# Molecular Mechanisms Underlying Cell Type-Specific Vulnerability in Huntington’s Disease

> **NIH NIH R35** · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · 2024 · $526,564

## Abstract

Abstract
The most common neurodegenerative diseases, including Alzheimer’s, Parkinson’s, and Huntington’s
diseases, all display distinct clinical presentations. The basis of these distinct clinical presentations is the
enhanced vulnerability of specific neuronal cell types to death or dysfunction in each disease, despite
widespread expression of disease-associated genes. My work uses innovative approaches to address these
long-standing questions of enhanced vulnerability, which have remained open questions in the field for
decades. I was centrally involved in developing a widely used cell type-specific profiling methodology known as
translating ribosome affinity purification (TRAP) that allows cell type-specific RNA profiling. My lab has recently
developed a new genetic in vivo screening platform for the CNS, a powerful new approach for brain studies as
it allows for systematically testing the causal effect (versus correlation) of each gene in the genome for disease
phenotypes, rather than more standard approaches that test a single gene per animal. Additionally, using
single cell sequencing approaches, we have also conducted the largest single cell studies of Huntington’s
disease patient tissue conducted to date. These studies have collectively revealed the scope of transcriptional
dysregulation in Huntington’s disease and Huntington’s disease model tissue, and also have implicated
neuronal innate immune activation as a likely key driver of cell type-specific vulnerability in Huntington’s
disease. My long-term research goal, starting with Huntington’s disease as a model disorder, is to elucidate the
basis of enhanced vulnerability in neurodegenerative disease, not only as a window for discovering valuable
insights into the cell biology of disease-relevant neuronal cell types, but also identifying new therapeutic
targets.

## Key facts

- **NIH application ID:** 10833050
- **Project number:** 5R35NS127327-03
- **Recipient organization:** MASSACHUSETTS INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** Myriam Heiman
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $526,564
- **Award type:** 5
- **Project period:** 2022-05-01 → 2030-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10833050

## Citation

> US National Institutes of Health, RePORTER application 10833050, Molecular Mechanisms Underlying Cell Type-Specific Vulnerability in Huntington’s Disease (5R35NS127327-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10833050. Licensed CC0.

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