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The role of Ldb1 in regulating pancreatic islet cell delamination and differentiation

Award Number: F31DK120217
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 12/01/2019
PERIOD OF PERFORMANCE END DATE: 11/30/2022

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The role of Ldb1 in regulating pancreatic islet cell delamination and differentiation - PROJECT SUMMARY Pancreatic islets are comprised of five hormone-secreting cell types and are vital regulators of glucose homeostasis in mammals. Specifically, glucagon producing α-cells and insulin producing b-cells act synchronously to tightly regulate blood glucose and allow for normal metabolic function in tissues. During diabetes, loss of functional b-cell mass leads to severe complications in suffering patients. With diagnoses of diabetes rising at an alarming rate worldwide, key to future diabetes treatments is a greater understanding of the transcriptional complexes mediating not only early b-cell, but whole islet differentiation and formation. The first step of specification of all islet cells is the delamination of endocrine progenitors (marked by Neurogenin3, Ngn3) out of the ductal epithelium through a process known as epithelial to mesenchymal transition (EMT), mediated by the Snail2 transcription factor. This step occurs as early as embryonic day (E)10.5 in mice and is absolutely required for formation of mature islets. Our lab previously showed that a transcriptional co-regulator, LIM domain binding protein 1 (Ldb1) is required for pancreatic development at various stages. In a pancreas-wide Ldb1 knockout, we observed disrupted progenitor pools at E13.5, and a severe loss of Ngn3+ endocrine progenitors at E15.5. Upon birth, these mice lack islet structures, highlighting the importance of Ldb1 in the development of endocrine cells and formation of islet structures. Additionally, these neonatal mutant mice exhibited an abnormal clustering of immature endocrine cells along the ducts. This observation, plus the loss of Ngn3+ cells, suggests that there is a delamination defect during development. For this training plan, I propose to investigate the role of Ldb1 in pancreatic endocrine progenitor delamination and the mechanisms by which Ldb1 complexes impart their effects. My overarching hypothesis is that Ldb1 is required for development of the endocrine progenitor population. In Aim 1, I will determine the contribution of Ldb1 to endocrine progenitor delamination, by assessing canonical EMT markers throughout development, as well as lineage tracing to determine the fate of endocrine progenitors in the absence of Ldb1. In Aim 2, I will characterize Ldb1-mediated regulatory mechanisms, with a focus on Ldb1 regulation of Ngn3 and Snail2. I will use Chromatin ImmunoPreciptation (ChIP)-Seq to determine targets directly bound by Ldb1, and RNA-Seq to gain insight into the genome-wide effects of Ldb1 loss in endocrine progenitors. A greater understanding of transcriptional control of EMT in the developing pancreas gained from this research will provide a deeper understanding of how islets arise, benefiting future diabetes therapies, including directed stem cell differentiation strategies.


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: 2023 ( Subtotal = -$18,351 )
2023	2022	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	9/27/2023	NON-COMPETING CONTINUATION	-$18,351
														Subtotal = -$18,351

Issue Date FY: 2022 ( Subtotal = $45,472 )
2022	2022	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	4/21/2022	NON-COMPETING CONTINUATION	$717
2022	2022	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	3	5/26/2022	NON-COMPETING CONTINUATION	-$1
2022	2022	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	11/18/2021	NON-COMPETING CONTINUATION	$44,756
														Subtotal = $45,472

Issue Date FY: 2021 ( Subtotal = $44,756 )
2021	2021	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	11/25/2020	NON-COMPETING CONTINUATION	$44,240
2021	2021	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	2/25/2021	NON-COMPETING CONTINUATION	$516
														Subtotal = $44,756

Issue Date FY: 2020 ( Subtotal = $0 )
2020	2019	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	11/19/2019	NEW	$0
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $43,736 )
2019	2019	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	1	9/5/2019	NEW	$0
2019	2019	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	9/5/2019	NEW	$43,736
														Subtotal = $43,736

Grand Total All Awards = $115,613

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The role of Ldb1 in regulating pancreatic islet cell delamination and differentiation

Award Number: F31DK120217

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 12/01/2019

PERIOD OF PERFORMANCE END DATE: 11/30/2022

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