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The Regulation of Lymphatic Muscle Cell Pacemaking by Intracellular Calcium Signals

Award Number: R00HL143198
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2021
PERIOD OF PERFORMANCE END DATE: 07/31/2024

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The Regulation of Lymphatic Muscle Cell Pacemaking by Intracellular Calcium Signals - Project Summary/Abstract Lymphedema is a disease characterized by chronic edema of the afflicted tissue due to lymphatic insufficiency. Treatment for lymphedema is palliative and requires the use of compression bandages and manual lymph drainage to push fluid out of the afflicted tissue, which is normally accomplished by the intrinsic pumping activity of lymphatic collecting vessels (cLV). cLVs from lymphedema patients, however, display only irregular or absent pumping ability and therefore restoring this intrinsic pump activity is an ideal therapeutic goal. Currently the mechanisms that drive the pacemaking and initiation of cLV contraction have not been defined. My recent findings show that mouse, rat, and human lymphatic muscle cells (LMCs) exhibit a steady diastolic depolarization that determines contraction frequency, and is the basis of cLV pacemaking and autorhythmicity. In murine cLVs, this diastolic depolarization is pressure-dependent and is mediated by activation of a calcium activated chloride channel, Anoctamin1 (Ano1) during diastole. In other autorhythmic pacemaking cells, an intracellular sarcoendoplasmic reticulum (SR) calcium clock underlies electrical autorhythmicity through activation of calcium sensitive ion channels. Whether an SR calcium clock is present in LMCs or if SR calcium release through either inositol triphosphate receptors (Itprs) or ryanodine receptors (RyRs) regulates Ano1 and cLV pacemaking is unknown. This proposal seeks to test the hypothesis that a SR dependent calcium clock is critical for lymphatic muscle excitability and pressure dependent chronotropy, This proposal utilizes novel technical approaches to simultaneously monitor either cytosolic or SR calcium using genetically encoded calcium indicators, GCaMP6f and GCaMP1-ER respectively, while simultaneously recording membrane potential in LMCs of contracting murine cLVs from genetically modified mice. Aim 1 will determine how intra- lymphatic pressure regulates the LMC SR calcium clock by determining the frequency, amplitude, duration, and spread of spontaneous SR calcium transients, and the dynamics of the luminal SR calcium concentration across a physiological pressure range. Additionally, the use of inducible smooth muscle knockouts of RyR2 and Itpr1 in addition to over-active and under-active knock-in mutations in Itpr1 and RyR2 will elucidate the functional contribution of RyR2 and Itpr1 to the subcellular calcium transients observed during diastole. Aim2 will utilize freshly dispersed LMCs from these genetic models to perform simultaneous cytosolic calcium imaging and perforated patch clamp to determine the discrete electrical contribution of calcium release from either Itpr1 or RyR2 channels through coupling with Ano1 or other calcium sensitive membrane channels. These findings will provide critical knowledge regarding how a pharmaceutical strategy targeting the mechanisms underlying SR calcium dynamics could activate lymphatic pacemaking and improve lymphatic function in patients.


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 = -$10,372 )
2025	2023	UNIVERSITY OF MISSOURI SYSTEM	121 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Blood Diseases and Resources Research	000	5	12/16/2024	NON-COMPETING CONTINUATION	-$10,372
														Subtotal = -$10,372

Issue Date FY: 2023 ( Subtotal = $248,869 )
2023	2023	UNIVERSITY OF MISSOURI SYSTEM	121 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Blood Diseases and Resources Research	000	5	8/15/2023	NON-COMPETING CONTINUATION	$248,869
														Subtotal = $248,869

Issue Date FY: 2022 ( Subtotal = $259,279 )
2022	2022	UNIVERSITY OF MISSOURI SYSTEM	316 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Blood Diseases and Resources Research	001	4	7/29/2022	NON-COMPETING CONTINUATION	$248,907
2022	2021	UNIVERSITY OF MISSOURI SYSTEM	121 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Blood Diseases and Resources Research	000	3	12/21/2021	EXTENSION WITH OR WITHOUT FUNDS	$10,372
														Subtotal = $259,279

Issue Date FY: 2021 ( Subtotal = $248,868 )
2021	2021	UNIVERSITY OF MISSOURI SYSTEM	316 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Blood Diseases and Resources Research	000	3	7/19/2021	EXTENSION WITH OR WITHOUT FUNDS	$248,868
														Subtotal = $248,868

Grand Total All Awards = $746,644

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The Regulation of Lymphatic Muscle Cell Pacemaking by Intracellular Calcium Signals

Award Number: R00HL143198

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2021

PERIOD OF PERFORMANCE END DATE: 07/31/2024

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