Document text
Principal Investigator: Pratibha Singh
Organization: INDIANA UNIVERSITY INDIANAPOLIS
Fiscal Year: 2024
Award: $396,250
Funding agency: National Heart Lung and Blood Institute
ABSTRACT
Hematopoietic stem cell (HSC) transplantation is a therapeutic cure for hematological malignancies, metabolic
disorders, and inherited and acquired bone marrow (BM) failure. However, myeloablative conditioning regimens
routinely used for transplantation cause acute and long-term BM damage, leading to impaired blood and immune
cell production, often causing fatal consequences. Although myeloablative irradiation/chemotherapy-induced
defects in the BM microenvironment/niche have been reported, the underlying mechanism(s) are not well
understood. The other crucial limiting factor for HSC transplantation is an inadequate number/quality of
transplantable HSPC collected from patients or donors. Emerging evidence suggests the pivotal role of neuronal
signals in the BM niche and HSC function. Peripheral neuropathy is a common complication associated with
radiotherapy and chemotherapy. Thus, a deficit of neuronal signals in the BM can impair hematopoietic
reconstitution. We recently reported that neuropeptide Y (NPY), one of the most abundant neurotransmitters,
regulates hematopoietic stem and progenitor cell (HSPC) release into circulation by regulating BM vascular
gateway function. Preliminary data showed that steady-state, NPY knockout (KO) mice have fewer HSPC and
BM niche endothelial cell (EC) and mesenchymal stromal cell (MSC) than wild-type (WT) mice. Interestingly,
total body irradiation (TBI) reduces NPY levels in mouse BM, accompanied by a scarcity of EC and MSC.
Furthermore, we found that BM EC and MSC from NPY KO mice produce higher reactive oxygen species (ROS)
than WT mice. Also, NPY supplementation enhances HSPC ex vivo expansion. Based on these observations,
we hypothesize that NPY is required for BM niche regulation and HSPC homeostasis, and cytotoxic stress-
induced deficit of NPY signals in the BM impairs NPY-regulated BM niche extrinsic and HSPC intrinsic
mechanisms leading to hematopoietic dysfunction. This hypothesis will be tested in three aims herein:
Specific aim 1 will investigate whether myeloablative irradiation-mediated deficit of NPY signals in the BM
causes acute and chronic defects in the BM niche and impairs hematopoietic regeneration. Using mouse HSC
transplantation models, we will evaluate the relationship between NPY signals and irradiation-induced structural
and functional defects in the BM niche and HSPC.
Specific aim 2 will identify the mechanism(s) via which NPY signals promote BM niche restoration and
hematopoietic regeneration. We will use molecular and functional analysis to explore how NPY signals control
oxidative stress and vascular integrity in the BM niche constituents.
Specific aim 3 will investigate whether NPY supplementation during ex vivo HSPC expansion can improve
hematopoietic engraftment after transplantation.
The proposed studies will shed new light on how stress-induced neuropathy contributes to stem cell niche
damage and blood stem cell defects and identify a potential therapeutic target to improve HSC transplantation.
Terms: <Acceleration><Active Oxygen><Acute><Adenosine Deaminase-Binding Proteins><Adrenergic Agents><Adrenergic Drugs><Adrenergics><Angiotensin Converting Enzyme><Angiotensin I-Converting Enzyme><Applications Grants><Approaches to prevention><Autoregulation><Blood><Blood Diseases><Blood Precursor Cell><Blood Reticuloendothelial System><Blood Vessels><Bone Marrow><Bone Marrow Reticuloendothelial System><CD143 Antigens><CD26><CD26 Antigens><CSF3><CSF3 gene><CXC-R4><CXCR-4><CXCR4><CXCR4 gene><Carboxycathepsin><Cell Body><Cell Communication and Signaling><Cell Count><Cell Number><Cell Signaling><Cell surface><Cells><Chemotherapy and Radiation><Chemotherapy and/or radiation><Chronic><Circulation><Collecting Cell><Complication><D2S201E><DNA Damage><DNA Injury><Data><Defect><Dipeptidyl Peptidase A><Dipeptidyl-Peptidase IV><Dose><Dysfunction><Endogenous Factors><Endothelial Cells><Engraftment><FB22><Functional disorder><G-CSF><GCSF><Generations><Grant Proposals><HM89><HSC niche><HSC transplantation><HSY3RR><Hematologic Cancer><Hematologic Diseases><Hematologic Malignancies><Hematologic Neoplasms><Hematological Disease><Hematological Disorder><Hematological Malignancies><Hematological Neoplasms><Hematological Tumor><Hematopoiesis><Hematopoietic><Hematopoietic Cancer><Hematopoietic Cellular Control Mechanisms><Hematopoietic Progenitor Cells><Hematopoietic Stem Cell Transplant><Hematopoietic Stem Cell Transplantation><Hematopoietic stem cells><Hemoglobin H Disease><Hereditary><Homeostasis><Homing><Human><Immune><Immunes><Impairment><Inherited><Intracellular Communication and Signaling><Ionizing Electromagnetic Radiation><Ionizing radiation><KO mice><Kininase A><Kininase II><Knock-out Mice><Knockout Mice><LAP3><LCR1><LESTR><MGC45931><Maintenance><Malignant><Malignant - descriptor><Malignant Hematologic Neoplasm><Mediating><Metabolic Diseases><Metabolic Disorder><Mice><Mice Mammals><Modeling><Modern Man><Molecular><Murine><Mus><NPY3R><NPYR><NPYRL><NPYY3R><Natural regeneration><Nerve Cells><Nerve Impulse Transmission><Nerve Transmission><Nerve Transmitter Substances><Nerve Unit><Neural Cell><Neurocyte><Neuronal Transmission><Neurons><Neuropathy><Neuropeptide Tyrosine><Neuropeptide Y Receptor><Neurotransmitters><Neutropenia><Non-Malignant><Null Mouse><Opportunistic Infections><Outcome><Oxidative Stress><Oxygen Radicals><PNS Diseases><Pathologic><Patients><Peptidyl-Dipeptidase A><Peripheral Nerve Diseases><Peripheral Nervous System Diseases><Peripheral Nervous System Disorders><Peripheral Neuropathy><Physiologic><Physiological><Physiological Homeostasis><Physiopathology><Play><Population><Premature Aging><Premature aging syndrome><Prevention approach><Pro-Oxidants><Production><Progenitor Cell Transplantation><Radiation><Radiation-Ionizing Total><Reactive Oxygen Species><Recovery><Regeneration><Regimen><Regulation><Reporting><Risk><Role><Signal Transduction><Signal Transduction Systems><Signaling><Stem Cell Transplantation><Stem cell transplant><Stress><Supplementation><System><Testing><Therapeutic><Thesaurismosis><Total Body Irradiation><Transplantation><Whole-Body Irradiation><Whole-Body Radiation><Wild Type Mouse><Work><acquired bone marrow failure><adaptive immunity><alpha-Thalassemia><axon signaling><axon-glial signaling><axonal signaling><biological signal transduction><blood cell formation><blood cell progenitor><blood disorder><blood progenitor><blood stem cell><blood stem cell niche><blood-forming stem cell><bone marrow failure syndrome><chemo-/radio-therapy><chemo-radio-therapy><chemo-radiotherapy><chemo/radiation therapy><chemoradiation><chemoradiation therapy><chemoradiation treatment><chemoradiotherapy><chemotherapy><chemotherapy and radiotherapy><conditioning><cytotoxic><exposed human population><gene manipulation><genetic manipulation><genetically manipulate><genetically perturb><genotoxicity><glia signaling><glial signaling><hematopoietic cell transplantation><hematopoietic cellular transplantation><hematopoietic engraftment><hematopoietic progenitor><hematopoietic progenitor cell transplantation><hematopoietic stem cell niche><hematopoietic stem progenitor cell><hematopoietic transplantation><hemopoietic><hemopoietic progenitor><hemopoietic stem cell><human exposure><improved><ionizing output><irradiation><mesenchymal stromal cell><metabolism disorder><migration><nerve signaling><neural signaling><neuronal><neuronal signaling><neuropathic><neuropeptide Y><neuroprotection><neuroprotective><neurotransmission><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><nonmalignant><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><pathophysiology><pharmacologic><preconditioning><progenitor cell expansion><progenitor cell function><progenitor cell homeostasis><progenitor cell niche><progenitor cell survival><progenitor expansion><progenitor function><progenitor niche><progenitor survival><progenitor transplantation><radiation or chemotherapy><radio-chemo-therapy><radio-chemotherapy><radiochemotherapy><reconstitute><reconstitution><regenerate><repair><repaired><response><restoration><secondary leukemia><senescence><senescent><social role><stem and progenitor cell expansion><stem and progenitor cell function><stem and progenitor cell niche><stem and progenitor cell transplantations><stem and progenitor function><stem cell expansion><stem cell function><stem cell homeostasis><stem cell niche><stem cell survival><therapeutic target><transplant><transplant model><treatment associated acute myelogenous leukemia><vascular><wildtype mouse><α-thalassemia>