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Genetic and Functional Studies of Human Ciliary Syndromes

Award Number: R01DK072301
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: 09/14/2019
PERIOD OF PERFORMANCE END DATE: 06/30/2025

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Genetic and Functional Studies of Human Ciliary Syndromes - The ciliopathies are a group of >100 genetic disorders unified by overlapping structural and/or functional defects of the cilium and the basal body. The study of these disorders has highlighted fundamental developmental and homeostatic mechanisms, while offering the opportunity to develop computational and functional tools to discover new causal genes; to expand the phenotypic spectrum of known genes; and to design rational therapeutic paradigms. In the backdrop of striking progress during the past two decades, major challenges and opportunities remain. Specifically, despite a diagnostic rate that for some ciliopathies approaches 90%, the predictive power of the genotype at the primary recessive locus remains insufficient to inform clinical manifestation. This is in part because our understanding of the pathomechanisms of pleiotropy and variable expressivity remain poorly understood. Moreover, almost all ciliopathy discovery work to date has: (a) focused on coding mutations and genomic rearrangements; and (b) assumed that the pathogenicity of alleles is constant in all cellular contexts. In this Renewal, we aspire to improve upon these knowledge gaps. First, we will take advantage of a genome-wide siRNA screen on cells ablated for BBS4 that report on aberrant Wnt signaling. This experiment harvested 81 genes that, when suppressed, exacerbate ciliary cellular phenotypes and therefore represent de facto candidates for harboring either causal or epistatic mutations in patients with ciliary disease. We will test this hypothesis by sequencing our phenotypically diverse patient cohort and testing functionally resultant candidate genes and alleles using state-of-the-art in vivo tools. Critically, the majority of these 81 genes are not components of the ciliary apparatus, offering the opportunity to forge new biological links between ciliary dysfunction and other cellular processes. In parallel, we will pursue studies that will explore a new phenomenon of allele pathogenicity, in which bona fide pathogenic missense variants behave as deleterious to protein function in some splice isoforms but benign in others. Using a combination of in vivo complementation testing and in vitro biochemical studies, we will ask how common these phenomena are and whether subcellular localization or stability might represent informative biochemical drivers of these phenomena. Finally, through a genome-wide screen for miRNAs that regulate ciliogenesis, we discovered let-7b as a regulator of ciliary length. Subsequent transcriptomic analysis identified 42 ciliary genes with differential expression correlated to let-7b dosage, and which harbor predicted let-7b sites in their 3’ UTR. We will use this rich dataset to ask whether such miRNA binding sites in 3’ UTRs of known ciliopathy genes contribute to causality and modification in this group of disorders. Together, our studies will inform the genetic architecture of the ciliopathy disease entity by discovering sites that likely modulate the expressivity of disease; by exploring the context-dependent effect of pathogenic variation; and by interrogating the contribution to disease of a largely unexplored class of variants impacting regulatory mechanisms.


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 = -$228,260 )
2025	2022	ANN & ROBERT H LURIE CHILDRENS HOSPITAL OF CHICAGO	225 E CHICAGO AVE	CHICAGO	IL	60611	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	18	4/10/2025	NON-COMPETING CONTINUATION	$0
2025	2022	ANN & ROBERT H LURIE CHILDRENS HOSPITAL OF CHICAGO	225 E CHICAGO AVE	CHICAGO	IL	60611	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	18	11/13/2024	NON-COMPETING CONTINUATION	-$228,260
														Subtotal = -$228,260

Issue Date FY: 2022 ( Subtotal = $441,234 )
2022	2022	ANN & ROBERT H LURIE CHILDRENS HOSPITAL OF CHICAGO	225 E CHICAGO AVE	CHICAGO	IL	60611	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	18	9/7/2022	NON-COMPETING CONTINUATION	$441,234
														Subtotal = $441,234

Issue Date FY: 2021 ( Subtotal = $441,234 )
2021	2021	ANN & ROBERT H. LURIE CHILDREN'S HOSPITAL OF CHICAGO	225 E CHICAGO AVE	CHICAGO	IL	60611	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	17	7/16/2021	NON-COMPETING CONTINUATION	$0
2021	2021	ANN & ROBERT H. LURIE CHILDREN'S HOSPITAL OF CHICAGO	225 E CHICAGO AVE	CHICAGO	IL	60611	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	17	6/22/2021	NON-COMPETING CONTINUATION	$441,234
2021	2020	ANN & ROBERT H. LURIE CHILDREN'S HOSPITAL OF CHICAGO	225 E CHICAGO AVE	CHICAGO	IL	60611	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	16	4/2/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $441,234

Issue Date FY: 2020 ( Subtotal = $437,709 )
2020	2020	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	16	6/10/2020	NON-COMPETING CONTINUATION	$441,234
2020	2019	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	15	12/23/2019	COMPETING CONTINUATION	$0
2020	2018	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	14	2/12/2020	NON-COMPETING CONTINUATION	-$3,525
														Subtotal = $437,709

Issue Date FY: 2019 ( Subtotal = $441,234 )
2019	2019	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	15	9/13/2019	COMPETING CONTINUATION	$441,234
2019	2018	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	14	3/20/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $441,234

Issue Date FY: 2018 ( Subtotal = $464,364 )
2018	2018	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	14	5/1/2018	NON-COMPETING CONTINUATION	$46,436
2018	2018	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	14	2/14/2018	NON-COMPETING CONTINUATION	$417,928
														Subtotal = $464,364

Issue Date FY: 2017 ( Subtotal = $464,364 )
2017	2017	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	13	4/12/2017	NON-COMPETING CONTINUATION	$417,928
2017	2017	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	13	6/22/2017	NON-COMPETING CONTINUATION	$46,436
														Subtotal = $464,364

Issue Date FY: 2016 ( Subtotal = $464,364 )
2016	2016	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	12	3/8/2016	NON-COMPETING CONTINUATION	$464,364
														Subtotal = $464,364

Issue Date FY: 2015 ( Subtotal = $497,517 )
2015	2015	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	11	3/9/2015	COMPETING CONTINUATION	$497,517
														Subtotal = $497,517

Issue Date FY: 2014 ( Subtotal = $432,149 )
2014	2014	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	10	4/9/2014	NON-COMPETING CONTINUATION	$432,149
														Subtotal = $432,149

Issue Date FY: 2013 ( Subtotal = $417,024 )
2013	2013	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	9	1/24/2013	NON-COMPETING CONTINUATION	$388,933
2013	2013	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	9	5/15/2013	NON-COMPETING CONTINUATION	$28,091
														Subtotal = $417,024

Issue Date FY: 2012 ( Subtotal = $432,149 )
2012	2012	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	8	4/2/2012	NON-COMPETING CONTINUATION	$432,149
														Subtotal = $432,149

Issue Date FY: 2011 ( Subtotal = $508,987 )
2011	2011	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	7	4/12/2011	COMPETING CONTINUATION	$2,649
2011	2011	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	7	6/13/2011	COMPETING CONTINUATION	$66,169
2011	2011	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	7	3/1/2011	COMPETING CONTINUATION	$440,169
														Subtotal = $508,987

Issue Date FY: 2010 ( Subtotal = $81,128 )
2010	2010	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Trans-NIH Recovery Act Research Support	002	6	9/29/2010	SUPPLEMENT FOR EXPANSION	$96,367
2010	2009	JOHNS HOPKINS UNIVERSITY	CHARLES & 34TH STREETS	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	5/6/2010	NON-COMPETING CONTINUATION	-$312,402
2010	2009	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	6	5/10/2010	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$297,163
														Subtotal = $81,128

Issue Date FY: 2009 ( Subtotal = $312,402 )
2009	2009	JOHNS HOPKINS UNIVERSITY	CHARLES & 34TH STREETS	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	8/24/2009	NON-COMPETING CONTINUATION	$312,402
														Subtotal = $312,402

Issue Date FY: 2008 ( Subtotal = $312,402 )
2008	2008	JOHNS HOPKINS UNIVERSITY	CHARLES & 34TH STREETS	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Kidney Diseases, Urology and Hematology Research	000	4	7/3/2008	NON-COMPETING CONTINUATION	$312,402
														Subtotal = $312,402

Issue Date FY: 2007 ( Subtotal = $318,778 )
2007	2007	JOHNS HOPKINS UNIVERSITY	CHARLES & 34TH STREETS	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Kidney Diseases, Urology and Hematology Research	000	3	8/7/2007	NON-COMPETING CONTINUATION	$318,778
														Subtotal = $318,778

Issue Date FY: 2006 ( Subtotal = $380,132 )
2006	2006	JOHNS HOPKINS UNIVERSITY	CHARLES & 34TH STREETS	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Kidney Diseases, Urology and Hematology Research	000	2	8/4/2006	NON-COMPETING CONTINUATION	$327,381
2006	2006	JOHNS HOPKINS UNIVERSITY	CHARLES & 34TH STREETS	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Kidney Diseases, Urology and Hematology Research	002	2	9/26/2006	SUPPLEMENT FOR EXPANSION	$52,751
														Subtotal = $380,132

Grand Total All Awards = $6,953,147

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Genetic and Functional Studies of Human Ciliary Syndromes

Award Number: R01DK072301

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: 09/14/2019

PERIOD OF PERFORMANCE END DATE: 06/30/2025

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