U01DK134995
Cooperative Agreement
Overview
Grant Description
The role of senescent beta cells in T1D and T2D - U01 application: The role of senescent beta cells in T1D and T2D abstract.
Recent studies, including our own, suggest a marked increase in SS-cells expressing key components of cellular senescence in islets from type 1 diabetes (T1D) and type 2 diabetic (T2D) patients, implicating SS-cell senescence as a critical contributor to islet dysfunction.
Recently, it was reported that ablation of senescent cells by non-specific senolysis in mouse models of T1D and T2D improved disease outcome. However, these studies did not determine which senescent cell type was relevant to the beneficial effect, nor did they address to what extent senescence occurs in the human endocrine pancreas before and during the development of T1D and T2D.
To close this knowledge gap, in specific aim 1 we will determine the prevalence, transcription signatures, and epigenomic landscapes of SS-cell senescence in T1D, pre-T1D, and T2D donors using immunostaining, imaging mass cytometry, single-cell RNAseq, single-cell ATACseq, DNA methylome determination, and CUT-and-TAG analysis for key histone marks.
In addition, we will evaluate the hypothesis that irreparable damage to telomeres drives senescence in SS-cells, a possible scenario that could provide a mechanism for senescence to occur in islet cells of diabetic patients.
In specific aim 2, we will test whether metabolic and/or inflammatory stressors drive senescence in human SS-cells and determine the effect of senescence on SS-cell function using scRNAseq and secretome analysis.
We will evaluate if induction of senescence and the senescence-associated secretory phenotype (SASP) in human islet cells is P16 dependent, employing the pseudo-islets approach and using our hyperglycemic xeno-transplantation model to assess the direct effect of senolytics on human islet function.
In specific aim 3, we will employ a novel transgenic mouse, the 'Senkiller' model, to enable cell-type specific and inducible ablation of senescent cells in any lineage, including SS-cells. Using this mouse model in combination with the appropriate SS-cell specific CRE driver, we will provide a definitive answer to the question if senescent SS-cells are critical in the development of glucose intolerance in models of T2D and islet autoimmunity in models of T1D.
Together, this proposal will determine the occurrence of senescence among islet cells from T1D and T2D donors using large cohorts and multiple experimental modalities, explore the natural drivers of senescence and consequences to islet function as well as secretion of pro-inflammatory substances, and employ novel mouse models to unequivocally determine if elimination of senescent B-cells impacts diabetes progression in mouse models of T1D and T2D.
The data generated here will address burning questions in the field, namely, is senescence increased in islets from diabetic patients, and are these cells important in the overall pathophysiology of T1D and T2D. These critical questions will have therapeutic relevance regarding the potential efficacy of targeting senescent SS-cells with senolytic therapies.
Recent studies, including our own, suggest a marked increase in SS-cells expressing key components of cellular senescence in islets from type 1 diabetes (T1D) and type 2 diabetic (T2D) patients, implicating SS-cell senescence as a critical contributor to islet dysfunction.
Recently, it was reported that ablation of senescent cells by non-specific senolysis in mouse models of T1D and T2D improved disease outcome. However, these studies did not determine which senescent cell type was relevant to the beneficial effect, nor did they address to what extent senescence occurs in the human endocrine pancreas before and during the development of T1D and T2D.
To close this knowledge gap, in specific aim 1 we will determine the prevalence, transcription signatures, and epigenomic landscapes of SS-cell senescence in T1D, pre-T1D, and T2D donors using immunostaining, imaging mass cytometry, single-cell RNAseq, single-cell ATACseq, DNA methylome determination, and CUT-and-TAG analysis for key histone marks.
In addition, we will evaluate the hypothesis that irreparable damage to telomeres drives senescence in SS-cells, a possible scenario that could provide a mechanism for senescence to occur in islet cells of diabetic patients.
In specific aim 2, we will test whether metabolic and/or inflammatory stressors drive senescence in human SS-cells and determine the effect of senescence on SS-cell function using scRNAseq and secretome analysis.
We will evaluate if induction of senescence and the senescence-associated secretory phenotype (SASP) in human islet cells is P16 dependent, employing the pseudo-islets approach and using our hyperglycemic xeno-transplantation model to assess the direct effect of senolytics on human islet function.
In specific aim 3, we will employ a novel transgenic mouse, the 'Senkiller' model, to enable cell-type specific and inducible ablation of senescent cells in any lineage, including SS-cells. Using this mouse model in combination with the appropriate SS-cell specific CRE driver, we will provide a definitive answer to the question if senescent SS-cells are critical in the development of glucose intolerance in models of T2D and islet autoimmunity in models of T1D.
Together, this proposal will determine the occurrence of senescence among islet cells from T1D and T2D donors using large cohorts and multiple experimental modalities, explore the natural drivers of senescence and consequences to islet function as well as secretion of pro-inflammatory substances, and employ novel mouse models to unequivocally determine if elimination of senescent B-cells impacts diabetes progression in mouse models of T1D and T2D.
The data generated here will address burning questions in the field, namely, is senescence increased in islets from diabetic patients, and are these cells important in the overall pathophysiology of T1D and T2D. These critical questions will have therapeutic relevance regarding the potential efficacy of targeting senescent SS-cells with senolytic therapies.
Funding Goals
NOT APPLICABLE
Grant Program (CFDA)
Awarding / Funding Agency
Place of Performance
Pennsylvania
United States
Geographic Scope
State-Wide
Related Opportunity
Analysis Notes
Amendment Since initial award the total obligations have increased 185% from $758,532 to $2,160,395.
Trustees Of The University Of Pennsylvania was awarded
The role of senescent beta cells in T1D and T2D
Cooperative Agreement U01DK134995
worth $2,160,395
from the National Institute of Diabetes and Digestive and Kidney Diseases in September 2022 with work to be completed primarily in Pennsylvania United States.
The grant
has a duration of 3 years 9 months and
was awarded through assistance program 93.847 Diabetes, Digestive, and Kidney Diseases Extramural Research.
The Cooperative Agreement was awarded through grant opportunity High-Resolution Exploration of the Human Islet Tissue Environment [HIRN Human Pancreas Analysis Consortium (HPAC)] (U01 - Clinical Trial Not Allowed).
Status
(Ongoing)
Last Modified 8/20/24
Period of Performance
9/19/22
Start Date
6/30/26
End Date
Funding Split
$2.2M
Federal Obligation
$0.0
Non-Federal Obligation
$2.2M
Total Obligated
Activity Timeline
Subgrant Awards
Disclosed subgrants for U01DK134995
Transaction History
Modifications to U01DK134995
Additional Detail
Award ID FAIN
U01DK134995
SAI Number
U01DK134995-2368579777
Award ID URI
SAI UNAVAILABLE
Awardee Classifications
Private Institution Of Higher Education
Awarding Office
75NK00 NIH NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
Funding Office
75NK00 NIH NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
Awardee UEI
GM1XX56LEP58
Awardee CAGE
7G665
Performance District
PA-90
Senators
Robert Casey
John Fetterman
John Fetterman
Budget Funding
| Federal Account | Budget Subfunction | Object Class | Total | Percentage |
|---|---|---|---|---|
| National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Health and Human Services (075-0884) | Health research and training | Grants, subsidies, and contributions (41.0) | $1,479,876 | 100% |
Modified: 8/20/24