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Developing MRI contrast agents to detect progression in renal disease as a consequence of acidema

Award Number: R01DK121847
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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Organic acidemias are a class of inborn metabolic disorders which disrupt amino acid metabolism and lead to abnormal accumulation of organic acids detectable in blood, urine and other biomaterials. While individually rare, collectively these disorders have a significant impact on children’s health. Chronic Kidney Disease (CKD) is a cardinal feature of several organic acidemias, and patients require routine monitoring of kidney function to manage their treatment. Methylmalonic Acidemia (MMA) is an organic acidemia with a frequency of 1/50,000 to 1/100,000 caused by mutations in methylmalonyl-CoA mutase (Mut) with a predictable evolution to CKD. In fact, CKD is developed at a median onset age of 6.5 y in MMA patients who are at high risk of developing renal insufficiency. Unfortunately, current methods for monitoring renal health which include measuring blood creatinine and blood nitrogen urea are not reliable for MMA patients. An alternative strategy is to administer MRI contrast agents to acquire functional information on the kidneys. This proposal involves administering well tolerated, organic compounds which create MRI contrast through Chemical Exchange Saturation Transfer (CEST). An attractive feature of this mechanism is that it enables production of pH maps which reflect the environment surrounding the agents and might be particularly useful for the kidneys, organs which control the acid-base balance of the body. We will design CEST pH sensors which can monitor progression towards CKD through changes in pH and perfusion, and will provide a reliable indicator of the overall health of the kidneys. In Aim 1, we will synthesize a set of imidazole-4,5-dicarboxyamide probes to provide pH sensitive MRI contrast. The proton exchange rates and resulting CEST contrast will be quantified as a function of pH in buffered solutions to determine the performance of these in vitro. We will also optimize our pH and perfusion imaging protocol and characterize the pharmacokinetics using C57BL/6 control mice. In Aim 2, we will evaluate the sensitivity of our best agents from Aim 1 for detecting the extent of renal disease in the C57BL/6 Mut-/-;TgINS-Alb-Mut mouse model of MMA and validate the pH measurements using ISUCA. C57BL/6 Mut-/-;TgINS-Alb-Mut mice manifest chronic tubulointerstitial nephritis and a decreased glomerular filtration rate (GFR) which is initiated by placing the mice on a high protein (HP) diet for 2 months. In Aim 3, we will test our best sensor on six groups of mice with three groups treated with sodium citrate through diet supplementation and three more with CoQ10 + Vitamin E supplemented into their diets. The groups will also include three different timings for the high protein challenge which induces kidney injury. We expect our new agents and imaging protocols could provide an earlier detection of CKD without need of invasive kidney biopsy. This is particularly critical in conditions where standard monitoring methods are not feasible, such as MMA.


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 = $395,652 )
2023	2023	HUGO W. MOSER RESEARCH INSTITUTE AT KENNEDY KRIEGER, INC.	707 N BROADWAY	BALTIMORE	MD	21205	BALTIMORE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	1/30/2023	NON-COMPETING CONTINUATION	$395,652
														Subtotal = $395,652

Issue Date FY: 2022 ( Subtotal = $395,652 )
2022	2022	HUGO W. MOSER RESEARCH INSTITUTE AT KENNEDY KRIEGER, INC.	707 N BROADWAY	BALTIMORE	MD	21205	BALTIMORE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	1/14/2022	NON-COMPETING CONTINUATION	$356,086
2022	2022	HUGO W. MOSER RESEARCH INSTITUTE AT KENNEDY KRIEGER, INC.	707 N BROADWAY	BALTIMORE	MD	21205	BALTIMORE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	4/13/2022	NON-COMPETING CONTINUATION	$39,566
														Subtotal = $395,652

Issue Date FY: 2021 ( Subtotal = $395,652 )
2021	2021	HUGO W. MOSER RESEARCH INSTITUTE AT KENNEDY KRIEGER, INC.	707 N BROADWAY	BALTIMORE	MD	21205	BALTIMORE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	3/3/2021	NON-COMPETING CONTINUATION	-$15,455
2021	2021	HUGO W. MOSER RESEARCH INSTITUTE AT KENNEDY KRIEGER, INC.	707 N BROADWAY	BALTIMORE	MD	21205	BALTIMORE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	2/1/2021	NON-COMPETING CONTINUATION	$411,107
														Subtotal = $395,652

Issue Date FY: 2020 ( Subtotal = $426,396 )
2020	2020	HUGO W. MOSER RESEARCH INSTITUTE AT KENNEDY KRIEGER, INC.	707 N BROADWAY	BALTIMORE	MD	21205	BALTIMORE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	3/20/2020	NEW	$426,396
														Subtotal = $426,396

Grand Total All Awards = $1,613,352

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Developing MRI contrast agents to detect progression in renal disease as a consequence of acidema

Award Number: R01DK121847

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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