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Endothelial cell-based therapy for pulmonary vascular disease using induced pluripotent stem cells

Award Number: K08HL173561
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 04/20/2024
PERIOD OF PERFORMANCE END DATE: 03/31/2029

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Endothelial cell-based therapy for pulmonary vascular disease using induced pluripotent stem cells - PROJECT SUMMARY The following proposal outlines a 5-year career training plan that will prepare Dr. Alexander Holtz to be an independent physician-scientist and leader in the field of induced pluripotent stem cell (iPSC) biology and cellular therapies for pulmonary vascular disorders. Pulmonary vascular diseases, such as pulmonary hypertension (PH), are devastating illnesses associated with high morbidity and mortality with frustratingly limited treatment options. Endothelial cell dysfunction is a core mechanistic driver of these disorders, especially in cases where gene mutations impact endothelial cell biology (FOXF1, BMPR2, etc.). Dr. Holtz’s long-term vision is to develop autologous endothelial replacement therapies where patient-derived iPSCs are generated, undergo gene-correction ex vivo, and then are differentiated to endothelial cells (iEndos) to provide a limitless supply of healthy donor endothelial cells for transplantation without the need for lifelong immunosuppression. Dr. Holtz presents his initial discoveries that patterning of iEndos with BMP9 shifts cells towards a ‘lung-like’ molecular profile, including induction of the lung endothelial cell marker TMEM100, and enables durable engraftment of transplanted iEndos into the mouse lung microvasculature. He also shows that this BMP9- mediated patterning process requires active Notch signaling. Using this novel system, Dr. Holtz will test the hypothesis that BMP9 and Notch signaling cooperatively induce TMEM100 expression to produce functional, engraftable cells for treatment of monogenic pulmonary vascular disorders. Specifically, he will 1) assess the differentiation capacity, longevity, and progenitor function of engrafted iEndos in the lung microvasculature; 2) utilize a ‘competitive lung reconstitution assay’ to delineate the functional role of BMP9- and Notch-mediated induction of TMEM100 to facilitate iEndo engraftment and to test the translational potential of iEndos derived from gene-corrected PH patient-specific hiPSCs (BMPR2, FOXF1); and 3) test the efficacy of endothelial replacement therapies in immunocompetent hosts using a mouse model of FOXF1-mediated pulmonary vascular disease. This work will provide a fundamental advancement towards developing endothelial replacement therapies for a broad range of congenital and acquired pulmonary vascular diseases. Dr. Holtz has 90% protected time from Boston Children’s Hospital Division of Genetics and Genomics to accomplish these aims under the guidance of Dr. Darrell Kotton at the Center for Regenerative Medicine at Boston University/Boston Medical Center. He has assembled a remarkable team of advisors with diverse expertise to assist in his career development and scientific research. Dr. Holtz details a comprehensive training plan that takes advantage of his unique cross-institutional collaboration that includes mentored research, didactic coursework, attendance and presentation at national meetings, preparation of manuscripts, and acquiring additional grant support culminating in an R01. Dr. Holtz has the commitment of both institutions to accomplish these goals and transition to an independent physician-scientist position by the end of the award.


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: 2026 ( Subtotal = $167,940 )
2026	2026	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Lung Diseases Research	000	3	3/24/2026	NON-COMPETING CONTINUATION	$167,940
														Subtotal = $167,940

Issue Date FY: 2025 ( Subtotal = $167,940 )
2025	2025	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Lung Diseases Research	000	2	2/28/2025	NON-COMPETING CONTINUATION	$167,940
														Subtotal = $167,940

Issue Date FY: 2024 ( Subtotal = $167,940 )
2024	2024	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Lung Diseases Research	000	1	4/19/2024	NEW	$167,940
														Subtotal = $167,940

Grand Total All Awards = $503,820

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Endothelial cell-based therapy for pulmonary vascular disease using induced pluripotent stem cells

Award Number: K08HL173561

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 04/20/2024

PERIOD OF PERFORMANCE END DATE: 03/31/2029

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