Regional and lobular heterogeneity of human pancreas morphology and function in type 1 diabetes pathogenesis

1型糖尿病发病机制中人胰腺形态和功能的区域和小叶异质性

基本信息

  • 批准号:
    10223289
  • 负责人:
  • 金额:
    $ 42.17万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-07-24 至 2024-04-30
  • 项目状态:
    已结题

项目摘要

Through programs such as the Network for Pancreatic Organ donors with Diabetes (nPOD), highly valuable tissues from persons with various stages and durations of type 1 diabetes (T1D) are now available. As a result, our collective knowledge of the pathogenic events underlying T1D development has improved substantially. However, studies simultaneously assessing functional and morphological traits of the human pancreas have not been performed, limiting our understanding of the processes governing organ physiology in health versus pathophysiology in T1D. Despite being in important research resource, investigations of isolated islets are confounded by the isolation procedure, which induces an inflammatory response, morphological modifications, and altered gene expression. Furthermore, the isolation procedure relies on the structural integrity of the islets to withstand the enzymatic and mechanical sorting process. Most importantly, separation of islets from their surrounding tissue removes any influence and information regarding the local adjacent elements, which could be of importance, especially in pathological settings. We believe the characterization of islets as well as exocrine tissues (function, regulation, and cellular interactions) and their roles in the pathogenesis of T1D would be improved through studies of viable human pancreatic tissue containing intact islets and acini. We propose to utilize the extremely novel pancreas tissue slice technology to substantially expand our knowledge of endocrine and exocrine function and their interaction in normal (i.e., control) and T1D pancreas tissues obtained through the nPOD program. This technology, originally established by Dr. Speier (mPD/PI, HMGU), produces “slices” of fresh pancreatic tissue with minimal mechanical damage and without enzymatic digestion; enabling in situ investigations of islet cell biology in a relatively unperturbed tissue setting. Following functional stimulation assays for endocrine (insulin and glucagon) and exocrine secretion (amylase, lipase, trypsinogen) as well as dynamic imaging studies of cellular signaling (Ca2+ flux), slices will be fixed and analyzed by 3D morphometry. Amongst the many questions that will be addressed, we seek to improve our understanding on the functional implications of the lobular and regional (i.e., head, body or tail) heterogeneous pancreatic morphology, including islet density, size and cellular composition, exocrine enzyme expression and distribution, as well as vascular and neuronal density. Furthermore, we aim to address its role in the distinct lobular and regional pathological progression of T1D (i.e., insulitis, β-cell dysfunction and destruction, loss of acinar cell/organ mass). Thus, we pose to test the hypothesis that the disparate organ weight loss as well as the lobular heterogeneity of insulitis and β-cell destruction within the human T1D pancreas is the result of inter-regional and intra-lobular differences in endocrine and exocrine pancreas morphology and function. Our objective is to correlate islet and exocrine physiology and pathophysiology to their location within the pancreas and to cellular characteristics of the surrounding microenvironment; efforts that should impact attempts at T1D prevention/reversal.
通过糖尿病胰腺器官捐献网络(nPOD)等项目,非常有价值

项目成果

期刊论文数量(0)
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MARK A. ATKINSON其他文献

MARK A. ATKINSON的其他文献

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{{ truncateString('MARK A. ATKINSON', 18)}}的其他基金

Human Pancreas Analysis Program-T2D
人类胰腺分析程序-T2D
  • 批准号:
    10907128
  • 财政年份:
    2023
  • 资助金额:
    $ 42.17万
  • 项目类别:
Biorepository and Coordinating Center for Studies on Cardiovascular Complications of Human Type 1 Diabetes
人类1型糖尿病心血管并发症研究生物储存库和协调中心
  • 批准号:
    10879240
  • 财政年份:
    2022
  • 资助金额:
    $ 42.17万
  • 项目类别:
Biorepository and Coordinating Center for Studies on Cardiovascular Complications of Human Type 1 Diabetes
人类1型糖尿病心血管并发症研究生物储存库和协调中心
  • 批准号:
    10672443
  • 财政年份:
    2022
  • 资助金额:
    $ 42.17万
  • 项目类别:
Biorepository and Coordinating Center for Studies on Cardiovascular Complications of Human Type 1 Diabetes
人类1型糖尿病心血管并发症研究生物储存库和协调中心
  • 批准号:
    10512888
  • 财政年份:
    2022
  • 资助金额:
    $ 42.17万
  • 项目类别:
Co-registration of Cell Organization, Phenotype and Function in the Human Pancreas During Type 1 Diabetes
1 型糖尿病期间人类胰腺细胞组织、表型和功能的共同注册
  • 批准号:
    10343979
  • 财政年份:
    2021
  • 资助金额:
    $ 42.17万
  • 项目类别:
Co-registration of Cell Organization, Phenotype and Function in the Human Pancreas During Type 1 Diabetes
1 型糖尿病期间人类胰腺细胞组织、表型和功能的共同注册
  • 批准号:
    10490416
  • 财政年份:
    2021
  • 资助金额:
    $ 42.17万
  • 项目类别:
Co-registration of Cell Organization, Phenotype and Function in the Human Pancreas During Type 1 Diabetes
1 型糖尿病期间人类胰腺细胞组织、表型和功能的共同注册
  • 批准号:
    10673726
  • 财政年份:
    2021
  • 资助金额:
    $ 42.17万
  • 项目类别:
Regional and lobular heterogeneity of human pancreas morphology and function in type 1 diabetes pathogenesis
1型糖尿病发病机制中人胰腺形态和功能的区域和小叶异质性
  • 批准号:
    10400943
  • 财政年份:
    2020
  • 资助金额:
    $ 42.17万
  • 项目类别:
Regional and lobular heterogeneity of human pancreas morphology and function in type 1 diabetes pathogenesis
1型糖尿病发病机制中人胰腺形态和功能的区域和小叶异质性
  • 批准号:
    10617206
  • 财政年份:
    2020
  • 资助金额:
    $ 42.17万
  • 项目类别:
Coord Core - Atkinson
坐标核心 - 阿特金森
  • 批准号:
    10254841
  • 财政年份:
    2020
  • 资助金额:
    $ 42.17万
  • 项目类别:

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