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Regulation of lymphatic muscle cell function by store operated calcium entry signaling

Award Number: R01HL175083
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2024
PERIOD OF PERFORMANCE END DATE: 06/30/2029

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Regulation of lymphatic muscle cell function by store operated calcium entry signaling - PROJECT SUMMARY Secondary lymphedema poses a significant financial and health burden afflicting 1 in 1000 Americans, resulting in a debilitating and incurable swelling and fibrosis in the affected extremity or tissue. The prevailing hypothesis for the pathogenesis of secondary lymphedema posits a role for lymphatic collecting vessel (cLV) pump failure in response to elevated lymphatic pressures observed in LE patients, and points to a deficit in lymphatic muscle cell (LMC) function. The process by which LMCs regulate pressure-dependent pacemaking, contractility, and transcriptional regulation are critically dependent on inositol triphosphate receptor 1 (IP3R1)-dependent Ca2+ oscillations, although the mechanisms that sustain LMC Ca2+ homeostasis remain unexplored. The central goal of this proposal is to address this knowledge gap and determine how LMC Ca2+ dynamics regulate contractile activity and transcriptional adaptation to ensure fluid transport homeostasis. The Ca2+ source that refills the store has been assumed to be only voltage-gated L-type channels, however our preliminary studies identified the novel expression of the SR Ca2+ sensor proteins Stim1 and Stim2 as well as the plasma membrane (PM) Ca2+ channels Orai1 and Orai3 in healthy LMCs, which are the critical components of store operated Ca2+entry (SOCE). Our preliminary findings also show functional SOCE in healthy LMCs in response to store depletion and that LMC Ca2+ oscillations are lost when SOCE is inhibited. Intriguingly, robust SOCE activation by excessive vasocontractile agonist signaling or SR Ca2+ leak drives cLVs into a contractile rigor and thus may contribute to lymphatic dysfunction. This led us to hypothesize that SOCE is a key modulator of lymphatic muscle cell function. We proposed the following aims to determine the role of SOCE in the regulation of lymphatic contractility and transcriptional regulation. Specific Aim1: Assess SR-PM junction formation and SOCE activity in LMCs. Specific Aim2: Determine the contribution of SOCE to pressure-dependent LMC pacemaking and contractility. Specific Aim3: Investigate the mechanisms by which IP3R1- Ca2+ oscillations and SOCE regulate LMC contractile protein expression through Ca2+-dependent transcription factor activation such as nuclear factor of activated T cells (NFATs). This project will provide novel information about the role of SOCE as a fundamental Ca2+ homeostatic mechanism in LMCs and the degree to which SOCE is required for acute and chronic cLV adaptation to pressure. These results will identify novel targets for pharmacological intervention in LE patients and may shed light on cLV contractile dysfunction reported in obesity, diabetes, and hypertension.


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 = $566,328 )
2025	2025	UNIVERSITY OF MISSOURI SYSTEM	121 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Cardiovascular Diseases Research	000	2	7/18/2025	NON-COMPETING CONTINUATION	$566,328
														Subtotal = $566,328

Issue Date FY: 2024 ( Subtotal = $587,042 )
2024	2024	UNIVERSITY OF MISSOURI SYSTEM	121 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Cardiovascular Diseases Research	000	1	5/15/2024	NEW	$587,042
2024	2024	UNIVERSITY OF MISSOURI SYSTEM	121 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Cardiovascular Diseases Research	001	1	5/21/2024	NEW	$0
														Subtotal = $587,042

Grand Total All Awards = $1,153,370

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Regulation of lymphatic muscle cell function by store operated calcium entry signaling

Award Number: R01HL175083

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2024

PERIOD OF PERFORMANCE END DATE: 06/30/2029

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