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Mechanism and Function of Endoplasmic Reticulum Protein Quality Control Machinery In The Maintenance of Hematopoietic Stem Cells

Award Number: R01HL146642
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Mechanism and Function of Endoplasmic Reticulum Protein Quality Control Machinery In The Maintenance of Hematopoietic Stem Cells - ABSTRACT Hematopoietic stem cells (HSCs) maintain tissue homeostasis and replenish blood system upon stresses. HSCs have evolved unique mechanisms to maintain genome and proteome integrity throughout life. While the genome integrity safeguard mechanisms have been extensively studied, little is known about how proteome integrity is maintained in HSCs and how dormant HSCs are protected from protein damage during development and physiological stresses. This proposal will address this knowledge gap. We recently found that the Sel1L ER-associated degradation (ERAD) pathway plays an essential role in the maintenance of HSCs. ERAD is the principal protein quality control mechanism responsible for targeting misfolded proteins in the ER for cytosolic proteasomal degradation. The Sel1L-Hrd1 complex is the most conserved branch of ERAD. Using a conditional knockout mouse model, we found that Sel1L deletion in hematopoietic cells significantly reduced steady-state HSC frequency and led to complete loss of HSC reconstitution capacity in stress conditions including bone marrow transplantation and 5-ﬂuorouracil (5-FU) mediated myeloablation. Interestingly, Sel1L deletion did not induce apoptosis or impair HSC engraftment. In contrast, we observed increased HSC cycling and reduced numbers of quiescent HSCs in Sel1L knockout mice. These data demonstrate the critical function of Sel1L ERAD in HSC maintenance and suggest a novel role for ER protein quality control machinery in regulating stem cell quiescence and self-renewal. ERAD monitors and regulates the maturation of transmembrane proteins. We found markedly decreased surface expression of CXCR4 and MPL, two master regulators of HSC quiescence and niche interaction, in Sel1L-knockout HSCs. Tracking HSC and niche cells at the single cell level in vivo showed aberrant localization of Sel1L-deficient HSCs in the bone marrow niche. We hypothesize that Sel1L ERAD governs HSC quiescence and self-renewal by regulating HSC transmembrane receptor maturation and HSC-niche interaction. We will establish the physiological significance of Sel1L ERAD in the maintenance of HSCs (Aim 1), determine the significance and mechanism of the ERAD- Unfolded Protein Response (UPR) crosstalk in HSCs (Aim 2), and elucidate the mechanism and significance of Sel1L ERAD in HSC-niche interactions (Aim 3). This study will provide significant insight into the post- translational regulation of HSC quiescence, self-renewal, and niche interaction by ER protein quality control mechanisms, and further identify novel determinants of HSC fates.


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 = $500,351 )
2023	2023	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Blood Diseases and Resources Research	000	5	4/18/2023	NON-COMPETING CONTINUATION	$500,351
														Subtotal = $500,351

Issue Date FY: 2022 ( Subtotal = $502,350 )
2022	2022	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Blood Diseases and Resources Research	000	4	3/18/2022	NON-COMPETING CONTINUATION	$452,113
2022	2022	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Blood Diseases and Resources Research	001	4	6/13/2022	NON-COMPETING CONTINUATION	$50,237
														Subtotal = $502,350

Issue Date FY: 2021 ( Subtotal = $504,293 )
2021	2021	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Blood Diseases and Resources Research	000	3	4/7/2021	NON-COMPETING CONTINUATION	$504,293
														Subtotal = $504,293

Issue Date FY: 2020 ( Subtotal = $506,177 )
2020	2020	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Blood Diseases and Resources Research	000	2	3/26/2020	NON-COMPETING CONTINUATION	$506,177
														Subtotal = $506,177

Issue Date FY: 2019 ( Subtotal = $522,632 )
2019	2019	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Blood Diseases and Resources Research	000	1	3/22/2019	NEW	$522,632
														Subtotal = $522,632

Grand Total All Awards = $2,535,803

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Mechanism and Function of Endoplasmic Reticulum Protein Quality Control Machinery In The Maintenance of Hematopoietic Stem Cells

Award Number: R01HL146642

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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