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Neurotoxicity and nephrotoxicity of diglycolic acid: a model of calcium chelation-induced mitochondrial dysfunction

Award Number: R15ES029704
ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project summary/abstract Diethylene glycol (DEG) has produced many mass poisonings that have led to severe acute kidney injury, peripheral neuropathy, and >800 deaths throughout the world. Although DEG is a health concern in the US because it is found in easily available consumer products, its toxicity offers a unique aspect in the relationship between its nephrotoxicity and its neurotoxicity. Because the toxic mechanism is not well understood, the proposed studies relating the mechanism of the renal damage and that of the peripheral neuropathy will advance the field by increasing the knowledge of such damage-associated pathways. Our studies have definitively shown that the metabolite responsible for the renal damage is diglycolic acid (DGA), however its role in the neuropathy is not established. Mechanistic studies with DGA have shown that it produces mitochondrial dysfunction as an inhibitor of oxidative phosphorylation leading to ATP depletion and ultimately cell death. DGA has also been shown to chelate free calcium in a similar strength as known calcium chelator EGTA. Part of the mechanism of DGA-induced cell death might include chelation of intracellular calcium, thereby decreasing transport of energy-producing substrates into the mitochondria by the calcium- regulated protein aralar, which then can explain the decreased production of ATP by the electron transport We hypothesize that DGA exerts a detrimental change in intracellular calcium homeostasis by chelating cytosolic calcium stores, thus leading to mitochondrial dysfunction in both the kidney and in sensorimotor neurons. Development of efficacious therapy to counteract DGA toxicity is needed for better treatment of DEG poisoning, so this research is critical to determine the mechanism by which DGA is toxic and to be able to develop and test potential new therapies. Aim 1 will establish an animal model of the neurotoxicity of DEG and will characterize the toxicity profile of DGA in the brain and kidney as it pertains to calcium homeostasis and aralar-mediated mitochondrial dysfunction. Aim 2 will examine the effects of DGA on calcium homeostasis in the renal proximal tubule (HPT) cell model and kinetically relate these changes to DGA-mediated mitochondrial dysfunction. Aim 3 will relate alterations by DGA in calcium-related proteins to changes in calcium homeostasis and will examine changes in aralar levels in HPT cells to test whether such manipulations rescue effects of DGA toxicity. Outcome. These mechanistic studies will significantly impact the field of kidney and neuronal function by using a unique toxicological model (DGA accumulation) to assess common mechanisms of toxicity between the two tissues. These in vivo and in vitro studies will convincingly show that DGA produces organ damage by altering calcium- regulated uptake of energy substrates thereby leading to inhibition of mitochondrial function. AREA Impact. This project will offer area undergraduates an excellent research training experience and thus will enhance the research capacity of the NW Louisiana region.


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: 2023 ( Subtotal = -$4,139 )
2023	2018	LOUISIANA STATE UNIVERSITY	1501 KINGS HWY	SHREVEPORT	LA	71103	CADDO	USA	Environmental Health	000	1	3/16/2023	NEW	-$4,139
														Subtotal = -$4,139

Issue Date FY: 2018 ( Subtotal = $438,000 )
2018	2018	LOUISIANA STATE UNIVERSITY	1501 KINGS HWY	SHREVEPORT	LA	71103	CADDO	USA	Environmental Health	001	1	8/27/2018	NEW	$3,000
2018	2018	LOUISIANA STATE UNIVERSITY	1501 KINGS HWY	SHREVEPORT	LA	71103	CADDO	USA	Environmental Health	000	1	7/27/2018	NEW	$435,000
														Subtotal = $438,000

Grand Total All Awards = $433,861

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Neurotoxicity and nephrotoxicity of diglycolic acid: a model of calcium chelation-induced mitochondrial dysfunction

Award Number: R15ES029704

ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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