The bone marrow is the major site of hematopoiesis where all blood cells emerge from the regulated differentiation of hematopoietic stem cells (HSCs). Studies from the applicant?s laboratory have uncovered key functions for innervation of the sympathetic nervous system (SNS) in the egress of HSCs from marrow. SNS nerves are required to entrain the circadian release of HSCs and also the circadian recruitment of mature leukocytes to the periphery. In addition, the bone marrow is also innervated by peptidergic sensory fibers whose functions in hematopoiesis remain unclear. In this application, we propose a 3-year experimental plan that will advance our knowledge on the neuroanatomy and neurophysiology of the bone marrow.
In Specific Aim 1, we will characterize the functions of sensory nerves in the marrow. We will define the functional neural circuits using immunofluorescence imaging and transneuronal viral tract tracing, and evaluate the interplay of signals between sensory and SNS fibers using pharmacological and genetic model systems.
In Specific Aim 2, we will identify the intercellular transduction pathways that relay SNS nerve signals in bone marrow. We will identify the stromal cell types that receive adrenergic signals mediating ROS oscillations which may represent an important link for the propagation of neural signals.
Specific Aim 3 will harness endogenous neural circuits to improve hematopoietic regeneration. We will establish selective bone marrow DREADDs using adenoviral transduction that will lead to organ-specific neural activation to enhance regeneration following genotoxic insults such as ionizing irradiation or chemotherapy. Manipulation of endogenous neural circuits may indeed provide a useful future strategy to accelerate hematopoietic regeneration. !

Public Health Relevance

! The bone marrow, a broadly distributed organ in which blood is generated, is highly innervated by nerves from sympathetic nervous system and sensory nerve fibers. This project seeks to map nerves in the bone marrow and evaluate their functional neural circuitry toward the development of model systems that will locally manipulate neural input for accelerating hematopoietic regeneration.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01DK116312-02
Application #
9567561
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Greenwel, Patricia
Project Start
2017-09-20
Project End
2020-08-31
Budget Start
2018-09-01
Budget End
2019-08-31
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Albert Einstein College of Medicine, Inc
Department
Type
DUNS #
079783367
City
Bronx
State
NY
Country
United States
Zip Code
10461
Xu, Chunliang; Gao, Xin; Wei, Qiaozhi et al. (2018) Stem cell factor is selectively secreted by arterial endothelial cells in bone marrow. Nat Commun 9:2449
Maryanovich, Maria; Zahalka, Ali H; Pierce, Halley et al. (2018) Adrenergic nerve degeneration in bone marrow drives aging of the hematopoietic stem cell niche. Nat Med 24:782-791
Wei, Qiaozhi; Frenette, Paul S (2018) Niches for Hematopoietic Stem Cells and Their Progeny. Immunity 48:632-648
Boulais, Philip E; Mizoguchi, Toshihide; Zimmerman, Samuel et al. (2018) The Majority of CD45- Ter119- CD31- Bone Marrow Cell Fraction Is of Hematopoietic Origin and Contains Erythroid and Lymphoid Progenitors. Immunity 49:627-639.e6