of T1D. We next investigated if the IN could distinguish risk and progression status in the NOD mouse model of T1D. We found that elastic net regression analysis of RNA sequencing data from the IN identifies gene signatures that separate at-risk from non-risk groups, progressors from non-progressors, and time to disease onset for progressors. These gene signatures identify disease progression at a time prior to measurable glucose dysregulation, outperforming the current clinical standard of a glucose tolerance test.We next investigated existing challenges to cell replacement therapy related to cell quality and cell delivery. Low availability of donor islets has led to development of pluripotent stem cell derived islets (sc-islets) as a potentially limitless source. However, sc-islets lack the metabolic maturity of donor islets, and the protocols to generate these cells take on the order of 30 days, making in vitro testing of a large number of treatments time and resource intensive. To investigate the effects of drug and metabolite treatments on sc-islet maturity without the need for lengthy cultures, we developed a metabolic network reconstruction specific to sc-islets. Transcriptomic data from mature human islets and sc-islets were used to tailor the model to our existing differentiation output, and we then used the model to screen a validated drug treatment and individual gene knock-ins for 443 genes. In vitro testing indicates that our model is capable of identifying targets to enhance metabolism in sc-islets in silico. To address delivery challenges, we investigated the role of polymer ratio on efficacy of scaffolds as an islet transplantation platform. Taken together, the dual approach of monitoring and therapeutic cell enhancement demonstrates the multifaceted needs of the T1D community. Enhanced monitoring has the potential to improve preventive treatment as incidence continues to rise, and improving cell therapies addresses the long-term needs of the existing T1D population.
- 일반주제명
- Biomedical engineering
- 일반주제명
- Biochemistry
- 일반주제명
- Cellular biology
- 키워드
- Islets
- 기타저자
- University of Michigan Biomedical Engineering
- 기본자료저록
- Dissertations Abstracts International. 86-11B.
- 전자적 위치 및 접속
- 로그인 후 원문을 볼 수 있습니다.
MARC
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■040 ▼aMiAaPQ▼cMiAaPQ
■0820 ▼a610
■1001 ▼aKing, Jessica Lynn.
■24510▼aPolymer Scaffold Approaches to Enhance Monitoring and Treatment of Type 1 Diabetes
■260 ▼a[Sl]▼bUniversity of Michigan▼c2025
■260 1▼aAnn Arbor▼bProQuest Dissertations & Theses▼c2025
■300 ▼a179 p
■500 ▼aSource: Dissertations Abstracts International, Volume: 86-11, Section: B.
■500 ▼aAdvisor: Shea, Lonnie D.
■5021 ▼aThesis (Ph.D.)--University of Michigan, 2025.
■520 ▼aType 1 diabetes (T1D) is an autoimmune disease with a prevalence of over 8 million people globally. Following autoimmune destruction of their pancreatic islets, T1D patients rely on exogenous insulin therapy to regulate their blood glucose levels. This lifelong therapy is associated with high burden of disease, and long-term risks for complications. As a result, the T1D research field has pursued cell replacement therapies as a treatment for patients with active disease, and preventive immunotherapies for recent onset patients who maintain a functional islet mass. This dissertation investigates the use of microporous polymer scaffolds as tools to address existing challenges in the development of cell replacement therapy and disease monitoring. We identify deficiencies in current cell replacement approaches and develop methods to improve cell quality and delivery. We also develop a monitoring platform for T1D progression that has the potential to inform immunotherapy treatment timing to sustain the greatest functional islet mass.In order to address the challenge of disease monitoring in a glucose agnostic manner, we implemented PCL scaffolds as immunological niches (IN) at a subcutaneous site. We first established that sequencing analysis of the IN distinguishes healthy from diabetic conditions in two murine models of T1D. We next investigated if the IN could distinguish risk and progression status in the NOD mouse model of T1D. We found that elastic net regression analysis of RNA sequencing data from the IN identifies gene signatures that separate at-risk from non-risk groups, progressors from non-progressors, and time to disease onset for progressors. These gene signatures identify disease progression at a time prior to measurable glucose dysregulation, outperforming the current clinical standard of a glucose tolerance test.We next investigated existing challenges to cell replacement therapy related to cell quality and cell delivery. Low availability of donor islets has led to development of pluripotent stem cell derived islets (sc-islets) as a potentially limitless source. However, sc-islets lack the metabolic maturity of donor islets, and the protocols to generate these cells take on the order of 30 days, making in vitro testing of a large number of treatments time and resource intensive. To investigate the effects of drug and metabolite treatments on sc-islet maturity without the need for lengthy cultures, we developed a metabolic network reconstruction specific to sc-islets. Transcriptomic data from mature human islets and sc-islets were used to tailor the model to our existing differentiation output, and we then used the model to screen a validated drug treatment and individual gene knock-ins for 443 genes. In vitro testing indicates that our model is capable of identifying targets to enhance metabolism in sc-islets in silico. To address delivery challenges, we investigated the role of polymer ratio on efficacy of scaffolds as an islet transplantation platform. Taken together, the dual approach of monitoring and therapeutic cell enhancement demonstrates the multifaceted needs of the T1D community. Enhanced monitoring has the potential to improve preventive treatment as incidence continues to rise, and improving cell therapies addresses the long-term needs of the existing T1D population.
■590 ▼aSchool code: 0127.
■650 4▼aBiomedical engineering
■650 4▼aBiochemistry
■650 4▼aCellular biology
■653 ▼aPolymer scaffolds
■653 ▼aType one diabetes
■653 ▼aPluripotent stem cells
■653 ▼aIslets
■653 ▼aCell replacement therapy
■690 ▼a0541
■690 ▼a0487
■690 ▼a0379
■71020▼aUniversity of Michigan▼bBiomedical Engineering.
■7730 ▼tDissertations Abstracts International▼g86-11B.
■790 ▼a0127
■791 ▼aPh.D.
■792 ▼a2025
■793 ▼aEnglish
■85640▼uhttp://www.riss.kr/pdu/ddodLink.do?id=T17358094▼nKERIS▼z이 자료의 원문은 한국교육학술정보원에서 제공합니다.
