Parathyroid Hormone-Related Protein and the Pancreatic Beta Cell

甲状旁腺激素相关蛋白和胰腺β细胞

基本信息

项目摘要

DESCRIPTION (provided by applicant): Parathyroid hormone-related protein (PTHrP), and its receptor, parathyroid hormone receptor 1 (PTH1R), expressed in almost every tissue including the beta cell, are required for life. Studies from our group and others, convincingly demonstrate that PTHrP improves beta cell survival, function and proliferation in rodent islets in vitro. Furthermore, we show that PTHrP has similar salutary effects in vivo, when overexpressed in beta cells of transgenic mice using the rat insulin II promoter (RIP). The RIP-PTHrP transgenic mice display islet hyperplasia, enhanced beta cell proliferation, survival, and function, with resultant hyperinsulinemia and mild hypoglycemia. Our recent data indicate that acute in vivo administration of the amino-terminal region of PTHrP(1-36), the ligand for the PTH1R, has salutary effects on beta cell function, proliferation and beta cell mass in normal mice. Most importantly, PTHrP enhances human beta cell proliferation and improves human beta cell function. However, despite the multiple positive effects of PTHrP on the beta cell, there is very little known regarding the mechanisms and signaling pathways through which PTHrP mediates its beneficial effects; or the physiological role of PTHrP signaling on normal beta cell growth and function; or how these favorable effects of PTHrP could be harnessed therapeutically to enhance islet function, proliferation, and survival. These are important issues that need to be addressed in the field of beta cell biology. This is especially critical given the current worldwide diabetes epidemic, the advent of islet transplantation as a treatment for diabetes, the current paucity of available islets for transplants, and the need to further enhance the growth and function of endogenous beta cells for the future cure or prevention of diabetes. Based on our data we hypothesize that PTHrP mediates its manifold salutary actions on the beta cell through distinct signaling pathways, that PTHrP-PTH1R signaling in the beta cell is important for beta cell growth and/or function either in basal and/or stress-induced conditions, and that these multiple positive effects of PTHrP on the beta cell can be harnessed therapeutically. Therefore, we will address these goals with the following Specific Aims: 1) To identify the signaling pathway(s) through which PTHrP enhances beta cell function, proliferation, and survival in vitro. 2) To establish the physiological role of PTH1R signaling in beta cell growth, function and survival in vivo. 3) To examine the role of PTHrP in islet transplant outcomes. Results from these studies should provide a better understanding of how PTHrP, a beta cell growth factor holding immense promise, mediates its beneficial effects on the beta cell, whether its therapeutic potential can be harnessed to improve islet growth and function in the context of islet transplantation, and in the future for regeneration of endogenous beta cells, in the prevention and cure of diabetes. PUBLIC HEALTH RELEVANCE: Studies from our lab and others have shown that parathyroid hormone-related protein (PTHrP) holds immense promise as a beta cell growth factor since it enhances function, proliferation, and survival of beta cells. Studies from the current proposal will unravel the mechanisms by which this growth factor mediates its beneficial effects in the beta cell both under normal conditions as well as under pathophysiological conditions of type 1 and type 2 diabetes. This will enable us to identify suitable molecular targets to improve islet growth and function for future therapeutic studies. Most importantly, these studies will examine whether the salutary effects of PTHrP on the beta cell can be harnessed therapeutically to improve islet transplants. These studies are especially critical given the current worldwide diabetes epidemic, the advent of islet transplantation as a treatment for diabetes, the current paucity of available islets for transplants, and the need to further enhance the growth and function of endogenous beta cells for the future cure or prevention of diabetes.
DESCRIPTION (provided by applicant): Parathyroid hormone-related protein (PTHrP), and its receptor, parathyroid hormone receptor 1 (PTH1R), expressed in almost every tissue including the beta cell, are required for life. Studies from our group and others, convincingly demonstrate that PTHrP improves beta cell survival, function and proliferation in rodent islets in vitro. Furthermore, we show that PTHrP has similar salutary effects in vivo, when overexpressed in beta cells of transgenic mice using the rat insulin II promoter (RIP). The RIP-PTHrP transgenic mice display islet hyperplasia, enhanced beta cell proliferation, survival, and function, with resultant hyperinsulinemia and mild hypoglycemia. Our recent data indicate that acute in vivo administration of the amino-terminal region of PTHrP(1-36), the ligand for the PTH1R, has salutary effects on beta cell function, proliferation and beta cell mass in normal mice. Most importantly, PTHrP enhances human beta cell proliferation and improves human beta cell function. However, despite the multiple positive effects of PTHrP on the beta cell, there is very little known regarding the mechanisms and signaling pathways through which PTHrP mediates its beneficial effects; or the physiological role of PTHrP signaling on normal beta cell growth and function; or how these favorable effects of PTHrP could be harnessed therapeutically to enhance islet function, proliferation, and survival. These are important issues that need to be addressed in the field of beta cell biology. This is especially critical given the current worldwide diabetes epidemic, the advent of islet transplantation as a treatment for diabetes, the current paucity of available islets for transplants, and the need to further enhance the growth and function of endogenous beta cells for the future cure or prevention of diabetes. Based on our data we hypothesize that PTHrP mediates its manifold salutary actions on the beta cell through distinct signaling pathways, that PTHrP-PTH1R signaling in the beta cell is important for beta cell growth and/or function either in basal and/or stress-induced conditions, and that these multiple positive effects of PTHrP on the beta cell can be harnessed therapeutically. Therefore, we will address these goals with the following Specific Aims: 1) To identify the signaling pathway(s) through which PTHrP enhances beta cell function, proliferation, and survival in vitro. 2) To establish the physiological role of PTH1R signaling in beta cell growth, function and survival in vivo. 3) To examine the role of PTHrP in islet transplant outcomes. Results from these studies should provide a better understanding of how PTHrP, a beta cell growth factor holding immense promise, mediates its beneficial effects on the beta cell, whether its therapeutic potential can be harnessed to improve islet growth and function in the context of islet transplantation, and in the future for regeneration of endogenous beta cells, in the prevention and cure of diabetes. PUBLIC HEALTH RELEVANCE: Studies from our lab and others have shown that parathyroid hormone-related protein (PTHrP) holds immense promise as a beta cell growth factor since it enhances function, proliferation, and survival of beta cells. Studies from the current proposal will unravel the mechanisms by which this growth factor mediates its beneficial effects in the beta cell both under normal conditions as well as under pathophysiological conditions of type 1 and type 2 diabetes. This will enable us to identify suitable molecular targets to improve islet growth and function for future therapeutic studies. Most importantly, these studies will examine whether the salutary effects of PTHrP on the beta cell can be harnessed therapeutically to improve islet transplants. These studies are especially critical given the current worldwide diabetes epidemic, the advent of islet transplantation as a treatment for diabetes, the current paucity of available islets for transplants, and the need to further enhance the growth and function of endogenous beta cells for the future cure or prevention of diabetes.

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Rupangi C Vasavada其他文献

Rupangi C Vasavada的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Rupangi C Vasavada', 18)}}的其他基金

Osteoprotegerin and the Pancreatic Beta Cell
骨保护素和胰腺β细胞
  • 批准号:
    9201325
  • 财政年份:
    2015
  • 资助金额:
    $ 28.4万
  • 项目类别:
Osteoprotegerin and the Pancreatic Beta Cell
骨保护素和胰腺β细胞
  • 批准号:
    8886641
  • 财政年份:
    2015
  • 资助金额:
    $ 28.4万
  • 项目类别:
Parathyroid Hormone-related Protein and the Pancreatic Beta Cell
甲状旁腺激素相关蛋白和胰腺β细胞
  • 批准号:
    8577579
  • 财政年份:
    2012
  • 资助金额:
    $ 28.4万
  • 项目类别:
Parathyroid Hormone-Related Protein and the Pancreatic Beta Cell
甲状旁腺激素相关蛋白和胰腺β细胞
  • 批准号:
    8008634
  • 财政年份:
    2009
  • 资助金额:
    $ 28.4万
  • 项目类别:
Parathyroid Hormone-Related Protein and the Pancreatic Beta Cell
甲状旁腺激素相关蛋白和胰腺β细胞
  • 批准号:
    7662453
  • 财政年份:
    2008
  • 资助金额:
    $ 28.4万
  • 项目类别:
Lactogens and Pancreatic Beta Cell Survival
泌乳素和胰腺 β 细胞存活
  • 批准号:
    6961165
  • 财政年份:
    2005
  • 资助金额:
    $ 28.4万
  • 项目类别:
Lactogens and Pancreatic Beta Cell Survival
泌乳素和胰腺 β 细胞存活
  • 批准号:
    7118754
  • 财政年份:
    2005
  • 资助金额:
    $ 28.4万
  • 项目类别:
Lactogens and Pancreatic Beta Cell Survival
泌乳素和胰腺 β 细胞存活
  • 批准号:
    7486200
  • 财政年份:
    2005
  • 资助金额:
    $ 28.4万
  • 项目类别:
Lactogens and Pancreatic Beta Cell Survival
泌乳素和胰腺 β 细胞存活
  • 批准号:
    7268961
  • 财政年份:
    2005
  • 资助金额:
    $ 28.4万
  • 项目类别:
Lactogens and Pancreatic Beta Cell Survival
泌乳素和胰腺 β 细胞存活
  • 批准号:
    7677904
  • 财政年份:
    2005
  • 资助金额:
    $ 28.4万
  • 项目类别:

相似海外基金

Rational design of rapidly translatable, highly antigenic and novel recombinant immunogens to address deficiencies of current snakebite treatments
合理设计可快速翻译、高抗原性和新型重组免疫原,以解决当前蛇咬伤治疗的缺陷
  • 批准号:
    MR/S03398X/2
  • 财政年份:
    2024
  • 资助金额:
    $ 28.4万
  • 项目类别:
    Fellowship
CAREER: FEAST (Food Ecosystems And circularity for Sustainable Transformation) framework to address Hidden Hunger
职业:FEAST(食品生态系统和可持续转型循环)框架解决隐性饥饿
  • 批准号:
    2338423
  • 财政年份:
    2024
  • 资助金额:
    $ 28.4万
  • 项目类别:
    Continuing Grant
Re-thinking drug nanocrystals as highly loaded vectors to address key unmet therapeutic challenges
重新思考药物纳米晶体作为高负载载体以解决关键的未满足的治疗挑战
  • 批准号:
    EP/Y001486/1
  • 财政年份:
    2024
  • 资助金额:
    $ 28.4万
  • 项目类别:
    Research Grant
Metrology to address ion suppression in multimodal mass spectrometry imaging with application in oncology
计量学解决多模态质谱成像中的离子抑制问题及其在肿瘤学中的应用
  • 批准号:
    MR/X03657X/1
  • 财政年份:
    2024
  • 资助金额:
    $ 28.4万
  • 项目类别:
    Fellowship
CRII: SHF: A Novel Address Translation Architecture for Virtualized Clouds
CRII:SHF:一种用于虚拟化云的新型地址转换架构
  • 批准号:
    2348066
  • 财政年份:
    2024
  • 资助金额:
    $ 28.4万
  • 项目类别:
    Standard Grant
The Abundance Project: Enhancing Cultural & Green Inclusion in Social Prescribing in Southwest London to Address Ethnic Inequalities in Mental Health
丰富项目:增强文化
  • 批准号:
    AH/Z505481/1
  • 财政年份:
    2024
  • 资助金额:
    $ 28.4万
  • 项目类别:
    Research Grant
ERAMET - Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
ERAMET - 快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
  • 批准号:
    10107647
  • 财政年份:
    2024
  • 资助金额:
    $ 28.4万
  • 项目类别:
    EU-Funded
BIORETS: Convergence Research Experiences for Teachers in Synthetic and Systems Biology to Address Challenges in Food, Health, Energy, and Environment
BIORETS:合成和系统生物学教师的融合研究经验,以应对食品、健康、能源和环境方面的挑战
  • 批准号:
    2341402
  • 财政年份:
    2024
  • 资助金额:
    $ 28.4万
  • 项目类别:
    Standard Grant
Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
  • 批准号:
    10106221
  • 财政年份:
    2024
  • 资助金额:
    $ 28.4万
  • 项目类别:
    EU-Funded
Recite: Building Research by Communities to Address Inequities through Expression
背诵:社区开展研究,通过表达解决不平等问题
  • 批准号:
    AH/Z505341/1
  • 财政年份:
    2024
  • 资助金额:
    $ 28.4万
  • 项目类别:
    Research Grant
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了