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Exploring the role, regulation, and antimicrobial function of Paneth cell peptides PYY and NPY in maintaining gut microbial commensalism and innate immune defense

Award Number: R01DK113788
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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Exploring the role, regulation, and antimicrobial function of Paneth cell peptides PYY and NPY in maintaining gut microbial commensalism and innate immune defense - PROJECT SUMMARY/ABSTRACT Innate immune factors are critical for the selection and maintenance of regional commensal gut microbiota that provide beneficial functions for the host and deterrence against pathogens and pathobionts. In the previous grant cycle, we discovered that peptide YY (PYY), an anorexigenic or satiety-related gut hormone of intestinal enteroendocrine L-cell origin, is expressed by innate immune intestinal Paneth cells (PC) and functions as an antimicrobial peptide (AMP) in its unmodified PYY1-36 form (henceforth referred to as PC-PYY1-36). PYY's structure differs from other PC-α and β−defensins but is remarkably similar to the amphibian AMP, magainin-2, that has both anti-fungal and anti-bacterial properties. PC-PYY1-36 further differs from other PC-AMPs by selectively targeting and killing the virulent (hyphal), but not commensal (yeast) forms of polymorphic gut fungi like Candida albicans, thereby playing an important role in maintaining fungal (and also bacterial) commensalism of the gut. PC-PYY1-36 also differs from the endocrine PYY3-36 that is derived from DPP-IV conversion of L-cell PYY in structure and function by being vectorally secreted into and retained by intestinal mucus where its activity is optimal and protected from dipeptidyl peptidase IV (DPP-IV) modification that would otherwise convert it to the endocrine PYY3-36 form. We subsequently discovered that PCs also express another anorexigenic peptide highly related to PYY, neuropeptide Y (NPY1-36), that also has AMP properties. However, its regulation, antimicrobial spectrum, and compartmentalization upon secretion in luminal fluid rather than overlying mucus differs from that of PC-PYY. Based on our findings, we hypothesize that PC-PYY and PC-NPY are a novel class of PC- AMPs that play important roles in maintaining gut microbial commensalism and conferring innate immune defense against certain pathogens and pathobionts. Two specific aims are proposed: (1) to define and differentiate the drivers, mediators, and signaling pathways involved in regulation of PC-PYY and PC-NPY gene expression, secretion, and regional compartmentalization under physiological and pathophysiological conditions, and (2) to determine and differentiate the antimicrobial spectra of PC-PYY and -NPY in vitro and in vivo and their impact on gene expression and adaptive responses of targeted bacterial and fungal species. These studies will employ newly established in vivo (PC-PYY and PC-NPY KO and PC-PYY transgenic mice) as well as in vitro and ex vivo approaches. The MPI team combines unique expertise and resources in experimental research, multi'omic technologies, and host-microbe interactions (Chang, UChicago), experimental physiology and pathophysiology (Pierre, UWisc-M), and microbiology, bioinformatics, and genetics (Peters, UTHSC). Thus, the whole is much greater than the sum of the parts. The MPI groups have collaborated productively over the past two years to acquire the preliminary and feasibility data, establish proof of concept, and set in motion new lines of inquiry. The initial findings from these studies are in press with the journal Science.


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 = $617,458 )
2025	2025	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	6	2/20/2025	NON-COMPETING CONTINUATION	$617,458
														Subtotal = $617,458

Issue Date FY: 2024 ( Subtotal = $719,417 )
2024	2024	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	4/23/2024	COMPETING CONTINUATION	$719,417
														Subtotal = $719,417

Issue Date FY: 2022 ( Subtotal = -$56,899 )
2022	2020	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	7/20/2022	NON-COMPETING CONTINUATION	-$56,899
														Subtotal = -$56,899

Issue Date FY: 2020 ( Subtotal = $563,607 )
2020	2020	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	2/24/2020	NON-COMPETING CONTINUATION	$563,607
														Subtotal = $563,607

Issue Date FY: 2019 ( Subtotal = $655,138 )
2019	2019	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	2/22/2019	NON-COMPETING CONTINUATION	$655,138
														Subtotal = $655,138

Issue Date FY: 2018 ( Subtotal = $656,937 )
2018	2018	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	2	5/2/2018	NON-COMPETING CONTINUATION	$56,622
2018	2018	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	4/10/2018	SUPPLEMENT FOR EXPANSION	$90,720
2018	2018	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	3/1/2018	NON-COMPETING CONTINUATION	$509,595
														Subtotal = $656,937

Issue Date FY: 2017 ( Subtotal = $584,869 )
2017	2017	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	3/3/2017	NEW	$584,869
														Subtotal = $584,869

Grand Total All Awards = $3,740,527

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Exploring the role, regulation, and antimicrobial function of Paneth cell peptides PYY and NPY in maintaining gut microbial commensalism and innate immune defense

Award Number: R01DK113788

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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