# Proj 3 - Dysregulation of hematopoiesis and peripheral immune function and autophagy in aging and age-related diseases

> **NIH NIH P01** · ALBERT EINSTEIN COLLEGE OF MEDICINE · 2022 · $638,400

## Abstract

Functional changes in both adaptive and innate immunity contribute to immunosenescence during aging. The
immune system has also been implicated in inflammation, autoimmunity and reduced protein aggregate
clearance in the brains of patients with Alzheimer’s disease (AD). Aging immune cells harbor wide-ranging
impairment of autophagy pathways, including macroautophagy (MA) and chaperone-mediated autophagy
(CMA), which trigger functional alterations in key immune cell subsets, such as T cells and monocyte-derived
macrophages. Mechanisms responsible for the aging-associated decrease in autophagic activity and a
comprehensive characterization of their functional consequences has remained elusive, but may hold the key
for the development of innovative new therapies to counteract aging-associated neurodegenerative processes
and pathologies, including AD and AD related dementias.
 In previous periods of this PP, we have identified new and specific functions of autophagy in the immune system
and have characterized aging-associated dysregulation of MA and CMA in immune cells. This acquired
knowledge, established tools and gained expertise allows us to now work towards a better understanding of new
important concepts in the context of Geroscience – specifically, to define how an altered interplay between two
organ systems, the immune system and the central nervous system, facilitates propagation of dysregulated
autophagy-mediated proteostasis networks and leads to age-associated pathologies.
In this project, we will investigate the functional consequences of an aging hematopoietic and peripheral immune
system with impaired proteostasis in AD, as well as characterize the reciprocal effects of AD on immune cell
generation and function. We will determine the consequences of altered proteostasis in T cells in the
development and progress of Alzheimer’s disease (Aim1), characterize the role of age-associated autophagy-
defective innate immune cells originating from commonly occurring acquired clonal hematopoiesis in
neurodegeneration and AD during aging (Aim2) and elucidate how AD-associated proteotoxicity contributes to
the dysregulation of function and proteostasis in the bone marrow and peripheral immune cells (Aim3),
Integration in the PP: This project will utilize novel CMA reporter mice, develop new mouse models with
modulated autophagy in T cells to assess the consequences of improve proteostasis in T cells for AD pathology,
and establish and test novel AD mouse models harboring autophagy-impaired innate immune cells originating
form age-associated clonal hematopoiesis. We will also use the three experimental mouse models of AD. All
mice will be maintained by the Animal Core and shared by all the projects. Importantly, we will utilize chemical
modulators of CMA developed by Therapeutics Core to evaluate their ability to restore immune function and
inhibit or slow progress of neurodegeneration and AD pathology. Image-based analysis of the changes in
periph...

## Key facts

- **NIH application ID:** 10397012
- **Project number:** 5P01AG031782-15
- **Recipient organization:** ALBERT EINSTEIN COLLEGE OF MEDICINE
- **Principal Investigator:** Fernando Macian
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $638,400
- **Award type:** 5
- **Project period:** 2009-02-15 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10397012

## Citation

> US National Institutes of Health, RePORTER application 10397012, Proj 3 - Dysregulation of hematopoiesis and peripheral immune function and autophagy in aging and age-related diseases (5P01AG031782-15). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10397012. Licensed CC0.

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