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Mechanotransduction in Intestinal Smooth Muscle Cells

Award Number: R01DK052766
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/1997
PERIOD OF PERFORMANCE END DATE: 02/28/2026

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Mechanotransduction in Intestinal Smooth Muscle Cells - PROJECT SUMMARY/ABSTRACT Coordinated gastrointestinal (GI) tract motility is fundamental for normal GI tract function. Several cell types combine to regulate GI motility, with the smooth muscle cell (SMC) as the workhorse required to provide the physical power for contractions. Disruptions in SMC function contribute to common GI disorders, may occur after infections and inflammation, and associate with rare but devastating GI motility disorders like visceral myopathies and pseudo-obstruction. The gut wall is a highly complex multilayered structure under mechanical stress at baseline and constantly moving. Therefore, cells in the GI tract experience a range of types and amounts of mechanical stimuli. The normal coordinated motility requires an ability to sense and adjust to forces. In multiple cycles of this grant, we have dissected mechanisms of smooth muscle mechanotransduction, have made discoveries that advanced GI physiology and pathophysiology, and provided novel drug targets. However, our current understanding of SMC mechanosensing remains incomplete. It is established that SMCs, even as single cells, adjust their contractions in response to force in a process called the myogenic reflex. In vascular SMCs, the myogenic reflex depends on mechanogated ion channels, but in the GI tract, cellular and molecular mechanisms remain poorly understood. Therefore, the overall objective of our research is to determine the primary mechanogated ion channels involved in GI SMC mechanosensitivity. For this proposal, we created novel animal models and used cutting-edge techniques to generate compelling preliminary data. Our preliminary studies show that a recently discovered mechanogated ion channel Tmem63a is expressed in a subpopulation of SMCs, which are optimized for force sensing and distributed across the tissue to detect force. Indeed mechanosensitive ionic currents in a population of primary mouse GI SMCs have unique biophysical properties consistent with Tmem63a, the activation of which by force leads to a Ca2+ increase, modulating small and large bowel contractions and whole gut transit time. Interestingly, our data also show that patients with slow transit constipation have a decrease in Tmem63a. Thus, the central hypothesis that a mechanogated ion channel Tmem63a significantly contributes to the myogenic reflex will be tested in two Aims. In Aim 1, we determine Tmem63a function, its response to force, and its role in GI SMCs using conventional and cutting-edge techniques electrophysiology and Ca2+ imaging approaches. In Aim 2, we propose experiments to define the Tmem63a+ SMC population and to determine the role of Tmem63a SMCs in regulating GI smooth muscle function. Since Tmem63a is found in a subpopulation of SMCs, we use single-cell and spatial transcriptomics, novel Ca2+ imaging, smooth muscle contractility assays and in vivo whole gut transit. Successful completion of the proposed innovative experiments has both basic significance and clinical impact, evaluating and establishing a novel SMC mechanogated ion channel which contributes to SMC function and the myogenic reflex and, in the long term, may provide a novel target for functional and motility GI disorders.


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 = $0 )
2026	2025	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	27	1/12/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $543,867 )
2025	2025	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	27	8/22/2025	NON-COMPETING CONTINUATION	$543,867
														Subtotal = $543,867

Issue Date FY: 2024 ( Subtotal = $505,556 )
2024	2024	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	26	5/8/2024	NON-COMPETING CONTINUATION	$505,556
														Subtotal = $505,556

Issue Date FY: 2023 ( Subtotal = $549,720 )
2023	2023	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	25	3/20/2023	NON-COMPETING CONTINUATION	$549,720
2023	2022	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	24	7/3/2023	COMPETING CONTINUATION	$14,820
2023	2021	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	23	7/3/2023	NON-COMPETING CONTINUATION	-$14,820
														Subtotal = $549,720

Issue Date FY: 2022 ( Subtotal = $549,415 )
2022	2022	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	24	5/19/2022	COMPETING CONTINUATION	$549,415
2022	2021	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	23	5/11/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $549,415

Issue Date FY: 2021 ( Subtotal = $357,750 )
2021	2021	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	23	4/1/2021	NON-COMPETING CONTINUATION	$357,750
														Subtotal = $357,750

Issue Date FY: 2020 ( Subtotal = $357,750 )
2020	2020	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	22	9/2/2020	NON-COMPETING CONTINUATION	$0
2020	2020	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	22	4/14/2020	NON-COMPETING CONTINUATION	$357,750
														Subtotal = $357,750

Issue Date FY: 2019 ( Subtotal = $357,750 )
2019	2019	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	21	4/2/2019	NON-COMPETING CONTINUATION	$357,750
														Subtotal = $357,750

Issue Date FY: 2018 ( Subtotal = $357,750 )
2018	2018	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	20	4/25/2018	NON-COMPETING CONTINUATION	$357,750
														Subtotal = $357,750

Issue Date FY: 2017 ( Subtotal = $357,750 )
2017	2017	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	19	3/27/2017	COMPETING CONTINUATION	$357,750
2017	2015	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	18	8/14/2017	NON-COMPETING CONTINUATION	$0
2017	2015	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	18	6/1/2017	NON-COMPETING CONTINUATION	$0
														Subtotal = $357,750

Issue Date FY: 2015 ( Subtotal = $345,825 )
2015	2015	MAYO CLINIC	200 FIRST STREET, S. W.	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	18	8/12/2015	NON-COMPETING CONTINUATION	$345,825
														Subtotal = $345,825

Issue Date FY: 2014 ( Subtotal = $345,825 )
2014	2014	MAYO CLINIC	200 FIRST STREET, S. W.	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	17	8/21/2014	NON-COMPETING CONTINUATION	$345,825
														Subtotal = $345,825

Issue Date FY: 2013 ( Subtotal = $333,722 )
2013	2013	MAYO CLINIC	200 FIRST STREET, S. W.	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	16	8/30/2013	NON-COMPETING CONTINUATION	$333,722
														Subtotal = $333,722

Issue Date FY: 2012 ( Subtotal = $345,825 )
2012	2012	MAYO CLINIC	200 FIRST STREET, S. W.	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	15	8/21/2012	COMPETING CONTINUATION	$345,825
2012	2011	MAYO CLINIC	200 FIRST STREET	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	14	8/20/2012	NON-COMPETING CONTINUATION	$0
														Subtotal = $345,825

Issue Date FY: 2011 ( Subtotal = $314,697 )
2011	2011	MAYO CLINIC	200 FIRST STREET, S. W.	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	14	5/23/2011	NON-COMPETING CONTINUATION	$28,607
2011	2011	MAYO CLINIC	200 FIRST STREET, S. W.	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	14	1/24/2011	NON-COMPETING CONTINUATION	$286,090
														Subtotal = $314,697

Issue Date FY: 2010 ( Subtotal = $317,877 )
2010	2010	MAYO CLINIC ROCHESTER	200 FIRST STREET, S. W.	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	13	2/5/2010	NON-COMPETING CONTINUATION	$317,877
														Subtotal = $317,877

Issue Date FY: 2009 ( Subtotal = $321,088 )
2009	2009	MAYO CLINIC ROCHESTER	200 FIRST STREET, S. W.	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	12	2/9/2009	NON-COMPETING CONTINUATION	$288,979
2009	2009	MAYO CLINIC ROCHESTER	200 FIRST STREET, S. W.	ROCHESTER	MN	55905	OLMSTED	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	12	3/5/2009	NON-COMPETING CONTINUATION	$32,109
														Subtotal = $321,088

Issue Date FY: 2008 ( Subtotal = $321,088 )
2008	2008	MAYO CLINIC ROCHESTER	200 FIRST STREET, S. W.	ROCHESTER	MN	55901	OLMSTED	USA	Digestive Diseases and Nutrition Research	000	11	2/4/2008	COMPETING CONTINUATION	$321,088
														Subtotal = $321,088

Issue Date FY: 2007 ( Subtotal = $274,100 )
2007	2007	MAYO CLINIC ROCHESTER	200 FIRST STREET, S. W.	ROCHESTER	MN	55901	OLMSTED	USA	Digestive Diseases and Nutrition Research	000	10	12/19/2006	NON-COMPETING CONTINUATION	$274,100
														Subtotal = $274,100

Issue Date FY: 2006 ( Subtotal = $282,287 )
2006	2006	MAYO CLINIC ROCHESTER	200 FIRST STREET, S. W.	ROCHESTER	MN	55901	OLMSTED	USA	Digestive Diseases and Nutrition Research	000	9	12/23/2005	NON-COMPETING CONTINUATION	$282,287
														Subtotal = $282,287

Issue Date FY: 2005 ( Subtotal = $289,080 ) (Continued on the next page)
Grand Total All Awards = $8,579,282

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Mechanotransduction in Intestinal Smooth Muscle Cells

Award Number: R01DK052766

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/1997

PERIOD OF PERFORMANCE END DATE: 02/28/2026

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