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Decoding regulation of glucose homeostasis and metabolic responses to mitochondrial stress by AMPK

Award Number: F32DK126418
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

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Project Summary/Abstract High fasting plasma glucose and body mass index ranked 3rd and 4th, respectively, as global mortality risk factors in 2017. Metabolic dysfunction links these factors with modern disease epidemics such as Type 2 diabetes (T2D). Many current therapies and therapeutic development programs focus on symptoms rather than underlying metabolic dysfunction common among these diseases. A primary goal of this work is to define mechanisms driving maladaptive metabolism to develop more effective therapeutic strategies with potential for multi-disease applicability. Mitochondrial impairments (e.g. inefficient oxidative metabolism and insufficient mitochondrial quality control) are hypothesized as major pathologic components in these diseases. Therefore, understanding mechanisms of mitochondrial regulation in conjunction with defective metabolism in diseases is a means towards improving disease treatments going forward. AMP-activated protein kinase (AMPK) is a central regulator of cell metabolism and multiple aspects of mitochondrial biology. Deficient AMPK signaling often overlaps the pathological profile of mitochondrial impairments in disease. However, understanding whole-body effects of deficient AMPK signaling as a multi-faceted driver of metabolic dysfunction and disease has been hampered by lack of viable mammalian models. Organ-specific loss of AMPK mouse models have been critical for dissection of metabolic implications of AMPK for individual cell types in vivo, but do not address multi-organ defects in AMPK signaling that has been associated with insulin resistance and T2D. Additionally, developmental whole- body knockout of AMPKa1 and AMPKa2 catalytic subunits (AMPK-DKO) causes in utero lethality in mice. To address these issues, the first mouse model for inducible, whole-body AMPK-DKO (iAMPK-DKO) has been generated. This model circumvents lethality of developmental AMPK-DKO and recapitulates disease-relevant multi-organ defects in AMPK signaling. Preliminary data from this model demonstrate deficient glucose homeostasis that is relevant to the study of T2D including postabsorptive hyperglycemia and glucose intolerance as well as a seemingly paradoxical fasting induced hypoglycemia. Additionally, combining iAMPK-DKO with genetically induced chronic mitochondrial stress in mice results in unique metabolic profiles, which are likely relevant to glucose control. The PI for this project has extensive expertise with decoding in vivo metabolic physiology. Combining this expertise with assessment of organ-specific mitochondrial function in acutely isolated primary models, culture of organ-specific primary cells, molecular manipulation of gene expression, and confocal microscopy of cellular systems will enable testing of this proposal’s central hypothesis: AMPK preserves mitochondrial metabolism to maintain normal physiologic glucose homeostasis and enables metabolic flexibility to preserve glucose homeostasis during chronic mitochondrial stress. Testing this hypothesis offers insight in to the role of AMPK in glucoregulatory physiology and begins to decode the mechanisms by which AMPK supports glucose homeostasis in normal physiology and pathologic mitochondrial stress.


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 = -$23,913 )
2024	2023	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	3/15/2024	NON-COMPETING CONTINUATION	-$23,913
														Subtotal = -$23,913

Issue Date FY: 2023 ( Subtotal = $71,792 )
2023	2023	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	11/25/2022	NON-COMPETING CONTINUATION	$69,802
2023	2023	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	3/7/2023	NON-COMPETING CONTINUATION	$1,990
														Subtotal = $71,792

Issue Date FY: 2022 ( Subtotal = $67,582 )
2022	2022	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	2	5/26/2022	NON-COMPETING CONTINUATION	$1
2022	2022	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	4/21/2022	NON-COMPETING CONTINUATION	$1,191
2022	2022	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	11/18/2021	NON-COMPETING CONTINUATION	$66,390
														Subtotal = $67,582

Issue Date FY: 2020 ( Subtotal = $64,926 )
2020	2020	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	9/3/2020	NEW	$64,926
														Subtotal = $64,926

Grand Total All Awards = $180,387

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Decoding regulation of glucose homeostasis and metabolic responses to mitochondrial stress by AMPK

Award Number: F32DK126418

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

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