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Mechanism of action for the epithelial-specific ER stress sensor IRE1? in regulating intestinal homeostasis and host defense

Award Number: R01DK048106
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY Our overarching goal is to understand how the epithelial-specific ER stress sensor IRE1b (ERN2) and its ubiquitously expressed paralogue IRE1a (ERN1) contribute to intestinal homeostasis and host defense. A notable adaptation of the ER unique to epithelial cells lining mucosal surfaces, especially in the gut, is expression of the ER stress sensor IRE1b, a close paralogue of the major and most evolutionarily conserved ER stress sensor IRE1a. We recently discovered, however, that IRE1b functions distinctly from IRE1a in enzymatic activity, enabling it to act as a non-competitive inhibitor of IRE1a signaling in the ER stress response. Our new and ongoing studies demonstrate in vivo that IRE1b operates critically in goblet cell differentiation and assembly of the mucus barrier - with both activities dependent on the normal gut microbiota: gut microbes and their products stimulate IRE1b expression, and IRE1b in turn affects the assembly, taxonomy, and functional output of colonizing gut microbes. These data frame our central hypothesis that IRE1b acts as an environmentally induced mediator of innate epithelial host defense by affecting the ER stress response via IRE1a, and then goblet cell development, mucus assembly, and host epithelial-microbe interactions that shape the structure and function of the colon. In Aim 1, we will use recombinant proteins and biochemical and biophysical approaches to test how IRE1a and IRE1b may be activated by gut lumenal factors, explain how IRE1b oligomerizes with IRE1a, and elucidate what structural features and post-translational modifications modify this assembly, IRE1b signaling, and mechanisms for IRE1b activation and suppression of IRE1a function. In Aim 2, we will use wt and IRE1b-/- mice and colonoids prepared from these animals to determine how IRE1b links the gut microbiota with epithelial stress and development responses and identify core microbial pathways and metabolites that regulate IRE1b expression and perhaps function. In Aim 3, we will explain how the lack of IRE1b attenuates recovery from acute infection with C. rodentium. We found that IRE1b-/- mice have impaired assembly of the colonic mucus layer and dysbiosis - mimicking defects in the colonic mucosa seen in humans with ulcerative colitis (UC). As modeled by Citrobacter rodentium, the altered mucus layer in IRE1b-/- mice was associated with impaired recovery following normal clearance of the pathogen. We will (i) test if the dysbiotic gut microbiota, or unresolved epithelial ER stress, or both, drive the sustained inflammation following C. rodentium infection in IRE1b-/- mice; and (ii) determine if microbiota obtained from humans with UC phenocopy these effects and fail to induce IRE1b, goblet cell development, or an effective mucus barrier when reconstituted in germ-free wt IRE1b+/+ mice. ER stress is implicated in the chronic inflammatory and other intestinal diseases. The outcomes of these studies will be informative of the host-microbiota interactions that regulate epithelial development and host defense.


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: 2024 ( Subtotal = $725,462 )
2024	2024	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	31	5/8/2024	NON-COMPETING CONTINUATION	$725,462
														Subtotal = $725,462

Issue Date FY: 2023 ( Subtotal = $755,691 )
2023	2023	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	30	5/18/2023	NON-COMPETING CONTINUATION	$755,691
														Subtotal = $755,691

Issue Date FY: 2022 ( Subtotal = $759,238 )
2022	2022	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	29	3/23/2022	NON-COMPETING CONTINUATION	$759,238
														Subtotal = $759,238

Issue Date FY: 2021 ( Subtotal = $842,575 )
2021	2021	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	28	3/23/2021	COMPETING CONTINUATION	$809,756
2021	2021	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	28	9/2/2021	COMPETING CONTINUATION	$32,819
														Subtotal = $842,575

Issue Date FY: 2010 ( Subtotal = $680,921 )
2010	2010	CHILDREN'S HOSPITAL CORPORATION	300 LONGWOOD AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	17	3/30/2010	NON-COMPETING CONTINUATION	$680,921
														Subtotal = $680,921

Issue Date FY: 2009 ( Subtotal = $667,766 )
2009	2009	CHILDREN'S HOSPITAL CORPORATION	300 LONGWOOD AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	16	3/20/2009	NON-COMPETING CONTINUATION	$667,766
														Subtotal = $667,766

Issue Date FY: 2008 ( Subtotal = $648,323 )
2008	2008	CHILDREN'S HOSPITAL CORPORATION	300 LONGWOOD AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Digestive Diseases and Nutrition Research	000	15	3/28/2008	NON-COMPETING CONTINUATION	$648,323
														Subtotal = $648,323

Issue Date FY: 2007 ( Subtotal = $642,279 )
2007	2007	CHILDREN'S HOSPITAL CORPORATION	300 LONGWOOD AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Digestive Diseases and Nutrition Research	000	14	3/14/2007	NON-COMPETING CONTINUATION	$642,279
														Subtotal = $642,279

Issue Date FY: 2006 ( Subtotal = $651,563 )
2006	2006	CHILDREN'S HOSPITAL CORPORATION	300 LONGWOOD AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Digestive Diseases and Nutrition Research	000	13	4/28/2006	COMPETING CONTINUATION	$642,200
2006	2006	CHILDREN'S HOSPITAL CORPORATION	300 LONGWOOD AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	13	8/18/2006	SUPPLEMENT FOR EXPANSION	$9,363
														Subtotal = $651,563

Issue Date FY: 2005 ( Subtotal = $624,175 )
2005	2005	CHILDREN'S HOSPITAL CORPORATION	300 LONGWOOD AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Digestive Diseases and Nutrition Research	000	12	3/14/2005	NON-COMPETING CONTINUATION	$337,725
2005	2005	CHILDREN'S HOSPITAL CORPORATION	300 LONGWOOD AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Digestive Diseases and Nutrition Research	001	12	4/25/2005	SUPPLEMENT FOR EXPANSION	$286,450
														Subtotal = $624,175

Issue Date FY: 2004 ( Subtotal = $603,896 )
2004	2004	CHILDREN'S HOSPITAL CORPORATION	300 LONGWOOD AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Digestive Diseases and Nutrition Research	000	11	5/25/2004	NON-COMPETING CONTINUATION	$337,725
2004	2004	CHILDREN'S HOSPITAL CORPORATION	300 LONGWOOD AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Digestive Diseases and Nutrition Research	001	11	9/6/2004	SUPPLEMENT FOR EXPANSION	$266,171
														Subtotal = $603,896

Issue Date FY: 2003 ( Subtotal = $337,725 )
2003	2003	CHILDREN'S HOSPITAL CORPORATION	300 LONGWOOD AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Digestive Diseases and Nutrition Research	000	10		NON-COMPETING CONTINUATION	$337,725
														Subtotal = $337,725

Issue Date FY: 2002 ( Subtotal = $337,725 )
2002	2002	CHILDREN'S HOSPITAL CORPORATION	300 LONGWOOD AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Digestive Diseases and Nutrition Research	000	9	5/27/2002	NON-COMPETING CONTINUATION	$337,725
														Subtotal = $337,725

Issue Date FY: 2001 ( Subtotal = $361,788 )
2001	2001	CHILDREN'S HOSPITAL CORPORATION	300 LONGWOOD AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Digestive Diseases and Nutrition Research	000	8	5/4/2001	COMPETING CONTINUATION	$361,788
														Subtotal = $361,788

Issue Date FY: 2000 ( Subtotal = $64,391 )
2000	2000	CHILDREN'S HOSPITAL CORPORATION	300 LONGWOOD AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Digestive Diseases and Nutrition Research	001	7	9/22/2000	SUPPLEMENT FOR EXPANSION	$64,391
														Subtotal = $64,391

Issue Date FY: 1999 ( Subtotal = $217,366 )
1999	1999	CHILDREN'S HOSPITAL CORPORATION	300 LONGWOOD AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Digestive Diseases and Nutrition Research	000	7	6/28/1999	NON-COMPETING CONTINUATION	$217,366
														Subtotal = $217,366

Issue Date FY: 1998 ( Subtotal = $209,007 )
1998	1998	CHILDREN'S HOSPITAL CORPORATION	300 LONGWOOD AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Digestive Diseases and Nutrition Research	000	6	7/31/1998	NON-COMPETING CONTINUATION	$209,007
														Subtotal = $209,007

Grand Total All Awards = $9,129,891

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Mechanism of action for the epithelial-specific ER stress sensor IRE1? in regulating intestinal homeostasis and host defense

Award Number: R01DK048106

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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