Wednesday, April 17, 2024 4/17/2024

Targeting an atypical signaling hub to restore and protect whole body glucose homeostasis

Award Number: R01DK102233
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary/Abstract – Type 2 diabetes (T2D) has now reached epidemic proportions worldwide. During pre-diabetes, blood sugars rise and the risk of cardiovascular consequences, such as stroke, myocardial infarction and mortality, is already increasing by 2-4-fold. Despite this, there remains a fundamental gap in understanding how and why pre-diabetes develops. Strategies to halt or reverse T2D development require a multi-pronged approach, since the pathophysiology involves both dysfunction in pancreatic ß-cell glucose- stimulated insulin release, and in skeletal muscle (skm) glucose uptake/clearance from the circulation. Factors linked to failures in both processes are considered optimal therapeutic targets. We have identified the p21- activated kinase, PAK1, as such a factor; it is a signaling hub in both the ß-cells and skm that orchestrates multiple aspects of glucose homeostasis. PAK1 is deficient in T2D, suggesting that its loss may be a “roadblock” that prevents normal signaling in T2D. To overcome the roadblock of PAK1 deficiency, we need to understand the mechanisms linking PAK1 to its functions in ß-cells and skm. Our long-term goal is to understand how ß-cell and skm signaling can be manipulated to prevent or reverse pre-diabetes and halt the progression to T2D. Our central hypothesis is that 1) signaling through the PAK1 hub in the ß-cell controls functional ß-cell mass to reverse HFD-induced glucose intolerance, and that 2) PAK1 signals in skm confer protection from insulin resistance and engage in tissue crosstalk to enhance ß-cell function. The rationale for the proposed research is that once these new mechanisms of the PAK1 effectors are elucidated, select signaling pathways from the PAK1 hub can be manipulated to prevent or reverse T2D. During the last funding cycle, we revealed that restoring PAK1 in T2D human islet ß-cells reverses dysfunctional insulin secretion while reducing ß-cell mitochondrial dysfunction and apoptosis. We also showed that PAK1 enrichment in skm protects against HFD-induced glucose intolerance, and engages in tissue crosstalk to improve ß-cell function. Our provocative new preliminary data also indicate which PAK1 effectors carry out these essential functions. Therefore, the objective of this application is to test these candidate mechanisms linking PAK1 effector enrichment and protection of ß-cells and skm from diabetogenic stress and to evaluate candidate PAK1 effector enrichment therapeutics. We will use our inducible tissue-specific mouse models and human tissues/cells for these studies. In Aim 1, we will identify how the PAK1 effectors restore ß-cell function; in Aim 2, we will elucidate the mechanism(s) by which PAK1-effectors protect ß-cell mass; in Aim 3, we will discern the mechanisms by which skm PAK1 contributes to peripheral insulin sensitivity and ß-cell health. We will use innovative molecular tools to test novel hypotheses about these PAK1 effector actions in the context of a translation-focused institutional environment at City of Hope. This work will positively impact diabetes research by evaluating a promising candidate strategy to reverse pre-diabetes and halt progression to T2D and by uncovering novel mechanisms of glucose homeostasis.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $396,000 )
2024	2024	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	8	11/22/2023	NON-COMPETING CONTINUATION	$396,000
														Subtotal = $396,000

Issue Date FY: 2023 ( Subtotal = $440,000 )
2023	2023	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	7	11/28/2022	NON-COMPETING CONTINUATION	$396,000
2023	2023	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	7	1/9/2023	NON-COMPETING CONTINUATION	$44,000
														Subtotal = $440,000

Issue Date FY: 2022 ( Subtotal = $440,000 )
2022	2022	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	6	11/24/2021	NON-COMPETING CONTINUATION	$396,000
2022	2022	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	6	4/21/2022	NON-COMPETING CONTINUATION	$44,000
2022	2021	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	11/10/2021	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $440,000

Issue Date FY: 2021 ( Subtotal = $483,949 )
2021	2021	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	12/3/2020	COMPETING CONTINUATION	$440,000
2021	2021	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	5	5/21/2021	SUPPLEMENT FOR EXPANSION	$43,949
														Subtotal = $483,949

Issue Date FY: 2017 ( Subtotal = $382,500 )
2017	2017	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	7/31/2017	NON-COMPETING CONTINUATION	$382,500
														Subtotal = $382,500

Issue Date FY: 2016 ( Subtotal = $482,819 )
2016	2016	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1450 EAST DUARTE ROAD	DUARTE	CA	91010	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	7/21/2016	NON-COMPETING CONTINUATION	$382,500
2016	2014	INDIANA UNIVERSITY, BLOOMINGTON	509 EAST 3RD STREET	BLOOMINGTON	IN	47405	MONROE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	6/27/2016	NEW	$100,319
														Subtotal = $482,819

Issue Date FY: 2015 ( Subtotal = $282,181 )
2015	2015	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1450 EAST DUARTE ROAD	DUARTE	CA	91010	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	8/20/2015	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$382,500
2015	2014	INDIANA UNIVERSITY, BLOOMINGTON	509 EAST 3RD STREET	BLOOMINGTON	IN	47405	MONROE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	8/19/2015	NEW	-$100,319
														Subtotal = $282,181

Issue Date FY: 2014 ( Subtotal = $347,808 )
2014	2014	INDIANA UNIVERSITY, BLOOMINGTON	509 EAST 3RD STREET	BLOOMINGTON	IN	47405	MONROE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	9/12/2014	NEW	$347,808
														Subtotal = $347,808

Grand Total All Awards = $3,255,257

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Targeting an atypical signaling hub to restore and protect whole body glucose homeostasis

Award Number: R01DK102233

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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