Thursday, July 3, 2025 7/3/2025

Conserved mechanisms of ciliary signaling and cell-cell fusion

Award Number: R01GM146162
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/20/2022
PERIOD OF PERFORMANCE END DATE: 06/30/2026

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Conserved mechanisms of ciliary signaling and cell-cell fusion - We propose to use fertilization in the green alga Chlamydomonas as a model system to investigate conserved but still poorly understood cellular and molecular mechanisms of ciliary signaling and the gamete membrane fusion reaction. When Chlamydomonas gametes of opposite mating types are mixed together they adhere to each other by complementary adhesion receptors on their cilia. Interactions between the adhesion receptors SAG1 on plus gametes and SAD1 on minus gametes initiate a signaling pathway that is transmitted to the cell body and triggers a rapid increase in cellular cAMP that activates the gamete for cell-cell fusion. Regulation of ciiliary cyclic nucleotides by ciliary receptor engagement has been conserved throughout evolution and in almost all ciliary signaling events in vertebrates, the primary response to engagement of ciliary receptor is a change in the concentration of cAMP within the organelles. Moreover, in most vertebrate ciliary systems, the mechanisms that transmit the increase in ciliary cAMP to a cellular response are unclear. We have discovered that a protein kinase, GSPK, in Chlamydomonas functions at a previously unrecognized step in ciliary signaling. GSPK is localized in the cytoplasm, not the cilia, yet the entire cellular complement of GSPK is phosphorylated within 1 minute after engagement of the ciliary adhesion receptors. Furthermore, GSPK phosphorylation is upstream of the cAMP increase and GSPK function is required for the rapid increase in cAMP. Our findings set the stage for new strategies to investigate cellular and molecular mechanisms that couple ciliary receptor engagement to a cytoplasmic response. We will use a combination of cell biological, biochemical, and imaging strategies to investigate the mechanisms underlying GSPK function. Gamete activation also activates erection of apically localized protrusions, the plus and minus mating structures, from the plasma membrane of each gamete that are the sites of membrane fusion during fertilization..We have made exciting advances in understanding conserved molecular mechanisms of the gamete membrane fusion reaction, and we now know more about cell- cell fusion in Chlamydomonas than is known in any other system. 1) We showed that bilayer merger of the two cells is driven by trimer formation of eukaryotic class II fusion protein, HAP2, a ancient protein required for fertilization in organisms across kingdoms. 2) We have now identified the separate cell-cell adhesion proteins s FUS1 and MAR1 at the fusion site of each cell. 3) We demonstrated that the adhesion protein MAR1 on minus gametes not only binds to FUS1 on plus gametes, but MAR1 is also biochemically and functionally linked to HAP2. 4) We showed that membrane adhesion mediated by FUS1-MAR1 interactions releases the restrained, prefusion form of HAP2, leading to the irreversible structural rearrangements into the fusion-driving HAP2 trimer. 5) In collaborative laboratory studies and field studies in Africa, we showed that targeting the conserved fusion loop of Plasmodium HAP2 inhibits the mosquito transmission of malaria. Our discoveries now make possible a detailed, structure- and function-based molecular dissection of ciliary signaling and gamete fusion..


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 = $561,600 )
2025	2025	UNIVERSITY OF MARYLAND, COLLEGE PARK	3112 LEE BUILDING	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Biomedical Research and Research Training	000	4	6/5/2025	NON-COMPETING CONTINUATION	$561,600
														Subtotal = $561,600

Issue Date FY: 2024 ( Subtotal = $561,602 )
2024	2024	UNIVERSITY OF MARYLAND, COLLEGE PARK	3112 LEE BUILDING	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Biomedical Research and Research Training	000	3	6/25/2024	NON-COMPETING CONTINUATION	$561,602
														Subtotal = $561,602

Issue Date FY: 2023 ( Subtotal = $682,474 )
2023	2023	UNIVERSITY OF MARYLAND, COLLEGE PARK	3112 LEE BLDG 7809 REGENTS DR	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Biomedical Research and Research Training	000	2	6/26/2023	NON-COMPETING CONTINUATION	$561,600
2023	2023	UNIVERSITY OF MARYLAND, COLLEGE PARK	3112 LEE BLDG 7809 REGENTS DR	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Biomedical Research and Research Training	001	2	9/14/2023	SUPPLEMENT FOR EXPANSION	$120,874
														Subtotal = $682,474

Issue Date FY: 2022 ( Subtotal = $558,000 )
2022	2022	UNIVERSITY OF MARYLAND, COLLEGE PARK	3112 LEE BLDG 7809 REGENTS DR	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Biomedical Research and Research Training	000	1	9/19/2022	NEW	$558,000
														Subtotal = $558,000

Grand Total All Awards = $2,363,676

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Conserved mechanisms of ciliary signaling and cell-cell fusion

Award Number: R01GM146162

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/20/2022

PERIOD OF PERFORMANCE END DATE: 06/30/2026

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