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C. officinalis induction of Nrf2 inhibiting type 1 diabetes

Award Number: R01AT011907
ORGANIZATION: CENTER FOR DRUG EVALUATION AND RESEARCH, NIH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/25/2024
PERIOD OF PERFORMANCE END DATE: 12/31/2028

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C. officinalis induction of Nrf2 inhibiting type 1 diabetes - 7. Project Summary/Abstract Type 1 diabetes (T1D) is an autoimmune disease initiated by genetic predisposition and environmental influences culminating in the destruction of pancreatic β-cells with irreversible loss of insulin production. Despite strong predictive biomarkers of T1D, there is no cure and only one recently approved interventional therapy with moderate effects. Therefore, identification and development of novel T1D interventional therapeutics are needed and explored in this proposal. A potential source for novel interventional therapies is from the frequently used Cornus officinalis (CO) in the field of ethnopharmacology. We have recently shown that CO could inhibit cytokine mediated pancreatic β-cell death, promote cell viability/oxidative capacity, and increase expression of critical transcription factors necessary for pancreatic β- cell function (Mol.Cell.Endo.2019:494:110491). Our recent in vitro proteomic examination of CO stimulation of 1.1B4 cells revealed activation of the Keap1/Nrf2 pathway in the 1.1B4 pancreatic β-cell line (Mol.Cell.Endo.2022:557:111773). Specifically, we have shown that CO induces Nrf2 nuclear translocation along with increased protein expression of Nrf2-stimulated antioxidant genes such as Glutathione reductase (GR), Glutamate-cysteine ligase catalytic (GCLC), Heme Oxygenase-1 (HO-1) and Superoxide dismutase 2 (SOD2) along with others. To determine feasibility of a CO interventional approach in NOD mice, we performed a small- scale preliminary study examining if oral delivery of CO by gavage could be well tolerated and safely delivered daily. Ten wk. old female NOD male mice were given CO or water by oral gavage for 14 wks. once daily 5 days per wk. No detrimental effects were observed and mice in all treatment groups grew to similar sizes. In addition, diabetic onset, appearance of hyperglycemia (single glucose reading >130 mg/dl) and pancreatic insulitis was significantly inhibited in the CO treated NOD mice. Based on our findings, we hypothesize that CO can promote pancreatic β-cell viability via stimulation of the KEAP1/Nrf2 pathway to inhibit the progression of T1D. The hypothesis will be examined by the following specific aims: • Aim 1: Determine the effect of CO on T1D pathogenesis in the NOD mouse. • Aim 2: Measure the impact of CO on the KEAP1/Nrf2 pathway in primary islets. • Aim 3: Examine if Nrf2 activation is necessary for CO induced biological effects in the NOD. Our proposal will employ an interdisciplinary approach with combined expertise from an established research team to address a significant need for T1D treatment. The overall experimental design is innovative and will utilize state of the art proteomic technology in combination with in-vivo and in-vitro methods to reveal the pharmacological action of CO to serve as a novel supplemental interventional preventative treatment of T1D to promote β-cell survival and delay clinical progression.


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: 2026 ( Subtotal = $367,365 )
2026	2026	UNIVERSITY OF SOUTH FLORIDA	4202 E FOWLER AVE	TAMPA	FL	33620	HILLSBOROUGH	USA	Research and Training in Complementary and Integrative Health	000	3	3/24/2026	NON-COMPETING CONTINUATION	$367,365
														Subtotal = $367,365

Issue Date FY: 2025 ( Subtotal = $331,231 )
2025	2025	UNIVERSITY OF SOUTH FLORIDA	4202 E FOWLER AVE	TAMPA	FL	33620	HILLSBOROUGH	USA	Research and Training in Complementary and Integrative Health	000	2	12/9/2024	NON-COMPETING CONTINUATION	$331,231
														Subtotal = $331,231

Issue Date FY: 2024 ( Subtotal = $368,617 )
2024	2024	UNIVERSITY OF SOUTH FLORIDA	4202 E FOWLER AVE	TAMPA	FL	33620	HILLSBOROUGH	USA	Research and Training in Complementary and Integrative Health	000	1	3/25/2024	NEW	$368,617
														Subtotal = $368,617

Grand Total All Awards = $1,067,213

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C. officinalis induction of Nrf2 inhibiting type 1 diabetes

Award Number: R01AT011907

ORGANIZATION: CENTER FOR DRUG EVALUATION AND RESEARCH, NIH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/25/2024

PERIOD OF PERFORMANCE END DATE: 12/31/2028

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