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Mechanism of Proteotoxicity and Experimental Therapeutic Approaches in Porphyria

Award Number: R01DK116548
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/20/2017
PERIOD OF PERFORMANCE END DATE: 02/28/2027

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Mechanism of Proteotoxicity and Experimental Therapeutic Approaches in Porphyria - Project Summary Porphyrias are genetic disorders caused by mutations in enzymes involved in eight sequential biosynthetic conversions that combine glycine and succinyl coenzyme-A in the first enzymatic step to ultimately generate heme. Porphyrin accumulation also occurs in ‘secondary porphyrias’ in association with other diseases such as hepatitis C virus infection. Current major unmet needs with regard to the porphyria disorders include: (a) our present limited understanding of the biochemical mechanism of cell and tissue injury, (b) the molecular triggers of porphyria acute attacks, (c) the reasons why some individuals develop significant organ complications such as end-stage liver disease that requires liver or bone marrow transplantation, while others do not, and (d) the limited availability of drugs to treat the different porphyrias. Our central hypothesis is that the liver is susceptible to light-independent porphyrin-mediated proteotoxic damage that leads to cell and tissue injury in porphyria, and that drugs can be identified that lead to increased or decreased porphyrin accumulation. This hypothesis will be tested by pursuing three interconnected specific aims: (i) Define the mechanism of light-independent porphyrin- induced protein aggregation in internal organs, with a focus on the liver; (ii) Elucidate the mechanism of detoxification of porphyrin-induced proteotoxic damage using in vitro and in vivo models; and (iii) Characterize small molecules that decrease or increase tissue porphyrin accumulation and porphyrin-mediated proteotoxicity. We have assembled extensive preliminary results to support the likely success of our aims, including substantial evidence for porphyrin-mediated protein aggregation that is light-independent, the reversibility of protein aggregation and enzymes that are likely to be involved in reversing protein oxidation, and the use of zebrafish high-throughput screening to identify known drugs that decrease or increase porphyrin accumulation in liver. The drugs that decrease porphyrin accumulation will be tested for their mechanism of action and examined in preclinical porphyria experimental models as drugs that may be repurposed as potential new therapies. In parallel, drugs that increase porphyrin accumulation will be characterized as potential candidate drugs to avoid in patients with porphyria. Completion of our proposed aims provides fundamental knowledge regarding which proteins are prone to porphyrin-mediated oxidation and aggregation, the molecular signatures that define such aggregation, the mechanism of aggregate turnover and disaggregation, whether compounds we characterize are candidates for testing in patients with porphyria, and whether currently used drugs in non-porphyria disorders might need to be avoided or monitored in patients with porphyria. This proposal uses state-of-the-art technologies, multiple biochemical and porphyria animal model tools including zebrafish and mice, and introduces the novel concept of proteotoxicity as an alternative mechanism for porphyria exacerbations and progression that may shed light on genetic modifiers that account for liver disease progression in some patients but not others.


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: 2025 ( Subtotal = $446,614 )
2025	2025	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	7	4/4/2025	NON-COMPETING CONTINUATION	$446,614
														Subtotal = $446,614

Issue Date FY: 2024 ( Subtotal = $476,387 )
2024	2024	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	6	5/20/2024	NON-COMPETING CONTINUATION	$29,773
2024	2024	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	6	2/9/2024	NON-COMPETING CONTINUATION	$446,614
2024	2023	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	004	5	7/22/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$6,539
2024	2022	RUTGERS, THE STATE UNIVERSITY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	4	7/22/2024	COMPETING CONTINUATION	-$6,539
2024	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	11/9/2023	COMPETING CONTINUATION	$0
														Subtotal = $476,387

Issue Date FY: 2023 ( Subtotal = $496,238 )
2023	2023	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	3/29/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$496,238
														Subtotal = $496,238

Issue Date FY: 2022 ( Subtotal = $496,238 )
2022	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	4	3/8/2022	COMPETING CONTINUATION	$496,238
2022	2019	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	10/27/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $496,238

Issue Date FY: 2020 ( Subtotal = $0 )
2020	2018	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	12/16/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $452,565 )
2019	2019	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	675 HOES LN	PISCATAWAY	NJ	08854	MIDDLESEX	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	9/2/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$452,565
2019	2018	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	8/31/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $452,565

Issue Date FY: 2018 ( Subtotal = $496,478 )
2018	2018	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	7/31/2018	NON-COMPETING CONTINUATION	$496,478
														Subtotal = $496,478

Issue Date FY: 2017 ( Subtotal = $450,148 )
2017	2017	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	9/16/2017	NEW	$450,148
														Subtotal = $450,148

Grand Total All Awards = $3,314,668

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Mechanism of Proteotoxicity and Experimental Therapeutic Approaches in Porphyria

Award Number: R01DK116548

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/20/2017

PERIOD OF PERFORMANCE END DATE: 02/28/2027

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