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Multifidelity and multiscale modeling of the spleen function in sickle cell disease with in vitro, ex vivo and in vivo validations

Award Number: R01HL154150
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Multifidelity and multiscale modeling of the spleen function in sickle cell disease with in vitro, ex vivo and in vivo validations - Project Summary The spleen plays a key role in the human immune system but also clears senescent red blood cells (RBC) from the circulation and those altered by acquired or inherited diseases. In patients with sickle cell disease (SCD), the spleen is one of the first targets of pathogenic processes and a potential protector against major complications. Under hypoxic conditions, mutated sickle hemoglobin (HbS) polymerizes to fibers which increase both the stiffness and adhesion of RBC. Splenic filtration of altered RBC prone to sickling (a process that cannot be directly observed in human subjects) contributes to anemia and likely triggers acute splenic sequestration crises (ASSC). On the other hand, it potentially prevents complications associated with intravascular sickling. Self- amplified blockade of vessels with sickled RBCs is indeed a hallmark of vaso-occlusive crises, acute chest syndrome, and acute hepatic crises, that severely impact the life quality and expectancy of patients with SCD. We propose to formulate and validate a new predictive modeling framework for how the spleen filters altered RBC in SCD by synergistically integrating in silico, in vitro, ex vivo and in vivo data using multifidelity-based neural networks (NN). This will deliver predictive models that can continuously learn when new data become available, a paradigm shift in biomedical modeling. We will develop multiscale/multifidelity computational models (and corresponding NN implementations) that link sub-cellular, cellular, and vessel level phenomena spanning across four orders of magnitude in spatio-temporal scales. This scale coupling will be accomplished using a molecular dynamics/dissipative particle dynamics (MD/DPD) framework. We will validate these predictive computational models by data from in vitro and ex vivo experiments, and RBC quantitative features collected in SCD patients. Specifically, we will use three new spleen-on-a-chip microfluidic devices with oxygen control and the unique human spleen perfusion setup of our foreign partner, with the following aims: Aim 1: Develop and validate a splenic inter-endothelial slit filtration model; Aim 2: Develop new models of RBC macrophage adhesion and of phagocytosis in the spleen; Aim 3: Perform Spleen-on-a-Chip experiments and validation; Aim 4: Validate the predictive framework based on RBC samples from patients. Realization of our four Specific Aims will significantly increase our understanding of the complex pathogenic and protective roles of the spleen in SCD. Feeding our new multifidelity neural networks with morphological and functional measures of RBC circulating in SCD patients will lead to models for residual spleen function in SCD, which should help predict the risk of acute splenic sequestration crises, and guide optimal timing for Stem Cell Transplantation or Gene Therapy. The new paradigm in using deep learning tools to integrate data from different sources will be applicable to modeling many other blood diseases.


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 = $669,068 )
2025	2025	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Blood Diseases and Resources Research	001	5	1/21/2025	COMPETING CONTINUATION	$669,068
2025	2023	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Blood Diseases and Resources Research	002	4	5/22/2025	NON-COMPETING CONTINUATION	$0
2025	2023	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Blood Diseases and Resources Research	000	4	1/20/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $669,068

Issue Date FY: 2023 ( Subtotal = $636,323 )
2023	2023	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Blood Diseases and Resources Research	000	4	8/22/2023	NON-COMPETING CONTINUATION	$636,323
														Subtotal = $636,323

Issue Date FY: 2022 ( Subtotal = $650,173 )
2022	2022	BROWN UNIVERSITY	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Blood Diseases and Resources Research	000	3	8/17/2022	NON-COMPETING CONTINUATION	$650,173
														Subtotal = $650,173

Issue Date FY: 2021 ( Subtotal = $663,001 )
2021	2021	BROWN UNIVERSITY IN PROVIDENCE IN THE STATE OF RHODE ISLAND AND PROVIDENCE PLANTATIONS	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Blood Diseases and Resources Research	000	2	8/13/2021	NON-COMPETING CONTINUATION	$663,001
														Subtotal = $663,001

Issue Date FY: 2020 ( Subtotal = $705,243 )
2020	2020	BROWN UNIVERSITY IN PROVIDENCE IN THE STATE OF RHODE ISLAND AND PROVIDENCE PLANTATIONS	1 PROSPECT ST	PROVIDENCE	RI	02912	PROVIDENCE	USA	Blood Diseases and Resources Research	000	1	8/12/2020	NEW	$705,243
														Subtotal = $705,243

Grand Total All Awards = $3,323,808

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Multifidelity and multiscale modeling of the spleen function in sickle cell disease with in vitro, ex vivo and in vivo validations

Award Number: R01HL154150

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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