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Roles for Intracellular pH Dynamics in Cancer Cell Behaviors

Award Number: SC3GM132049
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: 06/11/2019
PERIOD OF PERFORMANCE END DATE: 05/31/2024

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Roles for Intracellular pH Dynamics in Cancer Cell Behaviors - Project Summary Constitutively increased intracellular pH (pHi) is common to most cancers regardless of tissue origin or genetic background. Increased pHi is necessary for survival of patient-derived tumor cells, and is sufficient to induce oncogenic phenotypes, including dysregulated tissue growth, dysplasia, and invasive cell migration. pH-regulated cell behaviors are predominantly mediated by changes in the protonation state of pH sensitive proteins, or pH sensors, which is viewed as a post-translational modification which cannot be resolved by mass spectrometry or antibodies. At the molecular level, changes in pHi can alter the protonation state of selective amino acid residues with pKa values near neutral, which can markedly affect protein conformations and function. By changing the protonation of multiple proteins in unison, pHi dynamics can coordinate complex cell processes. Although understudied, emerging evidence suggests that the higher pHi of most cancers contributes to pathogenesis. In this proposal, we will characterize pH sensitive cancer cell behaviors and identify pH sensors that regulate proliferation (Aim 1), programmed cell death (Aim 2) and metastasis (Aim 3). Using the genetic model organism Drosophila, we will bridge scales from tissue-level phenotypic analyses to individual pH-sensitive proteins that regulate these cancer cell behaviors. We will use cutting edge technologies including fluorescent cell cycle and apoptosis markers, genetically encoded pH bio-sensors, and quantitative imaging techniques to generate 3-D maps of intratumoral pHi. Our unpublished data with genetic modifier screens identified a number of candidate pH sensors with known roles in regulating these processes. We will test predictions on the pH-sensitive function of these candidate pH sensors. Significant outcomes from our studies include new insights on how pH-regulated cellular behaviors enable tumorigenesis and metastasis. The strengths of the PI in linking tissue-level phenotypes to individual pH-sensitive molecules permit unique insights in this under-studied area of biology. Further, understanding the molecular mechanisms of pH-sensitive proteins will inform novel therapeutic approaches to limit cancer 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: 2025 ( Subtotal = -$229 )
2025	2022	SAN JOSE STATE UNIVERSITY RESEARCH FOUNDATION	210 N 4TH ST FL 4	SAN JOSE	CA	95112	SANTA CLARA	USA	Biomedical Research and Research Training	000	4	11/26/2024	NON-COMPETING CONTINUATION	-$229
														Subtotal = -$229

Issue Date FY: 2022 ( Subtotal = $109,875 )
2022	2022	SAN JOSE STATE UNIVERSITY RESEARCH FOUNDATION	210 4TH ST 3RD FL	SAN JOSE	CA	95112	SANTA CLARA	USA	Biomedical Research and Research Training	000	4	5/19/2022	NON-COMPETING CONTINUATION	$109,875
														Subtotal = $109,875

Issue Date FY: 2021 ( Subtotal = $109,875 )
2021	2021	SAN JOSE STATE UNIVERSITY RESEARCH FOUNDATION	210 4TH ST 3RD FL	SAN JOSE	CA	95112	SANTA CLARA	USA	Biomedical Research and Research Training	000	3	5/20/2021	NON-COMPETING CONTINUATION	$109,875
														Subtotal = $109,875

Issue Date FY: 2020 ( Subtotal = $109,844 )
2020	2020	SAN JOSE STATE UNIVERSITY RESEARCH FOUNDATION	210 FOURTH ST 4TH FL	SAN JOSE	CA	95112	SANTA CLARA	USA	Biomedical Research and Research Training	000	2	4/27/2020	NON-COMPETING CONTINUATION	$109,844
														Subtotal = $109,844

Issue Date FY: 2019 ( Subtotal = $83,669 )
2019	2019	SAN JOSE STATE UNIVERSITY RESEARCH FOUNDATION	210 FOURTH ST 4TH FL	SAN JOSE	CA	95112	SANTA CLARA	USA	Biomedical Research and Research Training	000	1	6/11/2019	NEW	$83,669
														Subtotal = $83,669

Grand Total All Awards = $413,034

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Roles for Intracellular pH Dynamics in Cancer Cell Behaviors

Award Number: SC3GM132049

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: 06/11/2019

PERIOD OF PERFORMANCE END DATE: 05/31/2024

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