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Regulation of TRPM7 channel kinase under hypo and hypermagnesemic conditions.

Award Number: R15AI202918
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/02/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2029

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Regulation of TRPM7 channel kinase under hypo and hypermagnesemic conditions. - PROJECT SUMMARY T lymphocyte activation and proliferation is essential for the human adaptive immune response. Calcium and magnesium signaling pathways play a crucial role in this process, and their defects result in various forms of immunodeficiency and muscle disorders. ~25% of the U.S. population is magnesium deficient, which compromises immune response among other pathways. Thus, it is urgent to fully understand these understudied pathways and their impact on immune function. Hypermagnesemia, often accompanies kidney injury and disease. Several players involved in calcium and magnesium transport have been identified at the molecular level. One of them, TRPM7, a protein with dual ion channel and serine/threonine kinase function, is permeable to both calcium and magnesium. It is regulated by intracellular ionized magnesium. TRPM7 is highly expressed in immune cells and is required for T-cell development and activation of macrophages. Because of the channel- enzyme duality of TRPM7, overexpression or knockdown of the full gene do not address whether ion flux or phosphotransferase activity underlies observed phenotypes. Global knockout of TRPM7 gene in mice results in embryonic lethality. In order to examine TRPM7 ion transport and kinase functions separately, we have generated a novel heterozygous mouse model, stemming from our recent biophysical studies of magnesium and pH sensitivity. Under normal or hypermagnesemic conditions, the majority of TRPM7 channels are inhibited by cytoplasmic magnesium, whereas the kinase is constitutively active. In the new mutant mouse, a single amino acid substitution in TRPM7 reduced the channel’s magnesium sensitivity, making the channels constitutively active. In this proposal, we aim to investigate the contribution of TRPM7 channel activity to T-cell and macrophage function under normal, hypo and hypermagnesemic conditions. As extracellular magnesium levels strongly influence immune cells, we will determine whether TRPM7 channel serves as the main magnesium entry pathway, or the kinase is responsible for the cellular phenotype. We propose these Specific Aims: Aim 1: Generate and characterize a TRPM7 channel mutant mouse model to elucidate TRPM7 channel/kinase signaling in macrophages and lymphocytes, which are critical immune responders. Aim 2: Investigate TRPM7 channel and kinase properties in conditions of Mg2+ deficiency and excess. Aim 3: Define Mg2+ and cytotoxic divalent metal cation entry, which can impact the immune response. Completion of these Aims are expected to characterize the import of magnesium balance/sufficiency in several pathways vital to human health, including immune function.


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 = $540,878 )
2026	2026	WRIGHT STATE UNIVERSITY	3640 COLONEL GLENN HWY	DAYTON	OH	45435	GREENE	USA	Allergy and Infectious Diseases Research	000	1	9/2/2026	NEW	$540,878
														Subtotal = $540,878

Grand Total All Awards = $540,878

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Regulation of TRPM7 channel kinase under hypo and hypermagnesemic conditions.

Award Number: R15AI202918

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/02/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2029

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